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Background & aimsPatients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers.MethodsMembers of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey.ResultsSurveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%).ConclusionsThe perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties.Impact and implicationsOver the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Abstract Background The associations of weight change with all-cause and cause-specific mortality stratified by age remains unclear. We evaluated the age-stratified ( 10%, increase by 5% to 10%, and increase by > 10%. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, non-communicable disease, cardiovascular disease (CVD), and cancer mortality according to BMI change, with adjustment for potential confounders. Results During a median follow-up of 2.2 years (2,330,180 person-years), there were 10,197 deaths. A notable interaction emerged between weight change and age. For participants ≥ 65 years, compared with stable BMI, more than a 10% decrease in BMI was associated with higher risk of all-cause mortality (HR: 1.69, 95% CI: 1.54–1.86), non-communicable disease mortality (HR: 1.67, 95% CI: 1.52–1.84), CVD mortality (HR: 1.55, 95% CI: 1.34–1.80), and cancer mortality (HR: 1.59, 95% CI: 1.33–1.92). Similar patterns of results for 5% to 10% decrease in BMI were observed. More than a 10% increase in BMI was associated with increased risk of all-cause mortality (HR: 1.13, 95% CI: 1.04–1.24), non-communicable disease mortality (HR: 1.14, 95% CI: 1.04–1.25), and CVD mortality (HR: 1.27, 95% CI: 1.12–1.44). For participants

Objective Previous research reported that dietary addition with phytosterols improved the energy utilisation of the rumen microbiome, suggesting its potential to alleviate the negative energy balance of perinatal cows. This experiment aimed to explore the effects of feeding phytosterols on the metabolic status of perinatal cows through plasma metabolomics and faecal bacteria metabolism. Methods Ten perinatal Holstein cows (multiparous, 2 parities) with a similar calving date were selected four weeks before calving. After 7 days for adaptation, cows were allocated to two groups (n = 5), which respectively received the basal rations supplementing commercial phytosterols at 0 and 200 mg/d during a 42-day experiment. The milk yield of each cow was recorded daily after calving. On days 1 and 42, blood and faeces samples were all collected from perinatal cows before morning feeding for analysing plasma biochemicals and metabolome, and faecal bacteria metabolism. Results Dietary addition with phytosterols at 200 mg/d had no effects on plasma cholesterol and numerically increased milk yield by 1.82 kg/d (p>0.10) but attenuated their negative energy balance in perinatal cows as observed from the significantly decreased plasma level of β-hydroxybutyric acid (p = 0.002). Dietary addition with phytosterols significantly altered 12 and 15 metabolites (p0.10) but improved potentially beneficial bacteria such as Christensenellaceae family (p

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

In terms of prevalence, 11β-hydroxylase deficiency (11β-OHD), a common form of congenital adrenal hyperplasia, closely follows 21-hydroxylase deficiency. 11β-OHD has been attributed to diminished enzymatic activity owing to CYP11B1 gene variants, mainly encompassing single nucleotide variations and insertions-deletions. The involvement of chimeric CYP11B2/CYP11B1 genes in 11β-OHD has rarely been reported. We conducted a genetic investigation on a male infant with generalized pigmentation and abnormal steroid hormone levels. Whole-exome sequencing revealed a heterozygous variant in CYP11B1 inherited from the mother (NM_000497.4: c.1391_1393dup [p.Leu464dup]). Long-range polymerase chain reaction revealed an additional allele, a chimeric CYP11B2/CYP11B1 gene, inherited from the father. The current case report highlights the need to consider the occurrence of gene fusion variants in the diagnosis of neonatal or early infantile 11β-OHD.

Abstract Background The type II based CRISPR-Cas system remains restrictedly utilized in archaea, a featured domain of life that ranks parallelly with Bacteria and Eukaryotes. Methanococcus maripaludis, known for rapid growth and genetic tractability, serves as an exemplary model for studying archaeal biology and exploring CO2−based biotechnological applications. However, tools for controlled gene regulation remain deficient and CRISPR-Cas tools still need improved in this archaeon, limiting its application as an archaeal model cellular factory. Results This study not only improved the CRISPR-Cas9 system for optimizing multiplex genome editing and CRISPR plasmid construction efficiencies but also pioneered an effective CRISPR interference (CRISPRi) system for controlled gene regulation in M. maripaludis. We developed two novel strategies for balanced expression of multiple sgRNAs, facilitating efficient multiplex genome editing. We also engineered a strain expressing Cas9 genomically, which simplified the CRISPR plasmid construction and facilitated more efficient genome modifications, including markerless and scarless gene knock-in. Importantly, we established a CRISPRi system using catalytic inactive dCas9, achieving up to 100-fold repression on target gene. Here, sgRNAs targeting near and downstream regions of the transcription start site and the 5′end ORF achieved the highest repression efficacy. Furthermore, we developed an inducible CRISPRi-dCas9 system based on TetR/tetO platform. This facilitated the inducible gene repression, especially for essential genes. Conclusions Therefore, these advancements not only expand the toolkit for genetic manipulation but also bridge methodological gaps for controlled gene regulation, especially for essential genes, in M. maripaludis. The robust toolkit developed here paves the way for applying M. maripaludis as a vital model archaeal cell factory, facilitating fundamental biological studies and applied biotechnology development of archaea.

