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Abstract Both anaesthesiologists and surgeons experience challenges in managing airway stenosis and scar contracture in the face and neck. Herein, we report the case of a 38-year-old woman (BMI 23.1 kg/m2, third-degree burns covering 40% of her body, an American Society of Anaesthesiologists physical status III) with an unusual case of airway constriction. This patient had a predictable difficult airway (mouth opening of 2 cm, bilateral nostril scar hyperplasia, Mallampatti score III, scarring of the head and neck, and severe tracheal stenosis). Tracheal stenosis measuring 5.5 mm in width as observed 8 cm below the glottis, and the bronchoscope could not pass through it. After two failed attempts at laryngeal mask insertion, we decided to instead insert a custom-made tracheal tube under the guidance of a fiberoptic bronchoscope. The operation was successful, and the patient was transferred to the intensive care unit (ICU).

To improve the physicochemical properties and processing performance of black wheat flour dough, the effects of adding Glucose oxidase (GOD) on the gelatinization, thermomechanics dough tensile, rheology properties, and microstructure of black wheat flour were investigated using a rapid viscosity analyzer, a texture analyzer, and a scanning electron microscope, among other methods. The effects were also explained in terms of changes in protein fractions. The results showed that the moderate addition of GOD could significantly reduce the content of free sulfhydryl groups and increase the content of disulfide bonds in the dough of black wheat flour, thereby enhancing the degree of protein cross-linking and significantly improving the physicochemical properties of black wheat flour dough. The best improvement in dough structure and properties was achieved when the GOD addition was 0.8%, at which point the ratio of wheat alcohol-soluble protein to wheat gluten (0.81) was close to the optimal ratio (1.0). This study has provided a certain reference for the development of black wheat-based foods and the improvement of their edible quality.

Abstract Methods Web of Science, Cochrane library and PubMed were systematically searched up to January 2024 to identify studies examining the impact of financial incentives on diabetes management in patients. Studies were evaluated based on the robustness of their methodology, participant numbers, and quality scores. The Cochrane risk-of-bias tool was applied for randomized controlled trials, while the Newcastle–Ottawa Scale was used for non-randomized controlled trials to assess study quality. Due to the heterogeneity of the included studies, a narrative synthesis approach was utilized. Results In the study, we included 12 published research studies. Five studies investigated the influence of financial incentives on patient behavior, all demonstrating a significant positive impact on behaviors such as blood glucose monitoring, medication adherence, and physical activity. 10 studies analyzed the impact of financial incentives on HbA1c levels in diabetes patients. Among them, 5 studies reported that financial incentives could improve HbA1c levels through longitudinal historical comparisons. The other 5 studies did not find significant improvements compared to the control group. Three studies explored long-term effects, two studies targeting the adolescent population had no impact, and one study targeting adults had a positive impact. Conclusions In summary, this review found that financial incentives can positively influence patient behavior and enhance compliance, but their impact on HbA1c levels is inconsistent. Financial incentives may help adult patients maintain behavior even after the withdrawal of incentives.

Abstract Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks.

