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Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We explore the mechanism that can explain the production of lepton asymmetry and two types of sterile neutrino dark matter. The first type involves heavy sterile dark matter produced directly by the decay of Q-balls which are formed by first-order phase transition in the early universe; the second consists of keV sterile neutrino dark matter, produced resonantly with the aid of lepton asymmetry from Q-ball decay. Besides, gravitational waves from cosmic strings generated during the phase transition process could be detected at future interferometers. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) modulate all aspects of RNA metabolism, but a comprehensive picture of RBP expression across tissues is lacking. Here, we describe our development of the method we call HARD-AP that robustly retrieves RBPs and tightly associated RNA regulatory complexes from cultured cells and fresh tissues. We successfully use HARD-AP to establish a comprehensive atlas of RBPs across mouse primary organs. We then systematically map RNA-binding sites of these RBPs using machine learning-based modeling. Notably, the modeling reveals that the LIM domain as an RNA-binding domain in many RBPs. We validate the LIM-domain-only protein Csrp1 as a tissue-dependent RNA binding protein. Taken together, HARD-AP is a powerful approach that can be used to identify RBPomes from any type of sample, allowing comprehensive and physiologically relevant networks of RNA-protein interactions. RNA-binding proteins (RBPs) modulate all aspects of RNA metabolism. Here the authors introduce a method named HARD-AP that effectively isolates RBPs and their closely associated RNA regulatory complexes from both cultured cells and fresh tissues. [ABSTRACT FROM AUTHOR]

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal. [ABSTRACT FROM AUTHOR]

We utilize molecular dynamics simulations to investigate the microstructures of ions and polyelectrolytes in aqueous solutions under external electric fields. By focusing on the multi-body interactions between ionic components and H2O molecules, as well as their responses to the external electric fields, we clarify several nontrivial molecular features of the ionic and polyelectrolyte solutions, such as the solvations of cations and anions, clustering of the ions, and dispersions/aggregations of polyelectrolyte chains, as well as the corresponding responses of H2O molecules in these contexts. Our simulations illustrate the variations in structures of ionic solutions caused by reversing the charge sign of the ions, and elucidate the disparity in structures between anionic and cationic polyelectrolyte solutions in the presence of the external electric fields. This work clarifies the mechanism for the alternations in complex multi-body interactions in aqueous solutions caused by the application electric field, which can contribute to the fundamental understanding of the physical and chemical natures of ion-containing and charged polymeric systems. [ABSTRACT FROM AUTHOR]

Background and Objective: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development. Methods: Data were collected from 199 patients in the phase I (NCT02081378; 10−200 mg b.i.d. or 10−400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure–response (efficacy/safety) analyses. Results: PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure–response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens. Conclusions: Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation. [ABSTRACT FROM AUTHOR]

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineral density (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factors including alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advanced glycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated the relationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest that genetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox is not observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, in prospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even after adjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2D-related risk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2D and fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-related risk factors may be crucial in preventing fracture risk in T2D patients. [ABSTRACT FROM AUTHOR]

Camelina sativa oil (CSO) and Semen Ziziphi Spinosae oil (SZSO) are functional oils that have beneficial effects on brain health. This study evaluated the sedative and hypnotic effects of vegetable oils with various n − 6/n − 3 polyunsaturated fatty acids (PUFA) ratios and ɑ-linolenic acid (ALA) contents to mice. The n − 6/n − 3 PUFA ratios of CSO (CSO:SZSO = 1:0, 1.8 g/kg), SZSO (CSO:SZSO = 0:1, 1.8 g/kg), CSO-SZSO-L (CSO:SZSO = 1:1, 1.8 g/kg), and CSO-SZSO-H (CSO:SZSO = 1:1, 3.6 g/kg) were 0.51, 140, 1.69, and 1.69, respectively. The doses of ALA administered to mice with p-chlorophenylalanine-induced insomnia were approximately 0.64, 50 × 10–4, 0.32, and 0.64 g/kg, respectively. The mice were administered CSO, SZSO, and a low-dose combination of CSO and SZSO for seven days with no obvious hypnotic effects. However, the administration of a high-dose combination of CSO and SZSO significantly prolonged sleep duration in mice with induced insomnia and inhibited the serum levels of corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol. Interestingly, there were no significant effects on the structure and function of the hippocampal tissue. The results indicated that the anti-insomnia effects of these vegetable oils were positively correlated with a low n − 6/n − 3 PUFA ratio and the absolute amount of ALA. [ABSTRACT FROM AUTHOR]

Step error is the machining error between adjacent cutter location points in the feeding direction. In order to improve the computational efficiency, a hybrid particle swarm optimization method (HPSO) combining genetic algorithm (GA) and simulated annealing (SA) algorithm is proposed. The mapping relationship between local cutter contact (CC) curve in step error calculation and the particle search range and the fitness calculation model are established. The maximum fitness value is taken as step error. The chaotic initialization population is carried out by the Tent mapping. Two nonlinear control methods based on the Sigmoid function and the numbers of iterations are proposed for inertia weight and learning factors, respectively. Combined with the above optimizations, an improved particle swarm optimization algorithm (IPSO) is proposed algorithm is formed. Based on IPSO, the crossover and mutation strategies of GA are used to increase particle diversity, and then, Metropolis criterion from SA is applied to the particle selection; the improved crossover and mutation particle swarm optimization algorithm (ICMPSO) is formed. IPSO is used for Elite particles with higher fitness values to enhance the convergence speed. The other Ordinary particles employ ICMPSO to improve global search capability. The combination of IPSO and ICMPSO forms a whole hybrid particle swarm optimization (HPSO) method. All the proposed algorithms are implemented, and two typical free-form surfaces are taken as examples to calculate step errors. The calculation results show that the tool path generation time of the proposed method is lower than that of the geometric iterative algorithm and the standard particle swarm optimization algorithm, which verifies the feasibility and effectiveness. [ABSTRACT FROM AUTHOR]