Fish skin acts as the first immune barrier against pathogens from external environments. Recently, fish skin immunity research has gradually become a hot topic in aquaculture disease control. Interestingly, the skin can do air-breathing in some bimodal respiration fish. However, there is no comprehensive understanding of these two functions. In this study, the skin regeneration of loach (Paramisgurnus dabryanus) was investigated through morphological and histological observations. Then, original skins (OS) and the regenerated skins (RS) when their capillaries were the most abundant during healing, were collected for transcriptomic analysis. 285,899,386 clean reads with a total length of 42.34 Gb were obtained. A total of 1282 differentially expressed genes (DEGs) were detected, including 1030 DEGs up-regulated and 252 DEGs down-regulated in the comparison of RS vs. OS. Fc gamma R-mediated phagocytosis (containing gelsolin (Gsn)), chemokine signaling pathway (containing C–C motif chemokine ligand 28 (Ccl28)), and B cell receptor signaling pathway (containing CD80 molecule (Cd81)) were closely related to skin immune response of the loach. PI3K-Akt signaling pathway [containing fibronectin 1 (Fn1) and lysyl oxidase-like 2b (Loxl2b)], TGF-beta signaling pathway [containing thrombospondin 1 (Thbs1)], ECM-receptor interaction [containing integrin alpha 7 (Itga7), Itgb8, Itgb10 and Itgb5], and dilated cardiomyopathy [containing laminin subunit alpha1 (Lama1)] were closely associated with skin air-breathing of the loach. This study is conducive to explore the molecular mechanisms of skin immune response during its regeneration and air-breathing of bimodal respiration fish. This study will benefit for the aquaculture of P. dabryanus and its related species.

Abstract Background Dietary diversity has been suggested as a potential preventive measure against frailty in older adults, but the effect of changes in dietary diversity on frailty is unclear. This study was conducted to examine the association between the dietary diversity score (DDS) and frailty among older Chinese adults. Methods A total of 12,457 adults aged 65 years or older were enrolled from three consecutive and nonoverlapping cohorts from the Chinese Longitudinal Healthy Longevity Survey (the 2002 cohort, the 2005 cohort, and the 2008 cohort). DDS was calculated based on nine predefined food groups, and DDS changes were assessed by comparing scores at baseline and the first follow-up survey. We used 39 self-reported health items to assess frailty. Cox proportional hazard models were performed to examine the association between DDS change patterns and frailty. Results Participants with low-to-low DDS had the highest frailty incidence (111.1/1000 person-years), while high-to-high DDS had the lowest (41.1/1000 person-years). Compared to the high-to-high group of overall DDS pattern, participants in other DDS change patterns had a higher risk of frailty (HRs ranged from 1.25 to 2.15). Similar associations were observed for plant-based and animal-based DDS. Compared to stable DDS changes, participants with an extreme decline in DDS had an increased risk of frailty, with HRs of 1.38 (1.24, 1.53), 1.31 (1.19, 1.44), and 1.29 (1.16, 1.43) for overall, plant-based, and animal-based DDS, respectively. Conclusions Maintaining a lower DDS or having a large reduction in DDS was associated with a higher risk of frailty among Chinese older adults. These findings highlight the importance of improving a diverse diet across old age for preventing frailty in later life.

Abstract Background With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. Objective Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. Results The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend

Progranulin (PGRN), a multifunctional growth factor-like protein expressed by a variety of cell types, serves an important function in the physiologic and pathologic processes of fibrotic diseases, including wound healing and the inflammatory response. PGRN was discovered to inhibit pro-inflammation effect by competing with tumor necrosis factor-alpha (TNF-α) binding to TNF receptors. Notably, excessive tissue repair in the development of inflammation causes tissue fibrosis. Previous investigations have indicated the significance of PGRN in regulating inflammatory responses. Recently, multiple studies have shown that PGRN was linked to fibrogenesis, and was considered to monitor the formation of fibrosis in multiple organs, including liver, cardiovascular, lung and skin. This paper is a comprehensive review summarizing our current knowledge of PGRN, from its discovery to the role in fibrosis. This is followed by an in-depth look at the characteristics of PGRN, consisting of its structure, basic function and intracellular signaling. Finally, we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.

This study aimed to examine the relationship between the classroom environment (CE) and university identification (UI) and the chain mediating effects of student engagement and academic achievement (AA). 4,463 Chinese university students were assessed using the classroom environment and UI scales, and measures of student engagement. Results show: (1) a significant positive correlation between a supportive CE, high student engagement, high AA, and high UI; (2) AA plays a mediating role between CE and UI, while student engagement mediates CE and UI; and (3) student engagement and AA play a chain mediating role between CE and UI. This study verified that a positive CE helps strengthen university students' UI, and student engagement, AA, and a series of intermediary roles had a chain mediating effect. Universities should create a positive CE and encourage building good interpersonal relationships between students and others to further increase AA and UI among students.

Abstract Background Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. Methods This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. Results During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear

Abstract BUB1 mitotic checkpoint serine/threonine kinase B (BUB1b) has been unequivocally identified as an oncogene in various cancers. However, the potential mechanism by which BUB1b orchestrates the progression of lung adenocarcinoma (LUAD) remains unclear. Here we found that both the transcript and protein levels of BUB1b were dramatically upregulated in tumor tissues and contributed to the dismal prognosis of LUAD patients. Moreover, gain- and loss-of-function assays, conducted both in vitro and in vivo, confirmed that BUB1b enhanced the viability of LUAD cells. Mechanistically, BUB1b forms a complex with OTUD3 and NRF2 and stabilizes the downstream NRF2 signaling pathway to facilitate insensitivity to ferroptosis and chemotherapy. In BALB/c nude mice bearing subcutaneous tumors that overexpress BUB1b, a combined strategy of ML385 targeting and chemotherapy achieved synergistic effects, inhibiting tumor growth and obviously improving survival. Taken together our study uncovered the underlying mechanism by which BUB1b promotes the progression of LUAD and proposed a novel strategy to enhance the efficacy of chemotherapy.