Abstract Background Osteo-sarcopenia (OS) has become a global public health problem and a frontier research problem, as a combination of sarcopenia (SP) and osteoporosis (OP) diseases. The clinical performances include muscle weakness, systemic bone pain, standing difficulty, even falls and fractures, etc., which seriously affect the patient’s life and work. The pathological mechanism of the OS may be the abnormal metabolism which disrupts the equilibrium stability of the musculoskeletal system. Therefore, this study combined vitamin D (Vit. D) and whole-body vibration training (WBVT) to intervene in subjects of OS, aiming to evaluate the effectiveness and safety of the diagnosis and treatment protocol and to explore the efficacy mechanism. Methods We propose a multicenter, parallel-group clinical trial to evaluate the efficacy and safety of Vit. D combined with WBVT intervention in OS. Subjects who met the inclusion or exclusion criteria and signed the informed consent form would be randomly assigned to the WBVT group, Vit. D group, or WBVT+ Vit. D group. All subjects will be treated for 1 month and followed up after 3 and 6 months. The primary outcomes are lumbar bone mineral density (BMD) and appendicular skeletal muscle mass (ASM) measured by dual-energy X-ray absorptiometry (DXA) and handgrip strength measured by grip strength meter. Secondary outcomes include serum markers of myostatin (MSTN), irisin and bone turnover markers (BTM), SARC-CalF questionnaire, 1-min test question of osteoporosis risk, patient health status (evaluated by the SF-36 health survey), physical performance measurement that includes 5-time chair stand test, 6-m walk, and the short physical performance battery (SPPB). Discussion If Vit. D combined with WBVT can well relieve OS symptoms without adverse effects, this protocol may be a new treatment strategy for OS. After therapeutic intervention, if the serum marker MSTN/irisin is significant, both have the potential to become sensitive indicators for screening OS effective drugs and treatments, which also indicates that WBVT combined with Vit. D plays a role in improving OS by regulating MSTN/irisin. Trial registration Chinese Clinical Trial Registry ChiCTR2400082269 . Registered on March 26, 2024.

Currently, generative AI has undergone rapid development. Numerous studies have attested to the benefits of Gen AI in programming, mathematics and other disciplines. However, since Gen AI mostly uses English as the intrinsic training parameter, it is more effective in facilitating the teaching of courses that use international common notation, but few scholars have researched the fitness of Gen AI-assisted teaching of humanities courses in Chinese-language environments. To address these gaps, this study examined the learning behaviours of 30 students using Gen AI to help them answer questions on economic law tests using the Lag Sequential Analysis. The results show that the following: (1) The use of Gen AI to aid learning in an economic law course did not significantly improve the cognitive level of academics from the perspective of knowledge construction. (2) According to the characteristics of students' behavioural paths via Gen AI-assisted learning, their behavioural patterns can be classified into "autonomous and innovative," "moderate," and "lacking innovation." (3) Different learning modes when Gen AI-assisted teaching was used affected the final results, which were as follows: High-performing students favoured the "autonomous and innovative pattern," medium-performing students favoured the "moderate" pattern, and low-performing students favoured the "lacking innovation" pattern.

Amid the rapid evolution of artificial intelligence (AI), the intricate model structures and opaque decision-making processes of AI-based systems have raised the trustworthy issues in education. We, therefore, first propose a novel three-layer knowledge tracing model designed to address trustworthiness for an intelligent tutoring system. Each layer is crafted to tackle a specific challenge: transparency, explainability, and accountability. We have introduced an explainable AI (xAI) approach to offer technical interpreting information, validated by the established educational theories and principles. The validated interpreting information is subsequently transitioned from its technical context into educational insights, which are then incorporated into the newly designed user interface. Our evaluations indicate that an intelligent tutoring system, when equipped with the designed trustworthy knowledge tracing model, significantly enhances user trust and knowledge from the perspectives of both teachers and students. This study, thus, contributes a tangible solution that utilizes the xAI approach as the enabling technology to construct trustworthy systems or tools in education.

Introduction Nasopharyngeal carcinoma (NPC) is a highly lethal malignancy predominantly affecting East and Southeast Asia (1), where it accounts for approximately 70% of new cases worldwide annually (1), with the [...], Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk- transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.

