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Because of its strong penetrating capability, the natural seismic receiving function has become the most widely used method for detecting crust-mantle structure. As the understanding of the structure and dynamic processes in the crust and upper mantle has advanced, the broadband seismic array with relatively large station spacing has become incompetent to the high-resolution imaging. The Dense Nodal Seismic Array (DNA), composed of hundreds of short-period portable digital high-frequency seismometers, offers a solution with station spacing as small as a few hundred meters, allowing for the collection of substantial observational data in a short time (1-2 months). Its advantages mainly include three aspects: (1) Good cross-ray-path coverage in the crust, conducive to improving imaging resolution; (2) Densely distributed ray-paths, facilitating noise suppression through coherent stacking of receiver functions, allowing for high-frequency receiver function imaging of crustal structures; (3) High efficiency due to the short observation time. Therefore, short-period dense array has become one of seismic observation approach commonly adopted in deep crustal structure research for only a few years. This paper mainly introduces the origin of short-period dense array in deep crustal structure exploration, and demonstrates its exploration effect and application in different tectonic domains through several typical exploration examples. more...

Abstract Background Frailty is a common geriatric syndrome associated with many adverse health outcomes. Identifying the risk factors of frailty is crucial and the insulin resistance (IR) is considered as a potential target. The estimated glucose disposal rate (eGDR) is a simple and reliable surrogate marker of IR. Associations of eGDR with frailty have not been explored. This study aimed to investigate the associations of eGDR with frailty progression. Methods We used data from two prospective cohorts of the China Health and Retirement Longitudinal Study (CHARLS) and Health and Retirement Study (HRS). The eGDR was calculated as follows: eGDR (mg/kg/min) = 21.158 − (0.09×waist circumference) − (3.407×hypertension) − (0.551×glycosylated hemoglobin A1c) [waist circumference (cm), hypertension (yes = 1/no = 0), and glycosylated hemoglobin A1c (%)]. Participants were divided into three categories by tertiles of eGDR. Frailty index (FI) was calculated every two years and used to assess the degree of frailty which ranged from 0 to 100. Frailty progression was assessed by repeated measurements of FI during follow-up. Linear mixed-effect models were used to analyze the associations of eGDR with frailty progression. Results 8872 participants from CHARLS (mean age: 58.9 years, female: 53.3%) and 5864 participants from HRS (mean age: 67.0 years, female: 59.0%) were included. The median follow-up periods were 7.0 years in the CHARLS and 12.8 years in the HRS, respectively. Compared to participants with lower tertile (T1) of eGDR, those with upper tertile (T3) of eGDR showed decelerated FI progression (CHARLS, β: -0.294, 95%CI -0.390 to -0.198, P more...

Abstract Background Lysine acetylation is a critical post-translational modification regulating tumor initiation and progression. Lysine acetyltransferase 7 (KAT7)-mediated lysine acetylation is frequently dysregulated in cancer. However, the role of KAT7-mediated lysine acetylation in hepatocellular carcinoma (HCC) progression remains unclear. Methods Bioinformatic analysis was used to investigate the expression, clinicopathological characteristics and diagnostic prognostic value of KAT7 in HCC. CCK-8 assays, colony-forming assays, apoptosis assays and nude mouse xenograft models were utilized to detect the oncogenic functions of KAT7 in HCC. Immunoprecipitation (IP) assay and mass spectrometry (MS) analysis were performed to identify the KAT7-binding protein Y-box binding protein 1 (YBX1). Transcriptome sequencing and functional enrichment analysis were employed to elucidate the downstream pathway regulated by KAT7 and YBX1. Chromatin immunoprecipitation (ChIP) assay was used to evaluate YBX1 binding to the promoter regions of ribonucleotide reductase regulatory subunit M2 (RRM2) and thymidine kinase 1 (TK1). Weighted gene co-expression network analysis and selection operator regression analysis were used to build risk prediction models. Results This study demonstrated that elevated KAT7 expression is associated with poor prognosis in HCC patients. Knockdown of endogenous KAT7 in HCC cells attenuated tumorigenic phenotypes associated with cell proliferation, colony formation and orthotopic xenograft tumor growth, indicating a pro-tumorigenic role of KAT7 in HCC. YBX1 was identified as a novel non-histone substrate for KAT7, and the E508 residue of KAT7 is essential for binding. Following the functional enrichment analysis, KAT7 and YBX1 were correlated with nucleotide metabolism. Furthermore, KAT7 binds to YBX1 and modulates its post-translational expression, which enhances the transcriptional activity of the central nucleotide metabolism enzymes RRM2 and TK1. Additionally, we constructed a novel prognostic prediction model based on KAT7, YBX1, RRM2 and TK1, which validated the predictive accuracy and prognostic value of KAT7-mediated acetylation is consistent with clinical outcomes in HCC. Conclusions Our findings highlight that KAT7 acetylates YBX1 and promotes HCC progression by reprogramming nucleotide metabolism, offering therapeutic implications. more...

Abstract Background Comorbidities may complicate medical situations and have an impact on the treatment decisions and poor survival of cancer patients. How comorbidities cluster together and ultimately affect patients’ outcomes in gastrointestinal tract cancer (GTC) is a poorly understood area. Methods In a multicenter prospective observational study from 2012 to 2021, we grouped the comorbidities of patients with GTC by latent class analysis, obtaining two comorbidity classes. Cox regression models were initially used to predict mortality. LASSO techniques were used to reduce the dimension. The final model included the comorbidity classes and nine more predictors. Additionally, the performance of different simple multimorbidity measures were compared using the Bayesian information criterion (BIC), ROC curves and C-index. Finally, the performance of the final model was analyzed using ROC curves, calibration curves and decision curves. The nomogram was drawn to evaluate the model. Results We included 10,019 patients and obtained two comorbidity classes. Class 2 patients have a higher incidence of comorbidities, and a lower survival rate compared to Class 1 (P more...

Wuxi county has become a significant region for the vigorous development of Baijiu industry due to its abundant natural resources and profound Wu cultural deposits. In recent years, with the support of national policies, the Baijiu industry embraced new opportunities. In this paper, the current situation and quality characteristics of Baijiu production area in Wuxi county were analyzed in depth, and the targeted improvement strategies were proposed based on the development trends of domestic and international Baijiu cultures. The development of Baijiu industry in Wuxi county benefits from its uniquely advantageous geographical environment and climatic conditions, while being deeply influenced by the local Wu culture. As an integral part of traditional Chinese culture, Wu culture's beliefs in spirit worship and nature coincide with the reverence for nature and pursuit of harmony in Baijiu brewing techniques, imparting unique cultural connotations and flavor characteristics to the Baijiu in Wuxi county. Through sensory evaluation and chemical compositions analysis of Baijiu products in Wuxi county, it was found that the Baijiu from Wuxi county had harmonious aroma, mellow taste and stable quality. However, facing market challenges, it was recommended to strengthen brand building, talent cultivation, innovation, and industrial integration, delve deeper into Wu culture to enhance added value, and intensify marketing efforts to promote the transformation and upgrading of the Baijiu industry in Wuxi county towards sustainable development. more...