Abstract Diabetic foot ulcer (DFU) is a leading cause of high-level amputation in DM patients, with a low wound healing rate and a high incidence of infection. Vascular endothelial growth factor (VEGF) plays an important role in diabetes mellitus (DM) related complications. This study aims to explore the VEGF expression and its predictive value for prognosis in DFU, in order to provide basis for the prevention of DFU related adverse events. We analyzed 502 patients, with 328 in healing group and 174 in non-healing/recurrent group. The general clinical data and laboratory indicators of patients were compared through Spearman correlation analysis, ROC analysis and logistic regression analysis. Finally, the independent risk factors for adverse prognosis in DFU patients were confirmed. Spearman analysis reveals a positive correlation between the DFU healing rate and ABI, VEGF in wound tissue, and positive rate of VEGF expression, and a negative correlation with DM duration, FPG, HbA1c, TC, Scr, BUN, and serum VEGF. Further logistic regression analysis finds that the DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for adverse prognosis in DFU (p

Abstract Nanoplasmas induced by intense laser fields have attracted enormous attention due to their accompanied spectacular physical phenomena which are vigorously expected by the community of science and industry. For instance, the energetic electrons and ions produced in laser-driven nanoplasmas are significant for the development of compact beam sources. Nevertheless, effective confinement on the propagating charged particles, which was realized through magnetic field modulation and target structure design in big facilities, are largely absent in the microscopic regime. Here we introduce a reliable scheme to provide control on the emission direction of protons generated from surface ionization in gold nanoparticles driven by intense femtosecond laser fields. The ionization level of the nanosystem provides us a knob to manipulate the characteristics of the collective proton emission. The most probable emission direction can be precisely steered by tuning the excitation strength of the laser pulses. This work opens new avenue for controlling the ion emission in nanoplasmas and can vigorously promote the fields such as development of on-chip beam sources at micro-/nano-scales.

Abstract Understanding how student peers influence learning outcomes is crucial for effective education management in complex social systems. The complexities of peer selection and evolving peer relationships, however, pose challenges for identifying peer effects using static observational data. Here we use both null-model and regression approaches to examine peer effects using longitudinal data from 5,272 undergraduates, where roommate assignments are plausibly random upon enrollment and roommate relationships persist until graduation. Specifically, we construct a roommate null model by randomly shuffling students among dorm rooms and introduce an assimilation metric to quantify similarities in roommate academic performance. We find significantly larger assimilation in actual data than in the roommate null model, suggesting roommate peer effects, whereby roommates have more similar performance than expected by chance alone. Moreover, assimilation exhibits an overall increasing trend over time, suggesting that peer effects become stronger the longer roommates live together. Our regression analysis further reveals the moderating role of peer heterogeneity. In particular, when roommates perform similarly, the positive relationship between a student’s future performance and their roommates’ average prior performance is more pronounced, and their ordinal rank in the dorm room has an independent effect. Our findings contribute to understanding the role of college roommates in influencing student academic performance.

Abstract Background There is limited understanding regarding prospective associations of insomnia symptoms and trajectories with functional disability. We aimed to investigate the associations of insomnia symptoms and trajectories with functional disability. Method A total of 13 197 participants were eligible from the Health and Retirement Study. Insomnia symptoms included non-restorative sleep, difficulty initiating sleep, early morning awakening, and difficulty maintaining sleep. We also identified four distinct trajectories of insomnia symptoms: low, decreasing, increasing, and high insomnia symptoms. Functional status was assessed through activities of daily living (ADL) and instrumental activities of daily living (IADL). Results Participants experiencing one (HR, 1.21; 95% CI, 1.13–1.29), two (HR, 1.43; 95% CI, 1.29–1.57), or three to four (HR, 1.41; 95% CI, 1.25–1.60) insomnia symptoms had a higher risk of ADL disability than asymptomatic respondents. Similarly, participants with one or more insomnia symptoms had a higher risk of IADL disability. Furthermore, using the trajectory with low insomnia symptoms as the reference, decreasing insomnia symptoms (HR, 1.22; 95% CI, 1.12–1.34), increasing insomnia symptoms (HR, 1.21; 95% CI, 1.05–1.41), and high insomnia symptoms (HR, 1.36; 95% CI, 1.18–1.56) were all associated with an increased risk of ADL disability. Conclusion Both a single measurement and dynamic trajectory of insomnia symptoms are associated with the onset of ADL disability. Increased awareness and management of insomnia symptoms may contribute to the prevention of functional disability occurrence.

30Cr3 is a novel ultra-high strength steel (UHSS) with excellent strength and plastic toughness, which has been mainly used in aerospace shells and stressed parts. Currently, there is still a lack of systematic research and comprehensive evaluation on the laser cleaning of this particular material. In this study, a nanosecond pulsed laser was employed for the cleaning process. First, the energy distribution model was derived, the influence of the spatial and temporal distribution of laser energy on the cleaning quality was discussed, and the cleaning experiment was conducted. The results showed that a laser energy density of 15 J/cm2, combined with the beam overlap rate 52% in the x-direction and 61% in the y-direction, can effectively remove the oxide layer and thoroughly expose the natural metal matrix. Then, under the optimum parameters, the oxygen content decreased from 22.3% to 3.4%, the Fe content increased from 54.5 to 83.4%, the Fe3+ peak disappeared in the X-ray photoelectron spectroscopy (XPS), a remelted layer of only 1 μm was observed. Last, the roughness was slightly reduced from 3.573 μm to 2.985 μm, the hardness was restored to the original hardness level of the substrate (∼260 HV), and the electron back scatter diffraction (EBSD) showed that the structure hardly changed after cleaning, the grain size was comparable to that of the matrix. These findings indicated that laser cleaning can effectively remove the oxide layer of 30Cr3 UHSS without damaging the properties of the base material, which has promising application in the cleaning of UHSS.

Abstract Millirobots must have low cost, efficient locomotion, and the ability to track target trajectories precisely if they are to be widely deployed. With current materials and fabrication methods, achieving all of these features in one millirobot remains difficult. We develop a series of graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced polymer-to-graphene conversion process; this distortion resulted in the spontaneous twisting and peeling off of graphene sheets from the polymer substrate. The lightweight nature of graphene in combine with the laser-induced porous microstructure provides a millirobot scaffold with a low density and high surface hydrophobicity. Magnetically driven nickel-coated graphene-based helical millirobots with rapid locomotion, excellent trajectory tracking, and precise drug delivery ability were fabricated from the scaffold. Importantly, such high-performance millirobots are fabricated at a speed of 77 scaffolds per second, demonstrating their potential in high-throughput and large-scale production. By using drug delivery for gastric cancer treatment as an example, we demonstrate the advantages of the graphene-based helical millirobots in terms of their long-distance locomotion and drug transport in a physiological environment. This study demonstrates the potential of the graphene-based helical millirobots to meet performance, versatility, scalability, and cost-effectiveness requirements simultaneously.