Manganese is widely used in the iron and steel industry, batteries and other fields. The amount of the manganese oxide ores existing in China coeval with iron and their manganese-to-iron ratio is low. A study was conducted on a synchronous reduction roasting-magnetic separation of a ferromanganese ore with high content of iron taken from South Africa using CO as reductant. Under the conditions of 750°C roasting temperature, 40 min roasting time, 30% CO concentration roasting atmosphere and − 0.074 mm accounting for 82.56% grinding fineness, the iron removal rate was close to 70% through magnetic separation, with the grade and manganese recovery of manganese concentrate reaching 49% and 72.50% and the manganese-to-iron ratio increasing from 2.5 to 5.92. The X-ray diffraction analysis indicated that Mn2O3 and Fe2O3 in the raw ore was reduced to MnO and Fe3O4, respectively, without forming the intermediate product Mn3O4 in a weak reducing atmosphere. The SEM-EDS analysis of the roasted product showed that the simultaneous reduction of manganese and iron oxides could be achieved when the roasting temperature reaches 750°C. The crystal forms of MnO and Fe3O4 were more perfect, and the coexisting grains of Ca, Si and Al clustered further with increasing roasting temperature. [ABSTRACT FROM AUTHOR]

This experimental study examined ways to reduce stigma against children with attention-deficit/hyperactivity disorder (ADHD) symptoms. We randomly assigned 220 Chinese pre-service teachers to one of the four experimental groups in which they read a vignette describing a student with ADHD symptoms. The contents of the vignettes differed from one another on two dimensions: (a) the causes of the symptoms (biomedical versus social) and (b) the extent to which the student has exerted effort to improve (high effort versus low effort). Participants who received biomedical explanations of ADHD ascribed less blame to the target compared with those who received social explanations. However, the group difference was only significant in the "low-effort" group, but not in the "high-effort" group. Similarly, the "biomedical" group indicated higher levels of entity beliefs than the "social" group, but the group difference was only significant in the "low-effort" group but not in the "high-effort" group. Finally, participants in the "high-effort" condition reported a stronger intention to interact with the target compared with participants in the "low-effort" condition, whereas onset causal attributions did not affect participants' ratings on behavioural intention. These findings may have implications for reducing ADHD stigma and bear relevance to other kinds of social stigma. [ABSTRACT FROM AUTHOR]

Heterogeneous treatment effect (HTE) estimation plays a crucial role in developing personalized treatment plans across various applications. Conventional approaches assume that the observed data are independent and identically distributed (i.i.d.). In some real applications, however, the assumption does not hold: the environment may evolve, which leads to variations in HTE over time. To enable HTE estimation in evolving environments, we introduce and formulate the online HTE estimation problem. We propose an online ensemble-based HTE estimation method called ETHOS, which is capable of adapting to unknown evolving environments by ensembling the outputs of multiple base estimators that track environmental changes at different scales. Theoretical analysis reveals that ETHOS achieves an optimal expected dynamic regret O (T (1 + P T)) , where T denotes the number of observed examples and P T characterizes the intensity of environment changes. The achieved dynamic regret ensures that our method consistently approaches the optimal online estimators as long as the evolution of the environment is moderate. We conducted extensive experiments on three common benchmark datasets with various environment evolving mechanisms. The results validate the theoretical analysis and the effectiveness of our proposed method. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the "soil" of its occurrence and development, and the inflammatory microenvironment is an important part of the "soil". Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Central South University is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Ulcerative colitis, an inflammatory bowel disease, manifests with symptoms such as abdominal pain, diarrhea, and mucopurulent feces. The long non-coding RNA (lncRNA) ANRIL exhibits significantly reduced expression in UC, yet its specific mechanism is unknown. This study revealed that ANRIL is involved in the progression of UC by inhibiting IL-6 and TNF-α via miR-191-5P/SATB1 axis. We found that in patients with UC, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were significantly overexpressed in inflamed colon sites, whereas ANRIL was significantly under-expressed and associated with disease severity. The downregulation of ANRIL resulted in the increased expression of IL-6 and TNF-α in LPS-treated FHCs. ANRIL directly targeted miR-191-5p, thereby inhibiting its expression and augmenting SATB1 expression. Moreover, overexpression of miR-191-5p abolished ANRIL-mediated inhibition of IL-6 and TNF-α production. Dual luciferase reporter assays revealed the specific binding of miR-191-5p to ANRIL and SATB1. Furthermore, the downregulation of ANRIL promoted DSS-induced colitis in mice. Together, we provide evidence that ANRIL plays a critical role in regulating IL-6 and TNF-α expression in UC by modulating the miR-191-5p/SATB1 axis. Our study provides novel insights into progression and molecular therapeutic strategies in UC. [ABSTRACT FROM AUTHOR]