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC50, SMS2 = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t1/2, cornea = 1.11 h; t1/2, meibomian glands = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors. more...

Abstract Background Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited. Methods This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS). Results Twenty-three patients with a median age of 58.1 years (range 25.9–75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7–45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively. Conclusions Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients. more...

Abstract Background Immunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC. Methods Histone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments. Results In the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death–associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8+ T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC. Conclusion The combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials. more...

Abstract High-altitude pulmonary edema (HAPE) is a life-threatening altitude sickness afflicting certain individuals after rapid ascent to high altitude above 2500 m. In the setting of HAPE, an early diagnosis is critical and currently based on clinical evaluation. The aim of this study was to utilize the metabolomics to identify the altered metabolic patterns and potential biomarkers for HAPE. Serum samples from HAPE patients (n = 24) and healthy controls (n = 21) were analyzed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) to profile differential metabolites and explore dysregulated metabolic pathways. The correlation analysis and receiver operating characteristic (ROC) curve analysis were further performed to screen biomarkers for HAPE. A total of 119 differential metabolites between the control and HAPE groups were identified. Top dysregulated pathways included pyrimidine metabolism, citrate cycle, sulfur metabolism, phenylalanine metabolism and purine metabolism. After correlation analysis with clinical indices, 39 differential metabolites were obtained as potential biomarkers related to HAPE. Finally, 7 biomarkers, specifically S-nitroso-N-acetylcysteine, aminocaproic acid, emodin, threo-hydroxyaspartic acid, 6-hydroxynicotinic acid, 3-acetylphenol sulfate and cis-aconitic acid, were screened out through ROC analysis, which displayed high diagnostic accuracy for HAPE. Taken together, the altered serum metabolic profile is associated with the occurrence of HAPE. Diagnostic tests based on the biomarkers from metabolomics may hold promise as a strategy for early detection of HAPE. more...

Abstract Chimeric antigen receptor (CAR)-T cell therapy has emerged as one of the most rapidly evolving modalities of immunotherapy, with substantial success in the treatment of hematological malignancies and encouraging outcomes in solid tumors. Yet, the efficacy of CAR-T therapy is hindered by challenges such as suboptimal expansion and persistence, adverse events, a scarcity of ideal targets, high immunosuppression, and insufficient infiltration due to the intricate tumor microenvironment, all of which limit its application. The 2024 European Society for Medical Oncology (ESMO) Congress presented novel CAR-T cell therapies for hematologic and solid malignancies, focusing on strategies such as cytokine modulation, innovative targets, allogeneic development, mRNA vaccine synergy, in vivo delivery and conditional activation to surmount these challenges. more...

Context Sepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection.Objective To determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality.Materials and methods A sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 µg/mL)-stimulated primary intestinal microvascular endothelial cells (IMVECs) and then determine NGR1’s safe dosage. Groups for each model were: in vivo—a control group, a CLP-induced sepsis group, and a CLP + NGR1 treatment group (30 mg/kg/d for 3 d); in vitro—a control group, a LPS-induced sepsis group, and a LPS + NGR1 treatment group (4 μM for 30 min). NGR1’s effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated.Results Sepsis resulted in approximately 60% mortality within 7 days post-CLP, with significant reductions in intestinal microvascular perfusion and increases in vascular leakage. Severe mitochondrial quality imbalance was observed in IMVECs. NGR1 (IC50 is 854.1 μM at 30 min) targeted Drp1, inhibiting mitochondrial translocation, preventing mitochondrial fragmentation and restoring IMVEC morphology and function, thus protecting against intestinal barrier dysfunction, vascular permeability, microcirculatory flow, and improving sepsis prognosis.Discussion and conclusions Drp1-mediated mitochondrial quality imbalance is a potential therapeutic target for sepsis. Small molecule natural drugs like NGR1 targeting Drp1 may offer new directions for organ protection following sepsis. Future research should focus on clinical trials to evaluate NGR1’s efficacy across various patient populations, potentially leading to novel treatments for sepsis. more...

Background: This study aims to evaluate the clinical effectiveness of repetitive transcranial magnetic stimulation (rTMS) when used as an add-on therapy for individuals with persistent postural-perceptual dizziness (PPPD). Methods: In this randomized controlled, double-blind trial conducted at Shangluo Central Hospital, patients with PPPD diagnosed in the neurology departments were included. Participants were randomized into a rTMS treatment group and a control group in a 1:1 ratio by the randomized grouping method. Patients in both groups received conventional treatment, with the rTMS treatment group underwent daily rTMS sessions, whereas the control group received sham rTMS treatments following the same schedule. The effectiveness of the treatments was primarily assessed using the Dizziness Handicap Inventory (DHI), Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD), which measured symptoms of vertigo, anxiety, and depression at baseline, after two weeks, and at the end of four weeks. Findings: Of the 46 participants recruited, 2 were excluded due to contraindications, 22 were randomly assigned to the rTMS treatment group, and 22 were assigned to the control group. Ultimately, 2 withdrew for personal reasons, and data from 42 participants were included in the outcome analysis. HAMA, HAMD and DHI scores were significantly lower in the rTMS treatment group than in the control group after 4 weeks of treatment (p more...

Abstract Relapsed/refractory T cell-derived malignancies present with high heterogeneity and poor prognoses. Recently, chimeric antigen receptor (CAR)-T cell therapy has shown remarkable safety and efficacy in the treatment of B cell-derived malignancies. However, the treatment of CAR-T cells in T cell-derived malignancies has more limitations, such as fratricide, T cell aplasia, and tumor contamination, mainly because of the similarity between normal and malignant T cells. Pan-T antigen CAR-T cells (such as CD5 and CD7 targets), the most widely used CAR-T cells in clinical trials, can cover almost all T cell-derived malignant cells but can also induce severe killing of CAR-T cells and normal T cells. Compared to autologous sources of CAR-T cells, allogeneic CAR-T cells can prevent tumor contamination and become universal products by gene-editing. However, none of these CAR-T cells could completely prevent immune deficiency and disease relapse after T-targeted CAR-T cell therapy. In this review, we summarize the current challenges of CAR-T cell therapy for T cell-derived malignancies in clinical practice and potential strategies to address these limitations. more...