ABSTRACT: Klebsiella pneumoniae can cause severe clinical mastitis in dairy cows, with K. pneumoniae type K57 (K57-KP) being the most common capsular serotype. To identify virulence factors and antimicrobial-resistance (AMR) genes of K57-KP with varying virulence, Galleria mellonella (greater wax moth) larvae were infected as a screening model to characterize virulence of 90 K57-KP strains, with 10 and 11 strains defined as virulent or attenuated, respectively, based on larval survival rates. Next, virulence of these 21 isolates was subsequently confirmed in adhesion and lactate dehydrogenase release assays, using bovine mammary epithelial cells cultured in vitro. Finally, genes associated with virulence and AMR were characterize with whole-genome sequencing. These 21 K57-KP strains were designated into 16 sequence types based on multi-locus sequence typing and allocated in phylogenetic analysis based on single nucleotide polymorphisms. We found great genetic diversity among isolates. In addition, adhesion-associated genes (e.g., fimA, sfaA, and focA) aminoglycoside-resistance genes (aph(6)-Id, strAB) were associated with virulence. This study provided new knowledge regarding virulence of K57-KP associated with bovine mastitis, which may inform development of novel diagnostic tools and prevention strategies for bovine mastitis.

BackgroundPrevious studies have demonstrated that naringenin possesses lipid-lowering effects; however, the underlying mechanisms, particularly its specific molecular targets, remain uncertain.MethodsUsing bioinformatics, three traditional Chinese medicine databases and one human disease database were integrated to establish two naringenin-target-hyperlipidemia modules: naringenin-oxidative stress (OS) and naringenin-lipid metabolism (LM). Data on 1,850 proteins from 1,871 genetic instruments were sourced from seven previous studies. Using Mendelian randomization based on data from the Integrative Epidemiology Unit genome-wide association study (case, n = 5,153; control, n = 344,069), we identified potential drug targets that were subsequently validated in the UK Biobank (396,565 individuals) and FinnGen (412,181 individuals) cohorts. Using molecular docking and molecular dynamics simulation to verify the binding ability of naringenin and causal protein.ResultsIn plasma, every standard deviation increase in apolipoprotein B (APOB) was associated with an increased risk of hyperlipidemia (odds ratio [OR] = 9.37, 95% confidence interval [CI], 5.12–17.12; P = 3.58e-13; posterior probability of hypothesis 4 [PPH4] = 0.997), and the same was observed for proprotein convertase subtilisin/kexin type 9 (OR = 1.81, 95% CI, 1.51–2.16; P = 6.87e-11; PPH4 = 1) and neurocan (OR = 2.34, 95% CI, 1.82–3.01; P = 4.09e-11; PPH4 = 0.932). The intersection of two modules and Mendelian randomization result identified APOB as a key regulatory target of naringenin in the treatment of hyperlipidemia. The binding energy between naringenin and APOB was determined to be −7.7 kcal/mol. Additionally, protein-protein interactions and protein-disease networks were analyzed to uncover potential connections between proteins and hyperlipidemia.ConclusionThis Mendelian randomization-based combined analysis offers a robust framework for elucidating the pharmacological effects of naringenin and identifying candidate proteins for further investigation in the context of hyperlipidemia treatment.

Despite over 60 years of helium development in the Sichuan Basin, the mechanism of helium enrichment remains poorly understood. Helium-rich gas is primarily found as gas composition analysis in the fields. This study explores the relationship between helium distribution and two regional shale formations (the Qiongzhusi and Wufeng-Longmaxi formation), basing on the spatial distribution of these shales, structural profiles, and reported helium concentrations. Our findings indicate a typical trend of helium enrichment within the Sichuan Basin, where helium concentrations generally increase from the basin margins toward its center. The R/Ra ratios in the natural gas are consistently below 0.1, indicating that the helium mainly originates from the granite basement. The Wufeng-Longmaxi Formation is absent from central to western parts of this basin. The hydrocarbon generation intensity of this shale is 3,627.26 m³/m2, which is 25,896.7 times greater than its helium generation intensity (0.14 m³/m2). Its helium capture time is short (237 Ma). There is no obvious correlation between the distribution of helium concentration and Wufeng-Longmaxi shale. The Qiongzhusi shale extends across the entire Sichuan Basin. Its hydrocarbon generation intensity is approximately 57 m³/m2, which is 267.4 times greater than its helium generation intensity (0.27 m³/m2). Beneath this shale, the Pre-Sinian granite exhibits a helium generation intensity exceeding 0.51 m³/m2, acting as the primary helium source rock in the basin. The helium capture time of Qiongzhusi shale is 435 Ma. Helium concentration increases as the burial depth of the Qiongzhusi shale decreases, and helium becomes isotopically lighter in the direction of fluid potential drop. This indicates that helium enrichment in the Sichuan Basin is predominantly influenced by the Qiongzhusi shale. From maximum burial depth to present, helium solubility in water has decreased by approximately 63.6% and 54.3% in the Wufeng-Longmaxi and Qiongzhusi shale respectively, suggesting that uplift processes contributed to helium degassing into gas reservoirs. The regional shale influenced the long-distance migration of helium, although faults can alter this pathway. Faults may either promote helium accumulation in shallow gas fields, such as the Jinqiu gas field, or lead to helium loss, as observed in the southeastern region of the Sichuan Basin.

The decline in both the quantity and quality of interaction has emerged as a notable challenge in online learning. However, the definition of interaction quality remains unclear. This study clarifies it as a decrease in the breadth of interaction, which refers to interaction that can only cover a smaller number of learners. To address this, a synchronous interaction modality, termed Multiple Online Interaction (MOI), based on Zoom's interactive tools, was introduced. In a quasi-experiment involving 58 Chinese L2 learners (with 30 beginner and 28 intermediate students), emotions were assessed using the Brief Mood Introspection Scale (BMIS) while real-time emotional dynamics were revealed through the analysis of 5129 facial expression images during a 35-min synchronous class. MOI participants reported higher levels of Lively and Happy but also experienced more Nervous and less Calm. These emotional dynamics, tracked through expression recognition technology, demonstrate that MOI's impact is primarily observed during the first Grammar & Practice section of the teaching. The empirical findings of this study provide practical insights for educators aiming to conduct effective online teaching in the future.