It remains a challenge to obtain biocompatible afterglow materials with long emission wavelengths, durable lifetimes, and good water solubility. Herein we develop a photooxidation strategy to construct near-infrared afterglow carbon nanodots with an extra-long lifetime of up to 5.9 h, comparable to that of the well-known rare-earth or organic long-persistent luminescent materials. Intriguingly, size-dependent afterglow lifetime evolution from 3.4 to 5.9 h has been observed from the carbon nanodots systems in aqueous solution. With structural/ultrafast dynamics analysis and density functional theory simulations, we reveal that the persistent luminescence in carbon nanodots is activated by a photooxidation-induced dioxetane intermediate, which can slowly release and convert energy into luminous emission via the steric hindrance effect of nanoparticles. With the persistent near-infrared luminescence, tissue penetration depth of 20 mm can be achieved. Thanks to the high signal-to-background ratio, biological safety and cancer-specific targeting ability of carbon nanodots, ultralong-afterglow guided surgery has been successfully performed on mice model to remove tumor tissues accurately, demonstrating potential clinical applications. These results may facilitate the development of long-lasting luminescent materials for precision tumor resection.Biocompatible afterglow materials have potential in imaging applications, but are challenging to prepare. Here the authors report the development of carbon nanodots with near-infrared afterglow, and demonstrate their use in imaging for tumour resection. [ABSTRACT FROM AUTHOR]

Puerarin (Pue) is a naturally bioactive compound with many potential functions in regulating blood glucose and lipid metabolism. However, the low bioavailability and rapid elimination in vivo limit the application of Pue in diabetic treatment. Here, we developed a metal-polyphenol-functionalized microgel to effectively deliver Pue in vivo and eventually alleviate the onset of diabetes. Pue was initially encapsulated in alginate beads through electrospray technology, and further immersed in Fe3+ and tannic acid solution from tannic acid (TA)–iron (Fe) coatings (TF). These constructed Pue@SA-TF microgels exhibited uniform spheres with an average size of 367.89 ± 18.74 µm and high encapsulation efficiency of Pue with 61.16 ± 1.39%. In vivo experiments proved that compared with free Pue and microgels without TF coatings, the biological distribution of Pue@SA-TF microgels specifically accumulated in the small intestine, prolonged the retention time of Pue, and achieved a high effectiveness in vivo. Anti-diabetic experimental results showed that Pue@SA-TF microgels significantly improved the levels of blood glucose, blood lipid, and oxidative stress in diabetic mice. Meanwhile, histopathological observations indicated that Pue@SA-TF microgels could significantly alleviate the damage to the liver, kidney, and pancreas in diabetic mice. Our study provided an effective strategy for oral delivery of Pue and achieved high anti-diabetic efficacy. [ABSTRACT FROM AUTHOR]

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. Methods: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. Results: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78–1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI − 2.56, 3.31) and ICU (MD 0.36; 95% CI − 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68–1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84–1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60–0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09–1.28). Conclusion: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted. [ABSTRACT FROM AUTHOR]

Cytochrome P450s are a large family of protein-encoding genes in plant genomes, many of which have not yet been comprehensively characterized. Here, a novel P450 gene, CYP82D47, was isolated and functionally characterized from cucumber (Cucumis sativus L.). Quantitative real-time reverse-transcription polymerase chain reaction analysis revealed that CYP82D47 expression was triggered by salicylic acid (SA) and ethephon (ETH). Expression analysis revealed a correlation between CYP82D47 transcript levels and plant defense responses against powdery mildew (PM) and Fusarium oxysporum f. sp. cucumerinum (Foc). Although no significant differences were observed in disease resistance between CYP82D47-RNAi and wild-type cucumber, overexpression (OE) of CYP82D47 enhanced PM and Foc resistance in cucumber. Furthermore, the expression levels of SA-related genes (PR1, PR2, PR4, and PR5) increased in CYP82D47-overexpressing plants 7 days post fungal inoculation. The levels of ETH-related genes (EIN3 and EBF2) were similarly upregulated. The observed enhanced resistance was associated with the upregulation of SA/ETH-signaling-dependent defense genes. These findings indicate the crucial role of CYP82D47 in pathogen defense in cucumber. CYP82D47-overexpressing cucumber plants exhibited heightened susceptibility to both diseases. The study results offer important insights that could aid in the development of disease-resistant cucumber cultivars and elucidate the molecular mechanisms associated with the functions of CYP82D47. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence suggests that there is an association between rheumatoid arthritis (RA) and Alzheimer's disease (AD). However, the causal relationship between RA and AD remains unclear. Therefore, this study aimed to investigate the causal relationship between RA and AD. Methods: Using publicly available genome-wide association study datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using the inverse-variance weighted (IVW), weighted median, MR‒Egger regression, simple mode, and weighted mode methods. Results: The results of MR for the causal effect of RA on AD (IVW, odds ratio [OR] = 0.959, 95% confidence interval [CI]: 0.941–0.978, P = 2.752E-05; weighted median, OR = 0.960, 95% CI: 0.937–0.984, P = 0.001) revealed a causal association between genetic susceptibility to RA and an increased risk of AD. The results of MR for the causal effect of AD on RA (IVW, OR = 0.978, 95% CI: 0.906–1.056, P = 0.576; weighted median, OR = 0.966, 95% CI: 0.894–1.043, P = 0.382) indicated that there was no causal association between genetic susceptibility to AD and an increased risk of RA. Conclusions: The results of this two-way two-sample Mendelian randomization analysis revealed a causal association between genetic susceptibility to RA and a reduced risk of AD but did not reveal a causal association between genetic susceptibility to AD and an increased or reduced risk of RA. [ABSTRACT FROM AUTHOR]