Abstract To investigate the effectiveness of cap-assisted endoscope synchronous advancement and tube direction adjustment for inserting transnasal ileus tubes in patients with malignant adhesive bowel obstruction (MABO). 25 patients with cap-assisted endoscopic synchronous method (Group A, Dec 2023–Apr 2024) were reviewed retrospectively. Accordingly, those with forceps-grasping method (Group B: 27, Aug 2022–Nov 2023) were included as controls. Both groups were similar in terms of age, sex, primary tumor, doctor experience distribution and technical success rate. The proportion of gynecological cancers was the highest in either group. The time required for insertion was shorter in Group A than in Group B (5 vs. 12 min; P = 0.000). Group A also had slightly longer tube insertion length than Group B (129.8 ± 14.1 vs. 121.3 ± 12.0 cm; P = 0.008), and the remission rate of intestinal obstruction symptoms in Group A was similar to that in Group B (75.0% vs. 74.1%; P = 0.940). There were no significant differences in complications between the two groups. One patient suffered MABO recurrence 14 days after withdrawal of the tube. Our findings indicate that transnasal ileus tube insertion with cap-assisted endoscopic synchronous method took shorter time and had the same rate of technical success and advantage of decompression compared with forceps-grasping method. more...

Abstract Background Intensive care units are critical environments where various alarm systems play a pivotal role in patient monitoring and safety. Alarm fatigue can lead to slower response times and missed alarms, compromising patient safety and increasing stress and burnout among intensive care unit nurses. Understanding how intensive care unit nurses respond to and manage these alarms is crucial in evaluating their impact on patient care and nursing well-being. Methods This descriptive qualitative study explored the experiences of intensive care unit nurses in alarm management. Conducted in the medical and surgical intensive care units of a Northern Taiwan medical center, the study involved 15 nurses. Semi-structured interviews were utilized to investigate the working experiences of ICU nurses in alarm management and to identify their coping strategies for dealing with the constant inundation of medical device alarms. The interviews were transcribed, and content analysis was applied to identify key themes in the responses. Results The study revealed five main themes in intensive care unit nurses’ strategies for managing alarms: (1) Mastering alarm signals and acting; (2) Team monitoring for life preservation; (3) Enhancing senses and distinguishing carefully; (4) Learning from the lessons of incidents for vigilant reflection; and (5) Detach alarms’ influence on daily life. These coping strategies are effective in alarm management, safeguarding patients’ lives, enhancing the serenity of the clinical environment, and mitigating the physical and mental exhaustion caused by alarm fatigue. Conclusions Intensive Care Unit nurses develop various coping strategies to manage medical device alarms, based on their experience. These strategies are crucial in maintaining patient safety and reducing nurse alarm fatigue. They can also be used for nursing education and clinical training. more...

Abstract Background Aging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR β-subunit (AChR-β) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-β expression. Methods Animal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-β expression. Results IL-6 expression gradually increased during aging, inhibiting AChR-β expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-β. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-β and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-β promoter to regulate its expression. Conclusions This study verifies AChR-β regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary. more...

Abstract Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function. more...

Abstract Background Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies. Methods This is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients’ medical charts and electronic medical record system. Results In total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52–251). Seven patients recovered from PcP after proper management while one died of septic shock. Conclusion PcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population. more...

Abstract Background Acute pain is a major concern after arthroscopic shoulder surgery, supraclavicular brachial plexus blockade has shown favorable postoperative analgesic effects. However, its duration of analgesia does not meet clinical needs. We aimed to explore whether the combination of different local anesthetic adjunct can prolong the analgesic duration of supraclavicular brachial plexus block for arthroscopic shoulder surgery. Methods In this prospective randomized controlled trial, we allocated 80 patients into four groups: Group DMD (dexamethasone 10 mg + ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group DM (ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group M (ropivacaine 100 mg + magnesium sulfate 250 mg) and Group D (ropivacaine 100 mg + dexmedetomidine 50 µg). The primary outcome was the time to first request for analgesia. Secondary outcome measures included cumulative opioid consumption at 6, 12, 18, 24, and 48 h postoperatively, VAS scores at 6, 12, 18, 24, and 48 h postoperatively and so on. Results The time to first request for analgesia in Group DMD was significantly longer than Group DM (P = 0.011) and Group M (P = 0.003). The cumulative opioid consumption at 18 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.002) and Group M (P = 0.007). The cumulative opioid consumption at 24 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.016). The VAS score at 6 h postoperatively in Group DMD was significantly lower than in Group DM and Group M. The VAS score at 12 h postoperatively in Group DMD was significantly lower than in Group M. For American Shoulder and Elbow Surgeons Score, Group DMD had a better score than Group DM and Group D. Conclusions The analgesic efficacy of supraclavicular brachial plexus blockade combined with dexamethasone, magnesium sulfate, and dexmedetomidine is significantly superior to the combination of magnesium sulfate and dexmedetomidine, and significantly superior to the use of magnesium sulfate alone. Trial registration This trial was registered in Chinese Clinical Trial Registry. (ChiCTR2200061181, Date of registration: June 15, 2022, http://www.chictr.org.cn ) more...

Abstract Compared to traditional lower-limb prostheses (LLPs), intelligent LLPs are more versatile devices with emerging technologies, such as microcontrollers and user-controlled interfaces (UCIs). As emerging technologies allow a higher level of automation and more involvement from wearers in the LLP setting adjustments, the previous framework established to study human factors elements that affect wearer-LLP interaction may not be sufficient to understand the new elements (e.g., transparency) and dynamics in this interaction. In addition, the increased complexity of interaction amplifies the limitations of the traditional evaluation approaches of wearer-LLP interaction. Therefore, to ensure wearer acceptance and adoption, from a human factors perspective, we propose a new framework to introduce elements and usability requirements for the wearer-LLP interaction. This paper organizes human factors elements that appear with the development of intelligent LLP technologies into three aspects: wearer, device, and task by using a classic model of the human-machine systems. By adopting Nielsen’s five usability requirements, we introduce learnability, efficiency, memorability, use error, and satisfaction into the evaluation of wearer-LLP interaction. We identify two types of wearer-LLP interaction. The first type, direct interaction, occurs when the wearer continuously interacts with the intelligent LLP (primarily when the LLP is in action); the second type, indirect interaction, occurs when the wearer initiates communication with the LLP usually through a UCI to address the current or foreseeable challenges. For each type of interaction, we highlight new elements, such as device transparency and prior knowledge of the wearer with the UCI. In addition, we redefine the usability goals of two types of wearer-LLP interaction with Nelson’s five usability requirements and review methods to evaluate the interaction. Researchers and designers for intelligent LLPs should consider the new device elements that may additionally influence wearers’ acceptance and the need to interpret findings within the constraints of the specific wearer and task characteristics. The proposed framework can also be used to organize literature and identify gaps for future directions. By adopting the holistic usability requirements, findings across empirical studies can be more comparable. At the end of this paper, we discuss research trends and future directions in the human factors design of intelligent LLPs. more...