BackgroundA nutritional diet is essential for children’s growth and development. This study aimed to investigate the relationship between dietary intake and growth and development of pupils to provide more specific nutritional recommendations for their healthy growth.MethodsThis cross-sectional study included 592 pupils, and standardized questionnaires were used to collect information on students’ sociodemographic characteristics, lifestyle habits and dietary intake. Growth and development assessment indicators were measured according to standard protocols. The multivariate generalized linear regression models adjusted for covariates were used to investigate the association between dietary intake and growth and development of pupils.ResultsThe generalized linear regression model showed that standing long jump of all pupils (β = −6.735, 95% CI: −12.064, −1.406) and body fat rate (β = −2.650, 95% CI: −4.794, −0.507), fat weight (β = −1.283, 95% CI: −2.286, −0.280) and chest circumference (β = −1.456, 95% CI: −2.789, −0.123) of boys were negatively correlated with dietary diversity score. Among all pupils, meat intake was positively correlated with chest circumference (β = 0.420, 95% CI: 0.119, 0.721) and negatively correlated with standing long jump(β = −1.991, 95% CI: −3.902, −0.080); milk intake was positively correlated with waist circumference (β = 0.470, 95% CI: 0.007, 0.932); soybean intake was negatively correlated with body fat rate (β = −0.583, 95% CI: −1.125, −0.042), fat weight (β = −0.262, 95% CI: −0.517, −0.006), and waist circumference (β = −0.607, 95% CI: −1.050, −0.164); and vegetable intake was negatively correlated with height (β = −0.290, 95% CI: −0.496, −0.084), and positively correlated with stature-sitting height index and waist circumference (p

ObjectivesTo evaluate the ability of the plaque characteristics of extracranial carotid and intracranial arteries to predict large atherosclerotic ischemic stroke recurrence via head and neck combined high-resolution vessel wall imaging (HR-VWI).MethodsThis prospective cohort study included 169 patients with large atherosclerotic ischemic stroke who underwent head and neck combined HR-VWI from April 2022 to May 2023. The baseline clinical data and atherosclerotic plaque characteristics of the intracranial and extracranial carotid arteries were collected, and the patients were followed up for 1 year, with the endpoint event defined as recurrent ischemic stroke. Clinical and imaging data were compared between the recurrent and nonrecurrent groups. Independent risk factors associated with stroke recurrence were assessed via multivariate Cox regression analysis. The receiver operating characteristic (ROC) curves of the relevant variables were also plotted, and the area under the curve (AUC) was calculated to assess their ability to predict stroke recurrence. Kaplan–Meier survival curves were used to compare the probability of stroke recurrence.ResultsDuring the 12-month follow-up, stroke recurrence occurred in 35 of the 169 patients. Multivariate Cox regression analysis revealed that the total number of intracranial and extracranial carotid plaques (p = 0.010) and coexisting extracranial carotid plaques and intracranial significantly enhanced plaques (p = 0.047) were independent risk factors for recurrent ischemic stroke. The AUCs for predicting stroke recurrence were 0.787 and 0.710, respectively. The Kaplan–Meier survival curve revealed that the risk of stroke recurrence was significantly greater in patients whose total number of intracranial and extracranial carotid plaques was >4.5 than in patients whose total number of plaques was

The early symptoms of hepatocellular carcinoma patients are often subtle and easily overlooked. By the time patients exhibit noticeable symptoms, the disease has typically progressed to middle or late stages, missing optimal treatment opportunities. Therefore, discovering biomarkers is essential for elucidating their functions for the early diagnosis and prevention. In practical research, challenges such as high-dimensional features, low sample size, and the complexity of gene interactions impact the reliability of biomarker discovery and disease diagnosis when using single-omics approaches. To address these challenges, we thus propose, Multi-level attention graph neural network (MLA-GNN) model for analyzing integrated multi-omics data related to liver cancer. The proposed protocol are using feature selection strategy by removing the noise and redundant information from gene expression and DNA methylation data. Additionally, it employs the Cartesian product method to integrate multi-omics datasets. The study also analyzes gene interactions using WGCNA and identifies potential genes through the MLA-GNN model, offering innovative approaches to resolve these issues. Furthermore, this paper identifies FOXL2 as a promising liver cancer marker through gene ontology and survival analysis. Validation using box plots showed that the expression of the gene FOXL2 was higher in patients with hepatocellular carcinoma than in normal individuals. The drug sensitivity correlation and molecular docking results of FOXL2 with the liver cancer-targeting agent lenvatinib emphasized its potential role in hepatocellular carcinoma treatment and highlighted the importance of FOXL2 in hepatocellular carcinoma treatment.