The purpose of this research is to explore the interaction between dietary leucine and isoleucine levels on whole-body composition, plasma and liver biochemical indexes, amino acids deposition in the liver, and amino acid metabolism of blunt snout bream (Megalobrama amblycephala). The test fish (average weight: 56.00 ± 0.55 g) were fed one of six diets at random containing two leucine levels (1.70% and 2.50%) and three isoleucine levels (1.00%, 1.20%, and 1.40%) for 8 weeks. The results showed that the final weight and weight gain rate were the highest in the fish fed low-level leucine and high-level isoleucine diets (P > 0.05). Furthermore, the crude lipid content was significantly adjusted by diets with diverse levels of leucine and isoleucine (P < 0.05). In addition, interactive effects of these two branched-chain amino acids (BCAAs) were found on plasma total protein, blood ammonia, and blood urea nitrogen of test fish (P < 0.05). Additionally, the liver amino acid profiles were significantly influenced by the interactive effects of the two BCAAs (P < 0.05). Moreover, interactive effects of dietary leucine and isoleucine were significantly observed in the expressions of amino acid metabolism-related genes (P < 0.05). These findings suggested that dietary leucine and isoleucine had interaction. Meanwhile, the interaction between them was more conducive to the growth and quality improvement of blunt snout bream when the dietary leucine level was 1.70% and isoleucine level was 1.40%. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is a common bleeding disorder in children. First-line medicines (glucocorticoids and immunoglobulin) may not be effective for some children, endangering their lives, posing challenges for healthcare facilities, and leading to an unfavorable prognosis. As a sialidase inhibitor, oseltamivir phosphate can reduce the destruction of platelets in liver macrophages by inhibiting the sialylation of platelets, and finally achieve the purpose of increasing platelet count. In this paper, three cases of children with ITP who failed first-line therapy and were cured by oral administration of oseltamivir phosphate granules were reported. The mechanism of action of oseltamivir phosphate granules was clarified. [ABSTRACT FROM AUTHOR]

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Vitamin K2 (menaquinone, VK2, MK) is an essential lipid-soluble vitamin that plays critical roles in inhibiting cell ferroptosis, improving blood clotting, and preventing osteoporosis. The increased global demand for VK2 has inspired interest in novel production strategies. In this review, various novel metabolic regulation strategies, including static and dynamic metabolic regulation, are summarized and discussed. Furthermore, the advantages and disadvantages of both strategies are analyzed in-depth to highlight the bottlenecks facing microbial VK2 production on an industrial scale. Finally, advanced metabolic engineering biotechnology for future microbial VK2 production will also be discussed. In summary, this review provides in-depth information and offers an outlook on metabolic engineering strategies for VK2 production. [ABSTRACT FROM AUTHOR]

Objective: To assess the outcomes after acupoint application in patients with pharyngeal pain in a real-world settings, and analyze the characteristics of effective population and prescription characteristics of acupoint application. Methods: Based on CHUNBO platform, patients with pharyngeal pain who were candidates for acupoint application on the basis of physician-evaluation, were enrolled in a nationwide, prospective, 69-week multicenter observational study from August 2020 to February 2022. Propensity score matching (PSM) was used to match the confounding factors and the association rules were used to analyze the characteristics of effective population and prescription characteristics of acupoint application. Outcome assessments included the disappearance rate of pharyngeal pain (within 3, 7, and 14 days), disappearance time of pharyngeal pain, as well as adverse events. Results: Of 7,699 enrolled participants, 6,693 (86.9%) received acupoint application and 1,450 (21.7%) with non-acupoint application. After PSM, there were 1,004 patients each in the application group (AG) and non-application group (NAG). The disappearance rate of pharyngeal pain in the AG at 3, 7, and 14 days were all higher than those in the NAG (P<0.05). The disappearance time of pharyngeal pain in the AG were shorter than that in the NAG (logrank P<0.001, hazard ratio=1.51, 95% confidence interval: 1.41–1.63). The median age of effective cases was 4 years, mainly 3–6 years old (40.21%). The disappearance rate of pharyngeal pain in the application group with tonsil diseases was 2.19 times higher than that in the NAG (P<0.05). The commonly used acupoints for the effective cases were Tiantu (RN 22), Shenque (RN 8) and Dazhui (DU 14). The commonly used herbs for the effective cases were Natrii sulfas, Radix et Rhizoma Rhei, and Herba Ephedrae. Among them, Natrii sulfas was applied to RN 8 most frequently (support 84.39%). A total of 1,324 (17.2%) patients experienced AEs, and mainly occurred in the AG, with significant difference in the incidence of AEs between goups (P<0.05). All AEs reported were the first grade, and the average regression days of AEs was 2.8 days. Conclusions: Acupoint application in patients with pharyngeal pain resulted in improved effective rate and shortened duration, especially children aged 3–6 years old, and those with tonsil diseases. Acupoint of RN 22, RN 8 and DU 14, Natrii sulfas, Radix et Rhizoma Rhei, and Herba Ephedrae were the most commonly used herbs in the treatment of pharyngeal pain. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase β1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Let Ω be a bounded smooth domain in ℝN (N ≥ 3). Assuming that 0 < s < 1, 1 < p , q ≤ N + 2 s N − 2 s with (p , q) ≠ (N + 2 s N − 2 s , N + 2 s N − 2 s) , and a, b > 0 are constants, we consider the existence results for positive solutions of a class of fractional elliptic system below, { (a + b [ u ] s 2) (− Δ) s u = v p + h 1 (x , u , v , ∇ u , ∇ v) , x ∈ Ω , (− Δ) s v = u q + h 2 (x , u , v , ∇ u , ∇ v) , x ∈ Ω , u , v > 0 , x ∈ Ω , u = v = 0 , x ∈ ℝ N \ Ω. Under some assumptions of hi(x, u, v, ∇u, ∇v)(i = 1, 2), we get a priori bounds of the positive solutions to the problem (1.1) by the blow-up methods and rescaling argument. Based on these estimates and degree theory, we establish the existence of positive solutions to problem (1.1). [ABSTRACT FROM AUTHOR]