Abstract Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy. more...

Abstract Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on the test set GSE43292 to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated DEGs. Subsequently, key genes were then identified through weighted gene co-expression network analysis, random forest, Recursive Feature Elimination for Support Vector Machines algorithm and cytoHubba plugin. The intersection yielded 3 CSA-signature genes, which were validated in the external validation set GSE163154. Additionally, we assessed the relationship between these CSA-signature genes and the immune landscape of the unstable plaque group. This study suggests that cellular senescence may play an important role in the progression mechanism of unstable plaques and is closely related to the influence of the immune microenvironment. Our research lays the foundation for studying the progression mechanism of unstable carotid plaques and provides some reference for targeted therapy. more...

The imbalance between the supply and demand of urban ecosystem services significantly impacts land resource utilization and residents’ quality of life. This study innovatively examines the spatio-temporal evolution of these services at the block scale in Xiamen, China, from 2012 to 2022, addressing a gap in current research that often focuses on larger scales like watersheds. Using multi-source data, six ecosystem services, including water conservation, carbon sequestration, and habitat quality, were assessed, revealing notable deficiencies. The study also employs the GMOP-PLUS model to simulate land use and ecosystem service changes under three scenarios—Natural development (ND), Economic development (ED), and Ecological low-carbon development (EL)—projected to 2027. Results highlight a significant spatial imbalance with a “North Supply, South Demand” pattern, particularly in southern urban areas. While all scenarios show a decline in green space and ecosystem services, the economic growth scenario improves economic benefits, and the ecological conservation scenario enhances low-carbon and ecological services. This research provides novel insights and optimization strategies for urban land use planning, aiming to enhance ecosystem services and support sustainable urban development. more...

BackgroundColorectal adenomas, which are precancerous lesions that can develop into colorectal cancer, present a significant challenge due to the lack of comprehensive early screening and clear identification of risk factors.ObjectivesWe conduct a double-blind, prospective cross-sectional analysis to examine the relationship between lifestyle, mental health, and colorectal adenomas.MethodsBetween June 2023 and July 2024, we surveyed 246 participants at Hubei Provincial Hospital of Traditional Chinese Medicine in Wuhan using a self-administered online questionnaire.ResultsThe majority of participants were over the age of 50 (49.6%), married or living with a partner (87.08%), and employed as office workers or technicians (44.3%). Among the total population, 435 individuals (53.5%) were diagnosed with colorectal adenomas. A significant positive association was observed between being a manager (OR = 2.340; 95% CI = 1.043–5.248) and the presence of colorectal adenomas, as well as having a BMI over 28 (OR = 6.000; 95% CI = 1.501–23.991). After adjusting for professional role and BMI, no significant associations were found between scores on the HADS-D (AOR = 1.031; 95% CI = 0.967–1.099) or PSS-10 (AOR = 0.971; 95% CI = 0.923–1.022) scales and colorectal adenomas. However, higher scores on the AUDIT (AOR = 1.001–1.144), CDS-12 (AOR = 1.028; 95% CI = 1.003–1.054), PSQI (AOR = 1.079; 95% CI = 1.003–1.161), and HADS-A (AOR = 1.156; 95% CI = 1.059–1.262) scales were significantly associated with an increased likelihood of colorectal adenomas.ConclusionThe study highlights the significance of addressing alcohol consumption, smoking, sleep quality, and anxiety to reduce the risk of colorectal adenomas. Targeted mental health interventions may play a crucial role in alleviating this health burden and enhancing overall population health. more...

Radiotherapy is a method of treating cancer through radiation aimed at killing cancer cells or inhibiting their growth. However, radiotherapy has numerous side effects because it kills tumors while causing damage to normal cells or tissues. The literature shows that radiation can cause damage to heart tissue. This study found that engineered yeast that produced butyrate can maintain small intestinal barrier function by recovering GPR109A to reduce intestinal damage caused by abdominal irradiation in mice. We unexpectedly found that engineered yeast could mitigate irradiation-induced heart damage via the gut-heart axis. Mechanistically, engineered yeast enhanced taurine and nicotinamide metabolism by increasing the relative abundance of Akkermansia and Lachnospiraceae_NK4A136; then, yeast modulated cardiac function by activating the Sgcg and Nppa genes to attenuate cardiac damage induced by abdominal irradiation. Finally, we confirmed that engineered yeast mitigated cardiac damage caused by total body irradiation, which protected other vital organs through the intestinal tract. This study has a profound impact on cancer treatment, the emergence of engineered yeast will alleviate radiotherapy side effects and benefit patients. more...

BackgroundUlcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with increasing incidence worldwide. Growing evidence highlights the pivotal role of nicotinamide adenine dinucleotide (NAD+) metabolism in UC pathogenesis, prompting our investigation into the subtype-specific molecular underpinnings and diagnostic potential of NAD+ metabolism-related genes (NMRGs).MethodsTranscriptome data from UC patients and healthy controls were downloaded from the GEO database, specifically GSE75214 and GSE87466. We performed unsupervised clustering based on differentially expressed NAD+ metabolism-related genes (DE-NMRGs) to classify UC cases into distinct subtypes. GSEA and GSVA identified potential biological pathways active within these subtypes, while the CIBERSORT algorithm assessed differential immune cell infiltration. Weighted gene co-expression network analysis (WGCNA) combined with differential gene expression analysis was used to pinpoint specific NMRGs in UC. Robust gene features for subtyping and diagnosis were selected using two machine learning algorithms. Nomograms were constructed and their effectiveness was evaluated using receiver operating characteristic (ROC) curves. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to verify gene expression in cell lines.ResultsIn our study, UC patients were classified into two subtypes based on DE-NMRGs expression levels, with Cluster A exhibiting enhanced self-repair capabilities during inflammatory responses and Cluster B showing greater inflammation and tissue damage. Through comprehensive bioinformatics analyses, we identified four key biomarkers (AOX1, NAMPT, NNMT, PTGS2) for UC subtyping, and two (NNMT, PARP9) for its diagnosis. These biomarkers are closely linked to various immune cells within the UC microenvironment, particularly NAMPT and PTGS2, which were strongly associated with neutrophil infiltration. Nomograms developed for subtyping and diagnosis demonstrated high predictive accuracy, achieving area under curve (AUC) values up to 0.989 and 0.997 in the training set and up to 0.998 and 0.988 in validation sets. RT-qPCR validation showed a significant upregulation of NNMT and PARP9 in inflamed versus normal colonic epithelia, underscoring their diagnostic relevance.ConclusionOur study reveals two NAD+ subtypes in UC, identifying four biomarkers for subtyping and two for diagnosis. These findings could suggest potential therapeutic targets and contribute to advancing personalized treatment strategies for UC, potentially improving patient outcomes. more...

Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Assisted by Alphafold2(AlphaFold-Multimer), we developed a humanized CD40 agonistic antibody that exhibits activation only in the presence of cross-linking. It also demonstrates that the current AlphaFold2(AlphaFold2-Multimer) can predict antibody-antigen complexes. Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E). Building upon this, we created a novel bispecific antibody (anti-PD-L1/CD40 bispecific antibody, referred to as ''BA4415'') designed to activate CD40 signaling specifically in the context of PD-L1 while simultaneously blocking PD-1/PD-L1 signaling. Results from functional evaluations using effector cells revealed the superior biological activity of BA4415 compared to the combination of each monoclonal antibody. BA4415 demonstrated the ability to enhance T-cell cytokine release in vitro assays, exhibiting superior functional attributes compared to the anti-PD-L1 antibody. Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors. more...

Acute pancreatitis (AP), a condition marked by its swift progression, substantial individual discrepancies, and profound concealment, poses a formidable challenge. Within its severe form, known as severe acute pancreatitis (SAP), the disease assumes an even more prevalent status, often entwined with dire complications such as pancreatic abscess, circulatory shock, and the direst of all, multiple organ failure. Regrettably, the conjunction of SAP with gastric mucosal exfoliation culminating in massive hemorrhage remains an exceptionally rare phenomenon within the clinical realm. This study delves into a retrospective analysis of a singular, yet remarkable clinical case, where SAP's therapeutic odyssey unexpectedly led to gastric mucosa stripping and catastrophic gastrointestinal bleeding. This paper endeavors to unravel the diagnostic intricacies, explore the treatment modalities, and prognosticate the outcome, all with the ultimate aim of fostering a heightened clinical vigilance and fostering a novel, nuanced understanding of SAP's exceptional complications within the intensive care arena. Furthermore, this study aspires to serve as a beacon of reference, illuminating the path for clinical practitioners confronted with such elusive yet critical scenarios. more...

ObjectivesThe study aimed to explore associations of the comprehensive dietary antioxidant index (CDAI) with femur bone mineral density (BMD) and risk of osteoporosis in American postmenopausal women.MethodsA total of 2,862 participants from the National Health and Nutrition Examination Survey were included in this study. The relationship between the CDAI and femur BMD was assessed via weighted multivariate linear regression model. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between the CDAI and the risk of osteoporosis was assessed by weighted logistic regression model. Moreover, the nonlinear relationship was also characterized by smooth curve fitting and weighted generalized additive model. The two-piecewise linear regression models and a recursive algorithm were used to find the inflection points.ResultsAfter adjusting all covariates, the weighted multivariable linear regression models demonstrated that the CDAI was positively correlated with femur BMD. Moreover, there were nonlinear relationships between CDAI and risk of osteoporosis. In the age below 70 years, the risk of osteoporosis decreased to 60.6 and 92.2% with each unit increase in CDAI value before and after the inflection point (−2.268), respectively. In the 70 years or older, the risk of osteoporosis decreased to 80.4% with each unit increase in CDAI value before the inflection point (−1.479). The weighted logistic regression model demonstrated that compared to the first tertile of CDAI, the highest tertile of CDAI was significantly associated with a lower risk of osteoporosis, with ORs of 0.375 (95% CI 0.284, 0.495) for individuals under the age of 70, and 0.626 (95% CI 0.481, 0.814) for individuals aged 70 or above.ConclusionThe present study indicated that postmenopausal women with higher CDAI scores have a lower risk of osteoporosis. In addition, there is a non-linear relationship between CDAI and the risk of osteoporosis. This finding suggests that the adoption of a comprehensive antioxidant dietary structure represented by high CDAI scores may have a positive impact on the prevention and management of osteoporosis in postmenopausal women. Particularly for those with lower CDAI scores, early screening and intervention for osteoporosis may be necessary. more...

Background: In several studies of head and neck squamous cell carcinoma (HNSC), the regulation of tumorigenesis and therapeutic sensitivity by pyroptosis has been observed. However, a systematic analysis of gasdermin family members (GSDMs, including GSDMA/B/C/D/E and PJVK), which are deterministic executors of pyroptosis, has not yet been reported in HNSC. Methods: We performed comprehensive analyses of the expression profile, prognostic value, regulatory network, and immune infiltration modulation of GSDMs in HNSC on the basis of a computational approach and bioinformatic analysis of publicly available datasets. Results: A total of 18.65 % (94/504) of HNSC patients harbored GSDM alterations, with the most dominant type being amplification. Compared with those in normal tissues, the mRNA and protein levels of GSDMs, especially GSDMD/E, were commonly elevated in HNSC (P more...

The exposure time in acute toxicology experiments can affect not only the accuracy of toxicity data such as lethal concentration 50 (LC50) at the species level, but also the dose-effect relationship establishment of pollutants at the community level. However, previous study on the time dependence of heavy metals is still lacking, and its impact on environmental criteria derivation and risk assessment has not been quantitatively characterized. In this study, the relationship between exposure time and toxicology data of four heavy metals (Cd, Cr, Cu, and Zn) was studied. Time-dependent species sensitivity distribution (SSD) surfaces of Chinese native freshwater species were established. The ecological indicators, including the hazardous concentration for 5% of species (HC5) values and water quality criteria (WQC), were derived for different exposure times. Finally, the dynamic ecological risks of heavy metals in major Chinese water basins were evaluated. The results indicated a linear negative correlation between the acute toxicity data of heavy metals and exposure time, and a decrease in derived HC5 values as exposure time increased. Compared to one-day experiments, the HC5 values for Cd, Cr, Cu, and Zn derived by four-day experiments decreased by 80.87 %, 74.44 %, 67.51 %, and 65.81 %, respectively. Based on the time dependence of the toxicity data, the WQCs for Cd and Cu derived in this study were found to be more stringent than the existing WQCs in China. Dynamic ecological risk assessments revealed that Cu poses a higher ecological risk than the other metals, particularly in the Songhua River, with risk values ranging from 40.4 % to 49.6 %. Therefore, the time dependence of metals should be fully considered in the formulation of acute WQC so as to provide better protection for the water ecosystem security. more...