During the late laying period, the intestinal barrier of laying hens is susceptible to damage, resulting in enteric infections and even systemic inflammatory responses, posing a major challenge for the poultry industry. Therefore, it is crucial to investigate methods for addressing intestinal inflammation in late laying hens. In order to maximize the production potential of egg laying chickens, farmers usually use various feed additives to prevent damage to the intestinal barrier. Composite yeast cultures have shown advantages in broiler applications. This study aims to assess the impact of composite yeast culture (CYC) on the intestinal barrier function, inflammatory cytokines, and microbial community structure of Hy-Line Brown laying hens. A total of 160 healthy Hy-Line Brown hens, aged 58 weeks and of similar weight, were randomly assigned to two groups, with four replicates per group and 20 hens in each replicate. The control group was fed a basal diet (Con), while the experimental group was provided with a diet supplemented with 40 g/kg of composite yeast culture (CYC). The test period was 25 days. The results indicated that: compared to the control group, CYC significantly improved the egg production rates of hens during days 11–15, 16–20, and 21–25 (p

The management of diabetic wounds presents a considerable challenge within the realm of clinical practice. Cellular-derived nanoparticles, or extracellular vesicles (EV), generated by human adipose-derived stem cells (hASCs) have been investigated as promising candidates for the treatment of diabetic wounds. Nevertheless, limitations on the yield, as well as the qualitative angiogenic properties of the EV produced, have been a persistent issue. In this study, a novel approach involving the use of various cell culture morphologies, such as cell spheroids, on hASC was used to promote both EV yield and qualitative angiogenic properties for clinical use, with an emphasis on the in vivo angiogenic properties exhibited by the EV. Moreover, an increase in the secretion of the EV was confirmed after cell spheroid culture. Furthermore, microRNA(miRNA) analysis of the produced EVs indicated an increase in the presence of wound healing-associated miRNAs on the cell spheroid EV. Analysis of the effectiveness of the treated EVs in vitro indicated a significant promotion of the biological function of fibroblast and endothelial cells, cell migration, and cell proliferation post-cell spheroid EV application. Meanwhile, in vivo experiments on diabetic rats indicated a significant increase in collagen production, re-epithelization, and angiogenesis of the diabetic wound after EV administration. In this investigation, we posit that the use of cell spheroids for the culture of hASC represents a novel approach to enhance the substantial secretion of extracellular vesicles while increasing the angiogenic wound healing properties. This innovation holds promise for augmenting the therapeutic potential of EVs in diabetic wound healing, aligning with the exigencies of clinical applications for these nanoparticles.

Perillae Folium (PF) is a well-known food and herb containing different chemotypes, which affect its quality. Herein, a method was proposed to classify and quantify PF chemotypes using gas chromatography–mass spectrometry (GC–MS) and Fourier transform-near infrared spectroscopy (FT-NIR). GC–MS results revealed that PF contains several chemotypes, including perilla ketone (PK) type, α-asarone (PP-as) type, and dillapiole (PP-dm) type, with the PK type being the predominant chemotype. Based on FT-NIR data, different chemotypes were accurately classified. The random forest algorithm achieved >90 % accuracy in chemotype classification. Furthermore, the main components of perilla ketone and isoegomaketone in PF were successfully quantified using partial least squares regression models, with prediction to deviation values of 3.76 and 2.59, respectively. This method provides valuable insights and references for the quality supervision of PF and other foods.

ABSTRACTColorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (ApcMin/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.