The primary organ for absorbing dietary fat is the gut. High dietary lipid intake negatively affects health and absorption by causing fat deposition in the intestine. This research explores the effect of a high-fat diet (HFD) on intestinal microbiota and its connections with endoplasmic reticulum stress and inflammation. 60 fish (average weight: 45.84 ± 0.07 g) were randomly fed a control diet (6% fat) and a high-fat diet (12 % fat) in four replicates for 12 weeks. From the result, hepatosomatic index (HSI), Visceralsomatic index (VSI), abdominal fat (ADF), Intestosomatic index (ISI), mesenteric fat (MFI), Triglycerides (TG), total cholesterol (TC), non-esterified fatty acid (NEFA) content were substantially greater on HFD compared to the control diet. Moreover, fish provided the HFD significantly obtained lower superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities. In contrast, an opposite result was seen in malondialdehyde (MDA) content in comparison to the control. HFD significantly altered intestinal microbiota in blunt snout bream, characterized by an increased abundance of Aeromonas, Plesiomonas proteobacteria, and firmicutes with a reduced abundance of Cetobacterium and ZOR0006. The transcriptional levels of glucose-regulated protein 78 (grp78), inositol requiring enzyme 1 (ire1), spliced X box-binding protein 1 (xbp1), DnaJ heat shock protein family (Hsp40) member B9 (dnajb9), tumor necrosis factor alpha (tnf-α), nuclear factor-kappa B (nf-κb), monocyte chemoattractant protein-1 (mcp-1), and interleukin-6 (il-6) in the intestine were markedly upregulated in fish fed HFD than the control group. Also, the outcome was similar in bax, caspases-3, and caspases-9, ZO-1, Occludin-1, and Occludin-2 expressions. In conclusion, HFD could alter microbiota and facilitate chronic inflammatory signals via activating endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Two pairs of new dimeric diketopiperazine alkaloids, (±)-dibrevianamides Q1 and Q2 ((±)-1 and (±)-2), together with seven previously reported analogues ((±)-3, 4–6, and (±)-7) were obtained from a marine-derived fungus Aspergillus sp. The structures of (±)-1 and (±)-2 were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. Speculated from the biogenesis, (±)-dibrevianamides Q1 and Q2 ((±)-1 and (±)-2) might be the key precursor of [2 + 2] diketopiperazine dimers ((±)-3). Compounds (+)-1 and (−)-2 displayed anti-H1N1 virus activity with IC50 values of 12.6 and 19.5 μM. Compound (+)-1 showed significant activity against Mycobacterium tuberculosis (MIC, 10.2 μg/mL). Key points: • Two pairs of new dimeric diketopiperazine alkaloids were obtained from the marine-derived fungus Aspergillus sp. • The structures of the new compounds were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. • (±)-Dibrevianamides Q1 and Q2 were speculated to be the key precursor of [2 + 2] diketopiperazine dimers (±)-asperginulin A. [ABSTRACT FROM AUTHOR]

Evidence for the prospective associations among parental failure mindset, helicopter parenting, and children's intelligence mindset is lacking. This three-wave longitudinal study (12 months apart between waves) addressed this research gap by testing whether perceived maternal helicopter parenting mediated the link between perceived maternal failure mindset and intelligence mindset. Participants included 525 Chinese adolescents (47.2% girls, Mage = 15.41 years, SD = 0.22). Random-intercept cross-lagged analysis suggests that mothers with stronger failure-is-debilitating mindsets are more likely to engage in helicopter parenting, which may in turn contribute to stronger endorsements of a fixed mindset of intelligence in their adolescent children. The relation between maternal helicopter parenting and children's intelligence mindset appeared to be reciprocal, i.e., children's fixed mindset may elicit more helicopter parenting over time. [ABSTRACT FROM AUTHOR]