Objective To develop and validate a risk prediction model related to inflammatory and nutritional indexes for postoperative pulmonary infection (POI) after radical colorectal cancer (CRC) surgery.Design Cross-sectional study.Participants This study analysed 866 CRC patients after radical surgery at a tertiary hospital in China.Methods Univariable and multivariable logistic regression (LR) analyses were used to explore influence factors of POI. Predictive models were constructed using LR, random forest, support vector machine, K-nearest neighbours, naive Bayes and XGBoost. The LR model was used to generate a nomogram for POI prediction. The discrimination and calibration of the nomogram were assessed using receiver operating characteristic (ROC) curves and calibration curves. The contributions of inflammatory and nutritional indexes to the nomogram were evaluated through Net Reclassification Improvement and integrated discrimination improvement, while clinical practicability was assessed using decision curve analysis.Main outcome measures POI during hospitalisation.Results Independent factors identified from multivariable LR for prediction POI included age, respiratory disease, Systemic Inflammation Response Index, albumin-to-globulin ratio, operative method and operative duration. The LR model demonstrated the best performance, with an area under the ROC curve of 0.773 (95% CI: 0.674 to 0.872). The nomogram has good differentiation ability, calibration and net benefit. Incorporating inflammatory and nutritional indexes into the nomogram enhanced predictive value compared with models excluding either factor.Conclusion The nomogram related to inflammatory and nutritional indexes may represent a promising tool for predicting POI after radical surgery in CRC patients. more...

Abstract Focus on the implications of common perioperative drugs for mitochondrial quality control and their subsequent impact on the overall physiological condition has been increasing. This review discusses the effects of perioperative drugs, such as intravenous and inhaled anesthetics, analgesics, local anesthetics on mitochondrial quality and their underlying mechanisms. These drugs influence mitochondrial properties, including morphology, dynamics, energy metabolism, and protein expression, thereby affecting the clinical outcomes of patients undergoing surgery. Such effects can be either protective or detrimental and are contingent upon multiple variables such as the specific drug used, dosage, application timing, and the patient's overall health status. Recognizing the effects of these perioperative drugs on mitochondrial quality control is crucial to selecting safer anesthetic protocols, reducing postoperative complications, enhancing postoperative recovery, and gaining insights into the development of innovative treatment methodologies and optimization of perioperative care. more...

Abstract Cervical cancer is a kind of tumor related to chronic HPV infection. Currently, the treatment of cervical cancer is guided mainly by clinicopathological factors. The role of tumor microenvironment in the prognosis and treatment of cervical cancer has been ignored. We aimed to use bioinformatics to identify the molecular subtypes in cervical cancer and construct a predictive nomogram combining a matrix-immune signature (MIS) and clinicopathological factors to support treatment decisions. Two cervical cancer subtypes with different prognoses were identified based on matrix- and immune-genes in TCGA-CESC. The MIS was developed using Cox regression and Lasso algorithm and verified in the Cancer Genome Characterization Initiative (CGCI) using time-dependent receiver operating characteristic (ROC) curve analysis. Multivariable analysis identified lymph node metastases, lymphovascular space invasion, and the MIS as independent prognostic factors, which were used to construct the predictive nomogram. The areas under the ROC curve of the model were 0.872, 0.879, and 0.803 for the 1-, 3-, and 5-year periods, respectively. The C-index was 0.845. Calibration curves confirmed the excellent prognosis prediction of the nomogram. The nomogram indicted a 3-year survival rate of > 90% in patients with a total score > 110.1. The constructed predictive nomogram has significant implications for prognostic assessment and treatment selection in cervical cancer. more...

Abstract Systemic infection with Candida albicans poses a significant risk for people with weakened immune systems and carries a mortality rate of up to 60%. However, current therapeutic options have several limitations, including increasing drug tolerance, notable off-target effects, and severe adverse reactions. Over the past four decades, the progress in developing drugs to treat Candida albicans infections has been sluggish. This comprehensive review addresses the limitations of existing drugs and summarizes the efforts made toward redesigning and innovating existing or novel drugs through nanotechnology. The discussion explores the potential applications of nanomedicine in Candida albicans infections from four perspectives: nano-preparations for anti-biofilm therapy, innovative formulations of “old drugs” targeting the cell membrane and cell wall, reverse drug resistance therapy targeting subcellular organelles, and virulence deprivation therapy leveraging the unique polymorphism of Candida albicans. These therapeutic approaches are promising to address the above challenges and enhance the efficiency of drug development for Candida albicans infections. By harnessing nano-preparation technology to transform existing and preclinical drugs, novel therapeutic targets will be uncovered, providing effective solutions and broader horizons to improve patient survival rates. Graphical abstracts more...

Parameters of foam penetration in earth pressure balance (EPB) shield tunnelling, such as permeability coefficients and penetration distances, significantly impact tunnel face stability. However, existing studies have faced inaccuracies in analysing these parameters due to imitations in experimental methods. This study addresses this issue by employing enhanced methods for a more precise analysis of foam penetration. Experiments involving three distinct sand types (coarse, medium, and fine) and three foam expansion ratios (FER) (10, 15, and 20) are conducted using a modified model test setup. Benefiting from a novel computer vision-based method, the model test outcomes unveil two distinct foam penetration paths: liquid migration (Lw) and bubble migration (Lf). Three penetration phases — namely, injection, blockage & drainage, and breakage — are identified based on Lw and Lf variations. The initial “injection” phase conforms to Darcy's law and is amenable to mathematical description. The foam with FER of 15 has the maximum viscosity and, hence the Lf and permeability in the penetration tests with FER of 15 are the lowest in the same sand. The bubble size distribution of foam with different FER shows minor differences. Nevertheless, the characteristics of foam penetration vary due to the distinct particle size distribution (PSD) of different sands. Foam penetration creates low-permeability layers in both medium and fine sands due to the larger bubble size of the foam compared to the estimated pore sizes of medium and fine sands. While the coarse sand results in a different situation due to its large pore size. The distinctive characteristics of foam penetration in different sand strata are notably shaped by FER, PSD, and pore size distributions. These insights shed light on the complex interactions during foam penetration at the tunnel face, contributing valuable knowledge to EPB shield tunnelling practices. more...