Biologically induced reactions in granular media (geomaterials) often rely on precipitates from enzymes or microbes to promote the formation of mineral precipitate crystals in its pores. However, there is a major knowledge gap in understanding the hypotheses behind the mechanisms of how, where, and when these biomineralization reactions influence the microbial or enzymatic precipitate growth in heterogeneous granular media, and its impact on its material properties at the pore scale. In this regard, we propose to identify the complex spatio-temporal mechanisms controlling enzymatic (EP) and microbial (MP) precipitates, the temporal distribution patterns (arrays) in heterogeneous granular media (rocks), and quantify the resultant alterations in its nanomechanical signatures due to enzymatic- or microbial-induced reactions. The rock material specimens were incubated with enzymes and microbial species followed by quantitatively analyzing their modified nanomechanical properties (Young's modulus, E; fracture toughness, KIC; hardness, H) and pore volume in addition to characterizing the nano-to-micro-structure. Analysis of the results reveals that bio-precipitates can occlude the nano-and-micro-pores in specimens with reduced pore volume (MP:12.4 %; EP:48.8 %), thereby yielding beneficial nanomechanical alterations (MP: +21.2 % H, +16 % E, +41.3 % KIC; EP: +38.5 % H, +17 % E, +22.2 % KIC) depending on distinct conditions of the bio-precipitated reactions. Looking forward, this work provides a blueprint for the rational design of inherently-heterogeneous granular media with further enhanced biomimicry toward more innovative and environmentally friendly solutions in natural and built infrastructure.

Abstract Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.

Abstract Background A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. Methods Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. Results Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. Conclusions The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.

Abstract Metal-organic frameworks (MOFs), recognized as advanced catalyst carriers due to their adjustable porous, diverse structure and highly exposed active sites, have earned increasing attention for their potential to address the longevity of catalytic centers. In this manuscript, we have devised and synthesized a multifunctional amino-pyridine benzoic acid (APBA) ligand to replace the modulator ligand of the MOF-808 and disperse the palladium catalytic centers atomically on the MOF-APBA. The resulting single-site catalytic system, Pd@MOF-APBA, demonstrates preeminent efficiency and stability, as evidenced by a high average turnover number (95000) and a low metal residue (4.8 ppm) in the Heck reaction. This catalyst has exhibited recyclability for multiple runs without significant loss of reactivity for gram-scale reactions. The catalyst’s high activity and efficiency can be attributed to the suitable electrical properties and structures of the N, N’-bidentate ligand for the catalytic palladium ions, postponing their deactivations, including leaching and agglomeration.

Background/purpose: The extent of three-dimensional soft tissue changes in patients with varied facial skeletal patterns following mandibular setback surgery remains unclear. In this study, we aimed to investigate the postoperative changes in soft tissue chin thickness among mandibular prognathism patients, focusing on those presenting different divergence patterns, such as hyperdivergent and normodivergent patients. Materials and methods: Cone-beam computed tomography images were obtained from 56 skeletal Class III patients who underwent only mandibular setback. Based on vertical craniofacial skeletal relationship, patients were divided into normodivergent group (27°37°) group. The three-dimensional displacements of Infradentale (Id), B point (B), and Pogonion (Pog), the soft tissue thickness of Id-Li (Labrale inferius), B-B' (soft tissue B point), and Pog-Pog’ (soft tissue Pog point) were measured. Factors influencing the change in soft tissue thickness were investigated. Results: Preoperative B-B' and Pog-Pog’ thickness were significantly thinner in the hyperdivergent group than normodivergent group. Postoperative changes in B-B' and Pog-Pog’ thickness were significantly larger in the hyperdivergent group than normodivergent group. A significant correlation was found between soft tissue thickness change (B-B' and Pog-Pog’) and the preoperative soft tissue thickness and superior movement (B and Pog). Conclusion: Hyperdivergent patients with skeletal class III have thinner preoperative soft tissue thickness (B-B' and Pog-Pog’) than normodivergent patients in the preoperation. Postoperative changes in B-B' and Pog-Pog’ thickness were significantly larger in the hyperdivergent group than normodivergent group. Postoperative superior movement of B and Pog correlated with postoperative change of soft tissue thickness.

Abstract Background Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence. Methods Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155−/− mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. Results Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16INK4A expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16INK4A/p21expression and senescence-associated β-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs. Conclusions Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.