Step error calculation of numerical control (NC) machining tool path is a premise for generating high-quality tool path and promoting its application. At present, iterative methods are generally used to calculate step error, and the computation time increases when accuracy improves. Neural networks can be calculated on GPUs and cloud platforms, which is conducive to reducing computation time and improving accuracy through continuous learning. This article innovatively introduces a BP neural network model to predict step error values. Firstly, the core parameters required for step error calculation are taken as the data samples to construct the neural network model, and map to the same scale through Z-score normalization to eliminate the adverse effects of singular parameters on the calculation results. Then, considering only a small number of parameters determine theoretical values of step error, the Dropout technique can drop hidden layer neurons with a certain probability, which is helpful to avoid overfitting and used in the neural network model design. In the neural network model training, this paper adds the Stochastic Gradient Descent with Momentum (SGDM) optimizer to the back propagation of network training in order to improves the network' stability and accuracy. The proposed neural network predicts step error of samples from three surface models, the results show that the prediction error decreases as sample training increases. After trained by 15% of the surface samples, the neural network predicts the step errors of the remaining samples. Compared with theoretical values, more than 99% of the predicted values have an absolute error less than 1 μm. Moreover, the cost time is only one-third of the geometric method, which verifies the effectiveness and efficiency of our method. [ABSTRACT FROM AUTHOR]

Iso-scallop tool path has uniform scallop height (maximum allowed value) between cutter location (CL) points on the adjacent line, which can maximize interval values of tool path and minimize total lengths of tool path. However, iso-scallop tool path generation process is more complicated than common iso-parameter and iso-planar tool path. In order to avoid exceptions happened in offsetting surface or transforming surface to mesh, this paper generates iso-scallop tool path directly on surface. To improve computational efficiency, based on geometric principle of scallop height and iso-scallop CL points, scallop points are iteratively calculated based on a discrete feature point set including the golden section points. An initial CL location is calculated to be closer to the wanted theoretical iso-scallop point. And an adaptive discretization method is proposed to obtain discrete feature points on surface. The minimum distance from feature points to the CL point is calculated iteratively for the wanted iso-scallop CL point. Both scallop points and iso-scallop CL points are calculated iteratively by a small amount of feature points for efficiency improvement. Two examples of typical freeform surface are used to test the presented method. The results indicate that the scallop height of iso-scallop tool path is uniform, and total lengths are shorter than lengths of iso-planar tool path. [ABSTRACT FROM AUTHOR]

Background: Necroptosis, a newly defined regulatable necrosis with membrane disruption, has been demonstrated to participate in trauma brain injury (TBI) related neuronal cell death. Heat shock protein 70 (HSP70) is a stress protein with neuroprotective activity, but the potential protective mechanisms are not fully understood. Methods and results: Here, we investigated the effects of HSP70 regulators in a cellular TBI model induced by traumatic neuronal injury (TNI) and glutamate treatment. We found that necroptosis occurred in cortical neurons after TNI and glutamate treatment. Neuronal trauma markedly upregulated HSP70 protein expression within 24 h. The results of immunostaining and lactate dehydrogenase release assay showed that necroptosis following neuronal trauma was inhibited by HSP70 activator TRC051384 (TRC), but promoted by the HSP70 inhibitor 2-phenylethyenesulfonamide (PES). In congruent, the expression and phosphorylation of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) were differently regulated by HSP70. Furthermore, the expression of HSP90α induced by neuronal trauma was further promoted by PES but decreased by TRC. The data obtained from western blot showed that the phosphorylation of RIPK3 and MLKL induced by HSP70 inhibition were reduced by RIPK3 inhibitor GSK-872 and HSP90α inhibitor geldanamycin (GA). Similarly, inhibition of HSP90α with GA could partially prevented the increased necroptosis induced by PES. Conclusions: Taken together, HSP70 activation exerted protective effects against neuronal trauma via inhibition of necroptosis. Mechanistically, the HSP90α-mediated activation of RIPK3 and MLKL is involved in these effects. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a cerebrovascular lesion caused by local ischemia and hypoxia. Diabetes mellitus (DM) is a chronic inflammatory disease that disturbs immune homeostasis and predisposes patients to ischemic stroke. The mechanism by which DM exacerbates stroke remains unclear, although it may involve disturbances in immune homeostasis. Regulatory T cells (Tregs) play a regulatory role in many diseases, but the mechanism of Tregs in diabetes complicated by stroke remains unclear. Sodium butyrate is a short-chain fatty acid that increases Treg levels. This study examined the role of sodium butyrate in the prognosis of neurological function in diabetic stroke and the mechanism by which Tregs are amplified in the bilateral cerebral hemispheres. We evaluated the brain infarct volume, observed 48-h neuronal injury and 28-day behavioral changes, and calculated the 28-day survival rate in mice. We also measured Treg levels in peripheral blood and brain tissue, recorded changes in the blood‒brain barrier and water channel proteins and neurotrophic changes in mice, measured cytokine levels and peripheral B-cell distribution in bilateral hemispheres and peripheral blood, and examined the polarization of microglia and the distribution of peripheral T-cell subpopulations in bilateral hemispheres. Diabetes significantly exacerbated the poor prognosis and neurological deficits in mice with stroke, and sodium butyrate significantly improved infarct volume, prognosis, and neurological function and showed different mechanisms in brain tissue and peripheral blood. The potential regulatory mechanism in brain tissue involved modulating Tregs/TGF-β/microglia to suppress neuroinflammation, while that in peripheral blood involved improving the systemic inflammatory response through Tregs/TGF-β/T cells. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the dynamic evolution process of overall brain health in liver transplantation (LT) recipients, we employed a deep learning–based neuroanatomic biomarker to measure longitudinal changes of brain structural patterns before and 1, 3, and 6 months after surgery. Methods: Because of the ability to capture patterns across all voxels from a brain scan, the brain age prediction method was adopted. We constructed a 3D-CNN model through T1-weighted MRI of 3609 healthy individuals from 8 public datasets and further applied it to a local dataset of 60 LT recipients and 134 controls. The predicted age difference (PAD) was calculated to estimate brain changes before and after LT, and the network occlusion sensitivity analysis was used to determine the importance of each network in age prediction. Results: The PAD of patients with cirrhosis increased markedly at baseline (+ 5.74 years) and continued to increase within one month after LT (+ 9.18 years). After that, the brain age began to decrease gradually, but it was still higher than the chronological age. The PAD values of the OHE subgroup were higher than those of the no-OHE, and the discrepancy was more obvious at 1-month post-LT. High-level cognition-related networks were more important in predicting the brain age of patients with cirrhosis at baseline, while the importance of primary sensory networks increased temporarily within 6-month post-LT. Conclusions: The brain structural patterns of LT recipients showed inverted U-shaped dynamic change in the early stage after transplantation, and the change in primary sensory networks may be the main contributor. Key Points: • The recipients' brain structural pattern showed an inverted U-shaped dynamic change after LT. • The patients' brain aging aggravated within 1 month after surgery, and the subset of patients with a history of OHE was particularly affected. • The change of primary sensory networks is the main contributor to the change in brain structural patterns. [ABSTRACT FROM AUTHOR]