Abstract Prediabetes and related complications constitute significant public health burdens globally. As an indicator closely associated with abnormal glucose metabolism and atherosclerosis, the utility of Pulse Pressure Index (PPI) as a prediabetes risk marker has not been explored. We performed a retrospective cohort analysis to investigate this putative association between PPI and prediabetes hazard. Our analysis encompassed 183,517 Chinese adults ≥ 20 years registered within the Rich Healthcare Group 2010–2016. PPI was defined as (systolic blood pressure − diastolic blood pressure)/systolic blood pressure. The relationship between PPI and prediabetes risk was assessed via Cox proportional hazards regression modeling. Non-linearity evaluations applied cubic spline fitting approaches alongside smooth curve analysis. Inflection points of PPI concerning prediabetes hazard were determined using two-piecewise Cox models. During a median follow-up of 3 years (2.17–3.96 years), new-onset prediabetes was documented in 20,607 patients (11.23%). Multivariate regression analysis showed that PPI was an independent risk factor for prediabetes, and the risk of prediabetes increased by 0.6% for every 1% increase in PPI (Hazard Ratio [HR]: 1.006, 95% Confidence Interval [CI] 1.004–1.008, P more...

Abstract Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases. more...

Abstract Improving fattening efficiency is an important goal of breeding commercial pigs, especially for the large-scale pig farms. Fattening efficiency index (FEI) can be used to evaluate the fattening efficiency. The aim of this study was to identify the factors affecting the fattening efficiency of commercial pigs in large-scale pig farms and further study the impact of these factors on the production performance of commercial pig batches at different production levels. The data of 9,570 batches was mainly consisted of four parts (farm facilities, general information of piglets, production performance of nursery pigs and finishing pigs). A total of 28 variables were evaluated by the multi-variable linear regression models. The differences in production factors significantly correlated with FEI at piglets-finishing stage were compared among high-performing (HP), moderate-performing (MP), and low-performing (LP) batches of commercial pigs during the nursery and finishing stage. Among the 28 variables, 18 were significantly correlated with fattening efficiency (P more...

The covered karst collapse has the characteristics of concealment, suddenness, uncertainty, and mechanism complexity, which leads to its prevention and treatment more difficult. In the process of covered karst collapse, soil caves formed in the overlying soil, develop and expand until the surface collapse. Numerical simulation such as the finite element method is an effective method of soil cave collapse; however, the finite element method can not solve the problem of large deformation of rock mass such as particle migration and soil collapse. Based on the analysis of the geological conditions of karst collapse in Jiangshan city, Zhejiang province, this study used the particle flow code (PFC) to simulate the formation process of covered karst soil cave and then to reveal the displacement of special soil particles, the development trend of cracks, and the change of system imbalance force on a micro level. The multi-field variation characteristics of the formation of covered karst soil cave under external force conditions were reproduced. The results show that the development process of karst soil cave could be summarized into three stages including crack generation, connected surface formation, and particle peeling. As the karst soil cave began to develop, there was a good consistency among the displacement curve of soil particles, the penetration degree of cracks, and the unbalance force, and the vertical expansion speed was larger than the horizontal speed. The critical flow velocity of the initial soil cavity is 0.104 cm/s when the overburden soil is clay. This study can provide basic information for the treatment of karst collapse. more...

Abstract Background In Taiwan, residents with and without dementia mostly co-live in long-term care facilities. The behavioral and psychiatric symptoms of dementia residents often pose challenges for others living together. This study explored the symbiotic experiences of residents without dementia co-living with those with dementia in long-term care facilities in Taiwan to present their experiences of living together. Methods This was a cross-sectional descriptive study with a phenomenological design. Semi-structured face-to-face interviews were conducted with 30 residents without dementia from three long-term care institutions in Taiwan. Colaizzi’s data processing steps were used for analysis. Results The analysis of interview transcripts revealed that the experiences of residents who lived with those with dementia were that of a “symbiosis.” Three core themes were found: “the impact of co-living,” “facing difficulties and coping,” and “companionship and reciprocity.” This study showed that residents without dementia may be affected by the behavioral and psychiatric symptoms of residents with dementia when co-living in long-term care facilities. However, there are also positive and mutually beneficial interactions between them. By helping people with dementia in their daily lives, residents without dementia feel happy and accomplished and their self-worth is enhanced. Furthermore, residents with dementia have more opportunities for social engagement and co-living interactions. Conclusion These results can guide long-term care facilities without special care dementia units to support residents without dementia, reduce the interference of the behavioral and psychiatric symptoms of residents with dementia, and promote mutual benefits. However, these findings warrant further investigation. more...

Abstract Mitochondria are crucial sites for protein quality control within cells. When mitochondrial stress is triggered by protein misfolding, it can accelerate abnormal protein aggregation, potentially inducing various diseases. This study developed a cascade‐responsive sensor, named AggHX, to monitor the microenvironment of protein aggregation induced by zinc (II) ions and the accompanying mitochondrial dysfunction. The AggHX consists of two key components: (1) A Zn2+ recognition group for triggering a fluorescent enhance response, and (2) a near‐infrared BODIPY scaffold that detects viscosity changes in cell aggregation via HaloTag. This sensor's mechanism of action is elucidated through photochemical and biochemical characterizations. To further investigate the relationship between protein aggregation and mitochondrial homeostasis, we employ fluorescence lifetime imaging microscopy to assess viscosity changes in protein aggregates under intracellular Zn2+ stress. This research provides insights into the dynamic behavior and spatial distribution of protein aggregates and mitochondria, contributing to a deeper understanding of their physiological roles in cellular processes and potential implications in disease pathology. more...