Abstract Diffusion Kurtosis Imaging (DKI)-derived metrics are recognized as indicators of maturation in neonates with low-grade germinal matrix and intraventricular hemorrhage (GMH-IVH). However, it is not yet known if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire DKI-derived metrics in neonates with low-grade GMH-IVH, and to demonstrate their association with later neurodevelopmental outcomes. In this prospective study, neonates with low-grade GMH-IVH and control neonates were recruited, and DKI were performed between January 2020 and March 2021. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age. Mean kurtosis (MK), radial kurtosis (RK) and gray matter values were measured. Spearman correlation analyses were conducted for the measured values and neurodevelopmental outcome scores. Forty controls (18 males, average gestational age (GA) 30 weeks ± 1.3, corrected GA at MRI scan 38 weeks ± 1) and thirty neonates with low-grade GMH-IVH (13 males, average GA 30 weeks ± 1.5, corrected GA at MRI scan 38 weeks ± 1). Neonates with low-grade GMH-IVH exhibited lower MK and RK values in the PLIC and the thalamus (P

Abstract Osteoporosis is a prevalent condition marked by reduced bone density and an elevated risk of fractures, especially among postmenopausal women. Exercise plays a crucial role in preventing and managing osteoporosis, with weight-bearing and impact exercises being particularly effective in enhancing bone density and mitigating disease risk. This study investigated the relationship between various types of impact exercises and osteoporosis using data from the Taiwan Biobank (TWB). The study sample comprised 5,123 individuals without osteoporosis and 1,770 individuals with the condition. Student’s t-test and logistic regression analyses were utilized to assess the associations between exercise types and osteoporosis risk. Results indicated that high-impact exercise significantly reduced the likelihood of developing osteoporosis compared to no exercise (odds ratio; OR = 0.573, 95% CI: 0.406–0.810, P = 0.002). Conversely, low-impact exercises did not show a significant overall association with osteoporosis (OR = 1.160, 95% CI: 0.932–1.445, P = 0.184). Stratified analysis by sex revealed that high-impact exercise was protective against osteoporosis in men (OR = 0.391, 95% CI: 0.202–0.755, P = 0.005), but not significantly so in women (OR = 0.671, 95% CI: 0.438–1.027, P = 0.066). These findings suggest that high-impact exercise is associated with a reduced risk of osteoporosis, particularly among Taiwanese men aged 30 to 70.

Abstract Biofilms produced by Candida albicans present a challenge in treatment with antifungal drug. Enhancing the sensitivity to fluconazole (FLC) is a reasonable method for treating FLC-resistant species. Moreover, several lines of evidence have demonstrated that berberine (BBR) can have antimicrobial effects. The aim of this study was to clarify the underlying mechanism of these effects. We conducted a comparative study of the inhibition of FLC-resistant strain growth by FLC treatment alone, BBR treatment alone, and the synergistic effect of combined FLC and BBR treatment. Twenty-four isolated strains showed distinct biofilm formation capabilities. The antifungal effect of combined FLC and BBR treatment in terms of the growth and biofilm formation of Candida albicans species was determined via checkerboard, time-kill, and fluorescence microscopy assays. The synergistic effect of BBR and FLC downregulated the expression of the efflux pump genes CDR1 and MDR, the hyphal gene HWP1, and the adhesion gene ALS3; however, the gene expression of the transcriptional repressor TUP1 was upregulated following treatment with this drug combination. Furthermore, the addition of BBR led to a marked reduction in cell surface hydrophobicity. To identify resistance-related genes and virulence factors through genome-wide sequencing analysis, we investigated the inhibition of related resistance gene expression by the combination of BBR and FLC, as well as the associated signaling pathways and metabolic pathways. The KEGG metabolic map showed that the metabolic genes in this strain are mainly involved in amino acid and carbon metabolism. The metabolic pathway map showed that several ergosterol (ERG) genes were involved in the synthesis of cell membrane sterols, which may be related to drug resistance. In this study, BBR + FLC combination treatment upregulated the expression of the ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes and downregulated the expression of the ERG6 and ERG9 genes compared with fluconazole treatment alone (p