The cisterna magna has been defined as the space between the inferior margin of the cerebellar vermis to the level of the foramen magnum, while an enlarged dorsal subarachnoid space at the occipito-cervical junction extending from the foramen magnum to the upper border of the axis (C2) is still ignored. Recently, the myodural bridge complex is proved to drive the cerebral spinal fluid flowing via this region, we therefore introduce the "occipito-atlantal cistern (OAC)" to better describe the subarachnoid space and provide a detailed rationale. The present study utilized several methods, including MRI, gross anatomical dissection, P45 sheet plastination, and three-dimensional visualization. OAC was observed to be an enlarge subarachnoid space, extending from the foramen magnum to the level of the C2. In the median sagittal plane, OAC was a funnel shape and its anteroposterior dimensions were 15.92 ± 4.20 mm at the level of the C0, 4.49 ± 1.25 mm at the level of the posterior arch of the C1, and 2.88 ± 0.77 mm at the level of the arch of the C2, respectively. In the median sagittal plane, the spino-dural angle of the OAC was calculated to be 35.10 ± 6.91°, and the area of OAC was calculated to be 232.28 ± 71.02 mm2. The present study provides OAC is a subarachnoid space independent from the cisterna magna. Because of its distinctive anatomy, as well as theoretical and clinical significance, OAC deserves its own name. [ABSTRACT FROM AUTHOR]

Two new phenolic glycosides, 2-(2-((1E,6Z)-3,8-dihydroxy-3,7-dimethylocta-1,6-dien-1-yl)-4-hydroxy-6-methylphenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1) and 2-(2-((E)-2-(2,6-dimethyl-2,3,4,7-tetrahydrooxepin-2-yl)vinyl)-4-hydroxy-6-methylphenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2) were isolated from Thalictrum scabrifolium. Their structures were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited anti-TMV activities with inhibition rates of 34.1 and 35.9% at a concentration of 20 μM/mL, respectively, compared with 35.3% for the positive control ningnanmycin. [ABSTRACT FROM AUTHOR]

Acute coronary syndrome (ACS) is one of the leading causes of death in cardiovascular disease. Percutaneous coronary intervention (PCI) is an important method for the treatment of coronary heart disease (CHD), and it has greatly reduced the mortality of ACS patients since its application. However, a series of new problems may occur after PCI, such as in-stent restenosis, no-reflow phenomenon, in-stent neoatherosclerosis, late stent thrombosis, myocardial ischemia-reperfusion injury, and malignant ventricular arrhythmias, which result in the occurrence of major adverse cardiac events (MACE) that seriously reduce the postoperative benefit for patients. The inflammatory response is a key mechanism of MACE after PCI. Therefore, examining effective anti-inflammatory therapies after PCI in patients with ACS is a current research focus to reduce the incidence of MACE. The pharmacological mechanism and clinical efficacy of routine Western medicine treatment for the anti-inflammatory treatment of CHD have been verified. Many Chinese medicine (CM) preparations have been widely used in the treatment of CHD. Basic and clinical studies showed that effectiveness of the combination of CM and Western medicine treatments in reducing incidence of MACE after PCI was better than Western medicine treatment alone. The current paper reviewed the potential mechanism of the inflammatory response and occurrence of MACE after PCI in patients with ACS and the research progress of combined Chinese and Western medicine treatments in reducing incidence of MACE. The results provide a theoretical basis for further research and clinical treatment. [ABSTRACT FROM AUTHOR]