Abstract Emerging evidence recognizes aberrant glycosylation as the malignant characteristics of cancer cells, but little is known about glycogenes’ roles in endometrial carcinoma (EC), especially the most aggressive subtype carrying TP53 mutations. Using unsupervised hierarchical clustering, an 11‐glycogene cluster is identified to distinguish an EC subtype associated with frequent TP53 mutation and worse prognosis. Among them, MGAT4A (alpha‐1,3‐mannosyl‐glycoprotein 4‐β‐N‐acetylglucosaminyltransferase A) emerges as the most consistently overexpressed glycogene, contributing to EC aggressiveness. In the presence of galectin‐9, MGAT4A increases EC cell proliferation and invasion via promoting glucose metabolism. N‐glycoproteomics further revealed GLUT1, a glucose transporter, as a glycoprotein modified by MGAT4A. Binding of galectin‐9 to the MGAT4A‐branched N‐glycan on GLUT1 enhances its cell membrane distribution, leading to glucose uptake increase. In addition, oncogenic mutations of TP53 gene in EC cells upregulate MGAT4A expression by disrupting the regulatory oversight exerted by wild‐type p53 on tumor‐suppressive miRNAs, including miR‐34a and miR‐449a/b. The findings highlight a new molecular mechanism involving MGAT4A‐regulated N‐glycosylation on the key regulator of glucose metabolism in p53 mutants‐driven EC aggressiveness, which may provide a strategic avenue to combat advanced EC. more...

Abstract Unfractionated heparin (UFH) is commonly used as an anticoagulant in sepsis treatment and has recently been found to have non‐anticoagulant effects, but underlying mechanisms remain unclear. This retrospective clinical data showed that UFH has significant protective effects in sepsis compared to low‐molecular‐weight heparin and enoxaparin, indicating potential benefits of its non‐anticoagulant properties. Recombinant protein chip screening, surface plasmon resonance, and molecular docking data demonstrated that UFH specifically bound to the cytoplasmic Drp1 protein through its zone 2 non‐anticoagulant segment. In‐vitro experiments verified that UFH's specific binding to Drp1 suppressed Drp1 translocation to mitochondria following “sepsis” challenge, thereby improving mitochondrial morphology, function and metabolism in vascular endothelial cells. Consequently, UHF comprehensively protected mitochondrial quality, thus reducing vascular leakage and improving prognosis in a sepsis rat model. These findings highlight the potential of UFH as a sepsis treatment strategy targeting non‐anticoagulation mechanism. more...

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets epithelial cells in the respiratory tract, triggering an acute proinflammatory response and chronic lung inflammation. Probiotic supplementation has shown promise in reducing the nasopharyngeal SARS-CoV-2 viral load, diminishing symptom frequency and duration, and mitigating inflammation; thus, it is a potential strategy for treating coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 infection. In this study, we evaluated the effects of the oral administration of the Lactobacillus plantarum GUANKE strain, a gram-positive bacterium originally isolated from a healthy individual, on SARS-CoV-2 infection in a human ACE2 transgenic mouse model. We found that GUANKE significantly reduced inflammatory cell infiltration and pulmonary interstitial exudation in mice. The transcription of CCL2, TNFA, IL1B, IL6, and IL17C in the lungs was reduced. The protein levels of TNF-α, IL-1β, IL-6, and IL-17 in the lungs were significantly lower in GUANKE-treated mice than in control mice. The viral load in GUANKE-treated mice was lower than that in saline-treated mice, although this difference did not reach statistical significance. L. plantarum GUANKE can decrease SARS-CoV-2-induced lung inflammation in mice, suggesting its potential for use as an agent for treating SARS-CoV-2 infection.IMPORTANCEMost otherwise healthy individuals develop only mild or moderate symptoms of coronavirus disease 2019 (COVID-19) caused by current strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and virus replication is mainly confined to the upper respiratory tract; however, the virus can infect the lower respiratory tract and promote inflammation. Probiotic supplementation has been shown to reduce nasopharyngeal SARS-CoV-2 viral load, reduce the overall number and duration of symptoms, and attenuate inflammation in clinical trials. We showed that a novel L. plantarum GUANKE strain alleviated SARS-CoV-2-induced pneumonia in mice. The transcription and production of inflammatory cytokines were suppressed, and GUANKE moderately reduced the viral load. L. plantarum GUANKE has the potential to become a candidate drug for the treatment of COVID-19 or other viral respiratory infections. more...

ABSTRACTConstructing synthetic microbial consortia is a challenging task but holds enormous potential for various applications. Our previous droplet-based microfluidic approach allowed for the isolation of bacteria that could utilize metabolites from an engineered bacterium BsS-RS06551 with anti-obesity potential, facilitating the construction of synthetic microbial consortia. Here, we identified a strain of Bifidobacterium pseudocatenulatum JJ3 that interacted with BsS-RS06551, and in vitro coculture showed that BsS-RS06551 was likely to interact with JJ3 through five dipeptides. Pathway analysis revealed that the vitamin B6 metabolism pathway was enriched in the coculture of BsS-RS06551 and JJ3 compared with the individual culture of BsS-RS06551. Additionally, we confirmed that the administration of JJ3 significantly alleviated obesity and related disorders in mice fed a high-fat diet. Notably, continuous ingestion of the synthetic microbial consortium comprising BsS-RS06551 and JJ3 not only exhibited a more pronounced impact on alleviating obesity compared to the individual administration of BsS-RS06551 or JJ3 but also enriched the population of Bifidobacterium longum and perturbed the vitamin B6 metabolism pathway in the gut. Synthetic microbial consortia represent a promising frontier for synthetic biology, and our strategy provides guidance for constructing and applying such consortia. more...

ABSTRACTIntestinal microbiota dysbiosis and metabolic disruption are considered essential characteristics in inflammatory bowel disorders (IBD). Reasonable butyrate supplementation can help patients regulate intestinal flora structure and promote mucosal repair. Here, to restore microbiota homeostasis and butyrate levels in the patient’s intestines, we modified the genome of Saccharomyces cerevisiae to produce butyrate. We precisely regulated the relevant metabolic pathways to enable the yeast to produce sufficient butyrate in the intestine with uneven oxygen distribution. A series of engineered strains with different butyrate synthesis abilities was constructed to meet the needs of different patients, and the strongest can reach 1.8 g/L title of butyrate. Next, this series of strains was used to co-cultivate with gut microbiota collected from patients with mild-to-moderate ulcerative colitis. After receiving treatment with engineered strains, the gut microbiota and the butyrate content have been regulated to varying degrees depending on the synthetic ability of the strain. The abundance of probiotics such as Bifidobacterium and Lactobacillus increased, while the abundance of harmful bacteria like Candidatus Bacilloplasma decreased. Meanwhile, the series of butyrate-producing yeast significantly improved trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice by restoring butyrate content. Among the series of engineered yeasts, the strain with the second-highest butyrate synthesis ability showed the most significant regulatory and the best therapeutic effect on the gut microbiota from IBD patients and the colitis mouse model. This study confirmed the existence of a therapeutic window for IBD treatment by supplementing butyrate, and it is necessary to restore butyrate levels according to the actual situation of patients to restore intestinal flora. more...