The cutting thickness of the flame cutting nozzle mainly depends on the characteristics of the cutting oxygen jet, and in the process of designing and manufacturing a flame cutting nozzle with an ultralarge thickness, it is impossible to carry out multiple experiments to optimize the design due to the difficulty in testing, safety, manufacturing cost, environmental pollution, and other problems. In this paper, the Laval-type cutting oxygen orifice channel was first designed by theoretical calculation, the pressure, velocity, Mach number, and density distribution characteristics of the cutting oxygen jet were investigated by numerical simulation, and the reliability and adaptability of the numerical simulation results were verified by experiments. Then, the numerical simulation comparison and estimation method of jet characteristics with the general-purpose G301-7# nozzle was used to study the cutting oxygen orifice channel of the ultralarge thickness flame cutting nozzle. The results show that under the condition of a 19 mm throat diameter and 10 atm inlet pressure, it was estimated that the length of cutting oxygen flow from the design nozzle can reach 1800 mm and the cutting thickness can reach 2500 mm based on the density value; the length of cutting oxygen flow can reach 2000 mm and the cutting thickness can reach 3800 mm based on the velocity value; the length of cutting oxygen flow can reach 1600 mm according to the value of the oxygen quality fraction; and the cutting thickness can reach 2800 mm based on the oxygen mass fraction content. Finally, trial production of the nozzle design, verification of the cutting test, the nozzle with a cutting thickness of 2500 mm at an oxygen pressure of 7 atm, and the cutting quality were all good.

Introduction and Objectives: Fatty liver disease is a multisystem disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a more accurate indicator of chronic kidney disease (CKD) than nonalcoholic fatty liver disease (NAFLD). However, the relationship between recently defined metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD is currently unclear. The objective of this cross-sectional study was to investigate the prevalence of CKD and albuminuria among individuals diagnosed with either MAFLD or MASLD. Patients and Methods: This study involved 5,492 participants who provided biochemical marker and liver ultrasound data from the U.S. National Health and Nutrition Examination Survey (2017–2020). Multiple logistic regression analyses were conducted to assess the independent associations of nonoverlapping MAFLD and MASLD with the presence of CKD or albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol). Results: MAFLD and MASLD were identified in 47% and 44.5% of the participants, respectively. Individuals with MAFLD-only had a greater prevalence of CKD (24.7% vs. 8.3 %, P < 0.006) and albuminuria (18.6% vs. 5%, P < 0.01) than did those with MASLD-only. Importantly, after adjusting for factors such as sex, age, ethnicity, and alcohol use, it was demonstrated that individuals in the MAFLD-only group had a 4.73-fold greater likelihood of having prevalent CKD than those in the MASLD-only group (P < 0.03). Conclusions: The MAFLD criteria better identify patients with CKD than do the MASLD criteria. Therefore, it is suggested that the MASLD criteria be reconsidered, as currently, the justification for changing from MAFLD to MASLD criteria may not be appropriate.

Background: The glycolytic pathway and immune response play pivotal roles in the intervertebral disc degeneration (IDD) progression. This study aimed to develop a glycolysis-related diagnostic model and analyze its relationship with the immune response to IDD. Methods: GSE70362, GSE23130, and GSE15227 datasets were collected and merged from the Gene Expression Omnibus, and differential expression analysis was performed. Glycolysis-related differentially expressed genes (GLRDEGs) were identified, and a machine learning-based diagnostic model was constructed and validated, followed by Gene Set Enrichment Analysis (GSEA). Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, and mRNA-miRNA and mRNA-transcription factor (TF) interaction networks were constructed. Immune infiltration was analyzed using single-sample GSEA (ssGSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm between high- and low-risk groups. Results: In the combined dataset, samples from 31 patients with IDD and 55 normal controls were analyzed, revealing differential expression of 16 GLRDEGs between the two groups. Using advanced machine learning techniques (LASSO, support vector machine, and random forest algorithms), we identified eight common GLRDEGs (PXK, EIF3D, WSB1, ZNF185, IGFBP3, CKAP4, RPL15, and, SSR1) and developed a diagnostic model, which demonstrated high accuracy in distinguishing IDD from control samples (area under the curve, 0.935). We identified 42 mRNA-miRNA and 33 mRNA-TF interaction pairs. Using the RiskScore from the diagnostic model, the combined dataset was stratified into high- and low-risk groups. SsGSEA revealed significant differences in the infiltration abundances of the four immune cell types between the groups. The CIBERSORT algorithm revealed the strongest correlation between resting natural killer (NK) cells and ZNF185 in the low-risk group and between CD8+ T cells and SSR1 in the high-risk group. Conclusions: Our study reveals a potential interplay between glycolysis-associated genes and immune infiltration in IDD pathogenesis. These findings contribute to our understanding of IDD and may guide development of novel diagnostic markers and therapeutic interventions.

Ovarian cancer is currently the second most common malignant tumor among gynecological cancers worldwide, primarily due to challenges in early diagnosis, high recurrence rates, and resistance to existing treatments. Current therapeutic options are inadequate for addressing the needs of ovarian cancer patients. Ferroptosis, a novel form of regulated cell death with demonstrated tumor-suppressive properties, has gained increasing attention in ovarian malignancy research. A growing body of evidence suggests that ferroptosis plays a significant role in the onset, progression, and incidence of ovarian cancer. Additionally, it has been found that immunotherapy, an emerging frontier in tumor treatment, synergizes with ferroptosis in the context of ovarian cancer. Consequently, ferroptosis is likely to become a critical target in the treatment of ovarian cancer.