The gravity recovery and climate experiment (GRACE) has emerged as a crucial source of land water storage information in hydrological analysis and research. Numerous factors contribute to regional terrestrial water storage (TWS), resulting in a complex mechanism. In the Loess Plateau region, the continuous alteration of natural conditions and profound impact of human activities have posed a serious threat to the natural ecosystem, leading to an escalating trend of TWS reduction. Addressing the specific analysis of how natural conditions and human activities affect TWS represents a pressing issue. This study employed the residual analysis method to discern the contribution rates of natural conditions and human activities, elucidated the spatial and temporal changes associated with each factor, and ascertained their individual influence. The findings indicated that TWS on the Loess Plateau exhibited a downward trend of −4.89 mm·a−1 from 2003 to 2017. The combined effects of climate change and human activities accounted for alterations in water resource reserves across most areas of the Loess Plateau, with human activities predominantly driving these changes. Precipitation emerged as the primary natural factor influencing TWS variations, and NDVI demonstrated a positive feedback effect on TWS at approximately 30%. Substantial spatial disparities in TWS existed within the Loess Plateau, with human activities identified as the primary cause for the decreasing trend. Vegetation restoration plays a positive role in saving water resources in the Loess Plateau to some extent, and vegetation growth exceeding the regional load will lead to water shortage. [ABSTRACT FROM AUTHOR]

Background: Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET. Methods: A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis. Results: In a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination. Conclusion: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband. [ABSTRACT FROM AUTHOR]

Importance: Multiple studies indicate a possible correlation between ADD3 rs2501577 and biliary atresia susceptibility; however, a conclusive determination has yet to be made. Objective: Investigate the role of ADD3 rs2501577 in biliary atresia susceptibility across diverse populations. Data sources: The study protocol has been registered on PROSPERO, an international platform for systematic review registration (PROSPERO ID: CRD42023384641). The following databases will be searched until February 1, 2023: PubMed, Embase, Cochrane, CBM, Web of Science, and CNKI. Study selection: Eight studies were selected from seven papers to assess the data. A total of 7651 participants were included, consisting of 1662 in the BA group and 5989 in the NC group. Data extraction and synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed while conducting the systematic reviews and meta-analyses. Two authors independently assessed the quality of the included studies using the Newcastle–Ottawa Quality Assessment Scale. The significance of the pooled odds ratio (OR) was evaluated with a Z test, and statistical heterogeneity across studies was assessed using the I2 and Q statistics. Publication bias was assessed using Egger's and Begg's tests. Main outcome(s) and measure(s): The primary study outcome was the development of biliary atresia. Subgroup analysis was performed based on race, region, and assessment of Hardy–Weinberg equilibrium (HWE). Results: The studies indicate that the ADD3 rs2501577 susceptibility locus increases the risk of developing biliary atresia, regardless of allelic, homozygote, dominant, and recessive gene inheritance models. Furthermore, ADD3 has been found to be associated with apoptosis, cell cycle, and cell damage repair based on functional analysis. Conclusions and relevance: The ADD3 rs2501577 polymorphic locus is associated with an increased risk of biliary atresia, particularly in Asian populations. This study recommends further investigation of the ADD3 rs2501577 locus in Asian populations to validate its role in the diagnosis of biliary atresia. [ABSTRACT FROM AUTHOR]

This study investigates the tensile deformation behavior of irradiated ZrCu amorphous–nanocrystalline (ANA) alloy with a view to capturing essential mechanisms for mechanical performance. Amorphous models of as-constructed metallic glass (MG), as-constructed ANA and irradiated ANA were synthesized and evaluated by molecular dynamics MD simulations. In the ANA models, effective stress activations energized local regions to stimulate a maze of shear transformation zones (STZs) at the interfaces due to the precipitation of Zr2Cu nanocrystal grains. The distinction in the formation and propagation of shear bands in as-constructed MG and ANA models is evidenced by the unusual distribution of STZs in the latter, as multiple shear bands were compelled to traverse specific orientations in their MG matrices with a beneficial structural effect. Shear band strengths predicated on quasi-steady stress evolution indicated a superior mechanical performance of the ANA models because fewer free volumes were sufficient to restrict the propagation of shear bands. As mature shear bands propagating in misaligned 45° and 135° directions intersected and were arrested at the ANA interface, an exclusive plasticity-enhanced effect was induced in the as-constructed ANA model. Remarkably, the transection of the MG matrix by shear bands at 45° and 135° in the irradiated ANA model surprisingly induced a cross-blocking effect by competitive shear band growth with a rise of free volumes, as multiple shear bands retarded propagation in parallel orientations to evolve a phenomenal plasticity-enhanced performance. Effectively, the correlation between irradiation-induced structural mechanisms, unique shear band performances and mechanical behavior is therefore established as a pathway to developing advanced materials with excellent mechanical performance. [ABSTRACT FROM AUTHOR]

Ménière's disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière's disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1β production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk−/− mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière's disease pathogenesis. The immune response has been suggested to be involved in the pathology of Ménière's disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Ménière's disease pathology. [ABSTRACT FROM AUTHOR]