Abstract Background The methylation of SHOX2 and RASSF1A shows promise as a potential biomarker for the early screening of lung cancer, offering a solution to remedy the limitations of morphological diagnosis. The aim of this study is to diagnose lung adenocarcinoma by measuring the methylation levels of SHOX2 and RASSF1A, and provide an accurate pathological diagnosis to predict the invasiveness of lung cancer prior to surgery. Material and methods The methylation levels of SHOX2 and RASSF1A were quantified using a LungMe® test kit through methylation-specific PCR (MS-PCR). The diagnostic efficacy of SHOX2 and RASSF1A and the cutoff values were validated using ROC curve analysis. The hazardous factors influencing the invasiveness of lung adenocarcinoma were calculated using multiple regression. Results: The cutoff values of SHOX2 and RASSF1A were 8.3 and 12.0, respectively. The sensitivities of LungMe® in IA, MIA and AIS patients were 71.3% (122/171), 41.7% (15/36), and 16.1% (5/31) under the specificity of 94.1% (32/34) for benign lesions. Additionally, the methylation level of SHOX2, RASSF1A and LungMe® correlated with the high invasiveness of clinicopathological features, such as age, gender, tumor size, TNM stage, pathological type, pleural invasion and STAS. The tumor size, age, CTR values and LungMe® methylation levels were identified as independent hazardous factors influencing the invasiveness of lung adenocarcinoma. Conclusion: SHOX2 and RASSF1A combined methylation can be used as an early detection indicator of lung adenocarcinoma. SHOX2 and RASSF1A combined (LungMe®) methylation is significantly correlated to age, gender, tumor size, TNM stage, pathological type, pleural invasion and STAS. The SHOX2 and RASSF1A methylation levels, tumor size and CTR values could predict the invasiveness of the tumor prior to surgery, thereby providing guidance for the surgical procedure.

Abstract Volume fracturing technology is commonly used to develop tight sandstone reservoirs. During the fracturing process, it is important to not only focus on achieving a larger stimulation volume but also on creating a fracture network conductivity that is suitable for the tight reservoir. However, while there have been numerous studies on optimizing the conductivity of individual fractures, the optimization of fracture network conductivity is still incomplete. To address this issue, a reservoir numerical model is established to optimize the equivalent conductivity of the post‐fracturing fracture network, considering it as a high permeability zone, optimizing the equivalent conductivity to 9.7 μm2 cm. Utilizing the discrete element theory, a “pipe domain” discrete element model is developed to analyze fracture expansion. The findings indicate that the ratios of first‐level, second‐level, and third‐level fractures differ based on the number of clusters, such as 1:4:8 and 1:5:9 for three‐cluster and four‐cluster perforations. By applying the hydropower similarity principle, the fracture network is treated as a three‐level circuit to determine the conductivity of each fracture level. Finally, the model is fitted based on conductivity to determine the optimal fracture conductivity for different fracture number ratios, thereby enhancing the flow capability.

Abstract Under Taiwan's National Health Insurance (NHI) system, it's crucial for all healthcare providers to accurately submit medical expense claims to the National Health Insurance Administration (NHIA) to avoid incorrect deductions. With changes in healthcare policies and adjustments in hospital management strategies, the complexity of claiming rules has resulted in hospitals expending significant manpower and time on the medical expense claims process. Therefore, this study utilizes the Lean Six Sigma DMAIC (Define, Measure, Analyze, Improve, Control) management approach to identify wasteful and non-value-added steps in the process. Simultaneously, it introduces Robotic Process Automation (RPA) tools to replace manual operations. After implementation, the study effectively reduces the process time by 380 min and enhances Process Cycle Efficiency (PCE) from 69.07 to 95.54%. This research validates a real-world case of Lean digital transformation in healthcare institutions. It enables human resources to be allocated to more valuable and creative tasks while assisting hospitals in providing more comprehensive and patient-centric services.

Abstract Background Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. Results We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. Conclusions Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.