Abstract Background Urinary tract infection (UTI) is a common cause of sepsis. Elderly patients with urosepsis in intensive care unit (ICU) have more severe conditions and higher mortality rates owing to factors such as advanced age, immunosenescence, and persistent host inflammatory responses. However, comprehensive studies on nomograms to predict the in-hospital mortality risk in elderly patients with urosepsis are lacking. This study aimed to construct a nomogram predictive model to accurately assess the prognosis of elderly patients with urosepsis and provide therapeutic recommendations. Methods Data of elderly patients with urosepsis were extracted from the Medical Information Mart for Intensive Care (MIMIC) IV 2.2 database. Patients were randomly divided into training and validation cohorts. A predictive nomogram model was constructed from the training set using logistic regression analysis, followed by internal validation and sensitivity analysis. Results This study included 1,251 patients. LASSO regression analysis revealed that the Glasgow Coma Scale (GCS) score, red cell distribution width (RDW), white blood count (WBC), and invasive ventilation were independent risk factors identified from a total of 43 variables studied. We then created and verified a nomogram. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) of the nomogram were superior to those of the traditional SAPS-II, APACHE-II, and SOFA scoring systems. The Hosmer-Lemeshow test results and calibration curves suggested good nomogram calibration. The IDI and NRI values showed that our nomogram scoring tool performed better than the other scoring systems. The DCA curves showed good clinical applicability of the nomogram. Conclusions The nomogram constructed in this study is a convenient tool for accurately predicting in-hospital mortality in elderly patients with urosepsis in ICU. Improving the treatment strategies for factors related to the model could improve the in-hospital survival rates of these patients.

Abstract Objective Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms. Methods The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments. Results Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic. Conclusion This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.

Abstract Patients suffering from osteoporotic fractures often require effective fixation and subsequent bone repair. However, the currently available materials are functionally limited and often fail to improve outcomes in this patient population. In this study, we developed orthopedic adhesives doped with romosozumab-loaded mesoporous bioactive glass nanoparticles to aid in osteoporotic fracture fixation and restore dysregulated bone homeostasis. These adhesives were designed to promote osteoblast formation while simultaneously inhibiting osteoclastic bone-resorbing activity, thus working synergistically to promote the healing of osteoporotic fractures. Orthopedic adhesives exhibit injectability, reversible adhesiveness, and malleability, enhancing their adaptability to complex clinical scenarios. Furthermore, the release of romosozumab from mesoporous bioactive glass nanoparticles accelerated osteogenesis and inhibited osteoclastogenesis, delaying the bone resorption process. This dual action contributes to the regulation of bone regeneration and remodeling. Notably, our orthopedic adhesive could restore the disrupted bone homeostasis associated with osteoporotic fractures.

Abstract Diode effects are of great interest for both fundamental physics and modern technologies. Electrical diode effects (nonreciprocal transport) have been observed in Weyl systems. Optical diode effects arising from the Weyl fermions have been theoretically considered but not probed experimentally. Here, we report the observation of a nonlinear optical diode effect (NODE) in the magnetic Weyl semimetal CeAlSi, where the magnetization introduces a pronounced directionality in the nonlinear optical second-harmonic generation (SHG). We demonstrate a six-fold change of the measured SHG intensity between opposite propagation directions over a bandwidth exceeding 250 meV. Supported by density-functional theory, we establish the linearly dispersive bands emerging from Weyl nodes as the origin of this broadband effect. We further demonstrate current-induced magnetization switching and thus electrical control of the NODE. Our results advance ongoing research to identify novel nonlinear optical/transport phenomena in magnetic topological materials and further opens new pathways for the unidirectional manipulation of light.

Finding out the specific location of the fault structure is of great significance for the engineering site selection and stability evaluation. Electrical resistivity tomography and acoustic logging are geophysical methods widely used in detecting fracture structures. Although electrical resistivity tomography is sensitive to low resistance bodies and has a large detection range, it is difficult to accurately delineate the boundary position of geological bodies because of its limited resolution. Acoustic logging can identify strata accurately, but its lateral detection range is limited. This study combined the advantages of the two methods in fault structure detection to improve the precision of geological body delineation. Firstly, the correlation between the resistivity of rock before and after fracture and the change of acoustic wave velocity was proved by physical property experiments. Then the case analysis of the resistivity and acoustic wave velocity characteristics of the fault structure and their combined application in the detection process was conducted. Finally, the depth correction of the inversion result of the electrical resistivity tomography was carried out using the acoustic logging data; and the three-dimensional distribution position of the fault structure in the underground space was obtained. Theresults show that the resistivity and acoustic wave velocity of the rock after fracture are lower than those before fracture. The fracture zone of the fault structure exists in the inversion section of the electrical resistivity tomography with a low resistivity anomaly region. On the wave velocity curve, the wave velocity value in the fracture zone decreases significantly. The combined detection mode of the two methods could provide a guidance for the delineation of the specific location of the fracture structure. The drilling results also verified that the inversion results of the electrical resistivity tomography corrected by acoustic logging data are more consistent with the actual geological conditions than those without correction.

Abstract The SnRK (sucrose non-fermentation-related protein kinase) plays an important role in regulating various signals in plants. However, as an important bamboo shoot and wood species, the response mechanism of PheSnRK in Phyllostachys edulis to hormones, low energy and stress remains unclear. In this paper, we focused on the structure, expression, and response of SnRK to hormones and sugars. In this study, we identified 75 PheSnRK genes from the Moso bamboo genome, which can be divided into three groups according to the evolutionary relationship. Cis-element analysis has shown that the PheSnRK gene can respond to various hormones, light, and stress. The PheSnRK2.9 proteins were localized in the nucleus and cytoplasm. Transgenic experiments showed that overexpression of PheSnRK2.9 inhibited root development, the plants were salt-tolerant and exhibited slowed starch consumption in Arabidopsis in the dark. The results of yeast one-hybrid and dual luciferase assay showed that PheIAAs and PheNACs can regulate PheSnRK2.9 gene expression by binding to the promoter of PheSnRK2.9. This study provided a comprehensive understanding of PheSnRK genes of Moso bamboo, which provides valuable information for further research on energy regulation mechanism and stress response during the growth and development of Moso bamboo.

Abstract Background Knowledge regarding the health impacts of daily eating frequency (DEF) and nighttime fasting duration (NFD) on mortality is very limited. Objective This study aimed to examine whether DEF and NFD are associated with CVD and all-cause mortality. Methods This was a prospective cohort study of a nationally representative sample from the United States, including 30,464 adults who participated in the National Health and Nutrition Examination Survey 2003–2014. Using 24-h dietary recall, DEF was assessed by the number of eating episodes, and NFD was calculated by the first and last eating time across a day. Death information was obtained from the National Death Index up to 2019. Weighted Cox proportional hazards regression models were used to assess survival relationships of DEF and NFD with mortality. Results During 307,686 person-years of follow-up, 4560 deaths occurred, including 1824 CVD cases. After adjustment for confounders, compared to DEF at 4–6 times, participants whose DEF was less than 3 times had greater CVD [hazard-ratio (HR) = 1.33, 95% confidence-interval (CI): 1.06–1.67] and all-cause (HR = 1.16, 95% CI: 1.01–1.33) mortality risks. Furthermore, compared to NFD of 10 to 11 h, participants whose NFD was shorter than 10 h had HRs of 1.30 (95% CI: 1.08–1.55) for CVD mortality and 1.23 (95% CI: 1.08–1.39) for all-cause mortality. NFD longer than 14 h was also related to CVD mortality (HR = 1.37, 95% CI: 1.12–1.67) and all-cause mortality (HR = 1.36, 95% CI: 1.19–1.54). Similar results for the association of NFD and DEF with heart-specific and stroke-specific mortality were observed. Conclusion This study found that DEF less than 3 times and NFD shorter than 10 h or longer than 14 h were independently associated with greater cardiovascular and all-cause mortality.

Objective: Characterized by its disabling nature, obsessive compulsive disorder (OCD) affects individuals profoundly, with nearly 40% of patients showing resistance to initial treatment methods. Despite being safe and easily accessible, transcranial direct current stimulation (tDCS) lacks extensive substantiation supporting its efficacy in treating OCD. The objective of this study was to evaluate how cathodal high-definition transcranial direct current stimulation (HD-tDCS) applied to the right orbitofrontal cortex affected patients with OCD in terms of efficacy. Method: 47 patients with OCD were enrolled. They were randomly allocated to active or sham stimulation groups, and underwent HD-tDCS stimulation treatment for 2 weeks. The central electrode located in the right orbitofrontal cortex region was cathodic. The severity of the patients' obsessive-compulsive symptoms, depression and anxiety were assessed before and after treatment. Result: Out of the total, 44 patients concluded the treatment, comprising 23 participants from the active stimulation group and 21 from the sham stimulation group. Notably, substantial reductions in symptoms related to OCD, depression, and anxiety were exhibited in both groups. With a response rate of 26.1% in the active stimulation group and 23.8% in the sham stimulation group, there was no significant difference in efficacy observed. Furthermore, the reduction in depression and anxiety symptoms at the conclusion of the treatment was not notably superior in the active stimulation group. Conclusion: This study provided evidence for the acceptability and safety of HD-tDCS. Nevertheless, the study did not reveal notable clinical effectiveness of tDCS in addressing moderate to severe OCD in comparison to the sham stimulation group.

IntroductionHepatitis E (HE), caused by the Hepatitis E virus (HEV), is a significant cause of acute viral hepatitis globally and a major public health concern, particularly in specific high-prevalence areas in China, which have diverse transmission routes and regional differences. Identifying the primary risk factors for HE transmission is essential to develop targeted interventions for vulnerable populations.MethodsThis study employed a 1:1 matched case–control methodology, using a standardized questionnaire complemented by medical records for data validation.ResultsAmong the 442 HE cases and 428 healthy controls, the case group had a higher prevalence of fatigue (46.21%) and loss of appetite (43.84%) compared to the control group. Furthermore, liver function indicators were significantly higher in the case group, with an average alanine aminotransferase (ALT) level of 621.94 U/L and aspartate aminotransferase (AST) level of 411.53 U/L. Severe HE patients were predominantly male, with significantly increased ALT and AST levels reaching 1443.81 U/L and 862.31 U/L respectively, along with a higher incidence of fatigue (90%) and loss of appetite (75%). Multifactorial analysis indicated that frequent dining out (OR = 2.553, 95%CI:1.686–3.868), poor hygiene conditions (OR = 3.889, 95%CI:1.399–10.807), and comorbid chronic illnesses (OR = 2.275, 95%CI:1.616–3.202) were risk factors for HE infection; conversely, good hygiene practices were protective factors against HE infection (OR = 0.698, 95%CI:0.521–0.934).ConclusionIn conclusion, HE infection in Zhejiang Province is closely associated with dietary habits and environmental hygiene, and individuals with chronic diseases or co-infections are at increased risk. This highlights the need for targeted health education to reduce the incidence of HE among these populations.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

N-acetyltransferase 10 (NAT10) is acknowledged as a tumor promoter in various cancers due to its role as a regulator of acetylation modification. Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME). However, the intercellular communication between esophageal squamous cell carcinoma (ESCC) cells and TAMs involving NAT10 remains poorly understood. This study aimed to elucidate the regulatory mechanism of NAT10 in modulating macrophage lipid metabolism and polarization. Experimental evidence was derived from in vitro and in vivo analyses. We explored the association between upregulated NAT10 in ESCC tissues, macrophage polarization, and the therapeutic efficacy of PD-1. Furthermore, we investigated the impact of methyltransferase 3 (METTL3)-induced m6A modification on the increased expression of NAT10 in ESCC cells. Additionally, we examined the role of exosomal NAT10 in stabilizing the expression of fatty acid synthase (FASN) and promoting macrophage M2 polarization through mediating the ac4C modification of FASN. Results indicated that NAT10, packaged by exosomes derived from ESCC cells, promotes macrophage M2 polarization by facilitating lipid metabolism. In vivo animal studies demonstrated that targeting NAT10 could enhance the therapeutic effect of PD-1 on ESCC by mediating macrophage reprogramming. Our findings offer novel insights into improving ESCC treatment through NAT10 targeting.

Abstract Earthquakes that rupture several faults occur frequently within the shallow lithosphere but are rarely observed for intermediate‐depth events (70–300 km). On 29 November 2007, the Mw7.4 Martinique earthquake struck the Lesser Antilles Island Arc near the deep end of the Wadati‐Benioff‐Zone. The sparse regional seismic network of 2007 previously hampered a detailed examination of this unusually complex event. Here, we combine seismic data from different studies with regional moment tensor inversion results and 3D full‐waveform modeling. We show that the earthquake is a doublet consisting of dip‐slip and strike‐slip motion along two oblique structures, both activated under extensional stress along the strike of the slab. Comparison with tectonic reconstructions suggests that the earthquake ruptured along a re‐activated ridge‐transform segment of the subducted Proto‐Caribbean spreading ridge. The unprecedented resolution of the source process highlights the influence of pre‐existing structures on localizing slab deformation also at intermediate‐depth.

Multiagent Reinforcement Learning (MARL) has been well adopted due to its exceptional ability to solve multiagent decision-making problems. To further enhance learning efficiency, knowledge transfer algorithms have been developed, among which experience-sharing-based and action-advising-based transfer strategies share the mainstream. However, it is notable that, although there exist many successful applications of both strategies, they are not flawless. For the long-developed action-advising-based methods (namely KT-AA, short for knowledge transfer based on action advising), their data efficiency and scalability are not satisfactory. As for the newly proposed experience-sharing-based knowledge transfer methods (KT-ES), although the shortcomings of KT-AA have been partially overcome, they are incompetent to correct specific bad decisions in the later learning stage. To leverage the superiority of both KT-AA and KT-ES, this study proposes KT-Hybrid, a hybrid knowledge transfer approach. In the early learning phase, KT-ES methods are employed, expecting better data efficiency from KT-ES to enhance the policy to a basic level as soon as possible. Later, we focus on correcting specific errors made by the basic policy, trying to use KT-AA methods to further improve the performance. Simulations demonstrate that the proposed KT-Hybrid outperforms well-received action-advising- and experience-sharing-based methods.

Suppressing random noise and improving the signal-to-noise ratio of seismic data holds immense significance for subsequent high-precision processing. As one of the most widely used denoising methods, self-learning-based algorithms typically partition the large zone into several smaller zones for individual training and processing, thereby achieving lower training costs. However, as the volume of seismic data that needs to be processed continues to increase, the cost advantage of this method becomes less apparent. This is because a larger data volume necessitates more independent training, ultimately increasing the overall training cost. Therefore, we propose a denoising method based on self-supervised learning to overcome the aforementioned problem. This method can directly acquire higher-quality training data from large zones by leveraging similarity differences, decreasing the need to divide the large zone into smaller parts for individual processing. As a result, it can effectively reduce the times for individual processing, leading to a decrease in the overall training cost. Compared to traditional denoising methods and self-supervised learning methods, the experimental results on both synthetic and field data demonstrate that the proposed denoising method exhibits superior performance in random noise attenuation and reduction in training costs.

Abstract Background Aslanger’s pattern in electrocardiogram (ECG) indicates that patients may have acute inferior myocardial infarction(AMI) with concomitant critical stenoses on other coronary arteries, which needs to be evaluated the timing of revascularization as risk equivalents of ST elevation myocardial infarction(STEMI). Case Presentation The patient was a 62-year-old male with chief complaint of intermittent exertional subxiphoid pain for 20 days from 30th June. One day after the last episode (19th July), the 18-lead electrocardiogram showed ST segment elevation of 0.05-0.1mV in lead III, ST segment depression in leads I, avL, and V2-V6, T wave inversion with positive terminal vector in lead V4-V5, and positive T wave in lead V6, which indicated Aslanger’s pattern. With increased Troponin I (0.162ng/mL, 0-0.02), The patient was diagnosed as acute non-ST-segment elevation myocardial infarction (NSTEMI) and admitted to coronary ward on 20th July. The coronary angiography showed 95% stenosis in the distal left main coronary artery (LM) to the ostium of the left anterior descending artery (LAD), 90% stenosis in the proximal segment of the LAD, and 80% stenosis in the middle segment of the LAD, and TIMI blood flow was graded score 2. Three drug-eluting stents were implanted at the lesions. The patient’s ECG returned close to normal one month after revascularization. Conclusion We presented an acute coronary syndrome case whose ECG showed with Aslanger’s pattern (i.e., isolated ST-segment elevation in lead III, associated ST-segment depression in lead V4-V6 with positive T wave/terminal vector, and greater ST-segment elevation in lead V1 than in lead V2), and was confirmed severe stenosis of the LM and the proximal segment of the LAD via coronary angiography. In clinical practice, especially in the emergency, patients with ECG presenting Aslanger’s pattern should be urgently evaluated with prompt treatment, and the timing of emergency coronary angiography and revascularization should be evaluated to avoid adverse outcomes caused by delayed treatment.

Abstract Background Hereditary hearing loss is a highly heterogeneous disorder. This study aimed to identify the genetic cause of a Chinese family with autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL). Methods Clinical information and peripheral blood samples were collected from the proband and its parents. Two-step high-throughput next-generation sequencing on the Ion Torrent platform was applied to detect variants as follows. First, long-range PCR was performed to amplify all the regions of the GJB2, GJB3, SLC26A4, and MT-RNR1 genes, followed by next-generation sequencing. If no candidate pathogenetic variants were found, the targeted exon sequencing with AmpliSeq technology was employed to examine another 64 deafness-associated genes. Sanger sequencing was used to identify variants and the lineage co-segregation. The splicing of the MYO15A gene was assessed by in silico bioinformatics prediction and minigene assays. Results Two candidate MYO15A gene (OMIM, #602,666) heterozygous splicing variants, NG_011634.2 (NM_016239.3): c.6177 + 1G > T and c.9690 + 1G > A, were identified in the proband, and these two variants were both annotated as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Further bioinformatic analysis predicted that the c.6177 + 1G > T variant might cause exon skipping and that the c.9690 + 1G > A variant might activate a cryptic splicing donor site in the downstream intronic region. An in vitro minigene assay confirmed the above predictions. Conclusions We identified a compound heterozygous splicing variant in the MYO15A gene in a Han Chinese family with ARNSHL. Our results broaden the spectrum of MYO15A variants, potentially benefiting the early diagnosis, prevention, and treatment of the disease.