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In the process of non-isothermal deformation of titanium alloy, the microstructure evolution is very complicated, which has direct effect on the properties of the titanium alloy. This study examines the effects of pure cooling and coupled deformation and cooling at the initial temperature of 940 °C and the cooling rate of 5,50 °C/s, and the strain rate of 0.1, 10s−1 respectively, on the microstructure evolution of Ti–6Al-2.5Mo-1.5Cr-0.5Fe-0.3Si alloy (TC6) were investigated. The microstructure after cooling was characterised, and the mechanism of non-isothermal deformation on microstructure evolution and the mechanism of secondary α phase (αs) precipitation were revealed. The results show that the secondary α phase precipitates in large quantities after cooling to a certain temperature, and the secondary precipitated has an obvious inhibiting effect on the diffusion growth of the primary α phase (αp). Secondary α phases can be divided into lamellar and equiaxial types. When the temperature drops sharply, the fine secondary α phase can be precipitated directly from the β matrix. Due to the large number of dislocations generated by the deformation, many small secondary α phases can be generated during the rapid cooling process. The orientation relationship between α phase and β matrix is destroyed by the deformation, resulting in a weakening of the anisotropy, so that the secondary α phase remains equiaxial during the precipitation process.

Abstract Background While TB-related mortality in the US declined four-fold from 1990 to 2019, country-level estimates of TB burden obscure within-state racial heterogeneity and changes in TB burden over time. In sixteen US Southern States and Washington DC, the effects of health inequities engendered by Jim-Crow laws enacted from the late 1800s to the 1960s have not been evaluated for TB-related mortality. We, therefore, sought to compare TB mortality rates and annualized rate of change (AROC) between 1990 and 2019 in former Jim-Crow vs. non-Jim-Crow states to help guide response efforts and inform resource prioritization to improve racial equity. Methods We evaluated whether TB-related mortality varied over time, from 1990 to 2019, between states that have a history of enacting Jim-Crow laws vs. states with no such history using estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). TB mortality per 100,000 population and bootstrap 95% uncertainty intervals (UIs) were modeled using the Cause of Death Ensemble model (CODEm) framework with varying combinations of predictive covariates. For changes over time, we present age-standardized AROC as the percent difference in the natural logarithm of the rate in 1990 and 2019 divided by 30 (i.e., 100*[ln(2019 Rate/1990 Rate)/(30)) and the corresponding 95% UIs. Results TB-related mortality in all US states declined between 1990 and 2019. From 1990 to 2019, most former Jim-Crow states had higher mortality rates than states that did not enact Jim-Crow laws. The most significant decline in TB mortality was in Washington DC, with a six-fold decline from 2.69 (2.46–2.96) per 100,000 population in 1990 to 0.45(0.37–0.55) in 2019, corresponding to an AROC of -0.83% (-0.86;-0.79). The lowest decline was in Iowa, from 0.30 (0.27–0.33) to 0.09 (0.07–0.11) (AROC: -0.70% (-0.76; -0.63)). Eleven of the 16 states and Washington DC in the third tertile of TB mortality rate in 1990 (range 0.81–2.69) had a history of Jim-Crow laws, whereas none of the 17 states in the first tertile (range 0.30–0.51) had such history. Conversely, mortality decreased relatively slowly in former Jim-Crow states than in non-Jim-Crow states. Conclusions Even though the 1964 Civil Rights Act dismantled Jim-Crow statutes, racial inequities in TB burden experienced by past generations may still be felt in subsequent generations. Understanding the role of structural racism at the intersection of science and medicine shows the complex ways historical laws, such as Jim-Crow laws, continue to negatively impact health outcomes and warn of future dangers, such as COVID-19, to avoid.

Abstract Under the condition of weak grid, the phase‐locked loop (PLL) is one of the main reasons for the sub‐synchronous oscillation of the grid‐connected inverter. Therefore, it is necessary to identify the PLL parameters of the grid‐connected inverter for the analysis of the inverter operating performance. This paper uses the sequence impedance model and measured impedance data of grid‐connected inverter to construct the identification function for parameter identification of PLL, and the function is calculated by particle swarm optimization algorithm to overcome the nonlinear problem of sequence impedance model. In addition, the identification frequency band is selected based on PLL parameter sensitivity to improve the parameter identification accuracy under the same impedance measurement error. At different frequencies, the positive correlation between the sensitivity of the PLL parameters and the identification accuracy is proven to determine the definite frequency band for PLL parameter identification of grid‐connected inverter. Finally, the feasibility and effectiveness of the above research are verified by simulation and semi‐physical experiments.

An edge-coloring of a graph $ G $ with colors $ 1, \ldots, t $ is an interval $ t $-coloring if all colors are used and the colors of edges incident to each vertex of $ G $ are distinct and form an interval of integers. A graph $ G $ is interval colorable if it has an interval $ t $-coloring for some positive integer $ t $. For an interval colorable graph $ G $, the least and the greatest values of $ t $ for which $ G $ has an interval $ t $-coloring are denoted by $ w(G) $ and $ W(G) $. Let $ G $ be a graph with vertex set $ V(G) = \{u_1, \ldots, u_{m}\} $, $ m\geq2 $, and let $ h_m = (H_i)_{i\in\{1, \ldots, m\}} $ be a sequence of vertex-disjoint with $ V(H_i) = \{x_1^{(i)}, \ldots, x_{n_i}^{(i)}\} $, $ n_i\geq 1 $. The generalized lexicographic products $ G[h_m] $ of $ G $ and $ h_m $ is a simple graph with vertex set $ \cup_{i = 1}^{m}V(H_i) $, in which $ x_p^{(i)} $ is adjacent to $ x_q^{(j)} $ if and only if either $ u_i = u_j $ and $ x_p^{(i)}x_q^{(i)}\in E(H_i) $ or $ u_iu_j\in E(G) $. In this paper, we obtain several sufficient conditions for the generalized lexicographic product $ G[h_m] $ to have interval colorings. We also present some sharp bounds on $ w(G[h_m]) $ and $ W(G[h_m]) $ of $ G[h_m] $.

Despite accumulating evidence for the adverse effects of magnesium (Mg) deficiency or excess on grain crops, how Mg imbalance affects plant growth and potassium (K) and calcium (Ca) nutrition in vegetable crops is still unclear. The aim of this study was to ascertain the response of plant growth, nutrient uptake and Mg-K-Ca interactions in tomato (Solanum lycopersicum L.) to various levels of Mg supply. The growth parameters and nutrient contents of hydroponic plants were measured under the Mg levels of 0, 0.5, 1.0, 1.5 and 3.0 mmol/L Mg2+ from seedling to fruit ripening stage. Results showed that both Mg deficiency (0 mmol/L Mg2+) and excess (3.0 mmol/L Mg2+) negatively affected shoot and root growth, leading to a noticeable decrease in total plant biomass across different stages (41.2-52.8% and 17.7-38.3%, respectively). Mg imbalance additionally altered leaf morphology and disrupted chloroplast structure. As a consequence of increased Mg levels, the Mg contents in various plant organs increased, whereas the Ca contents decreased substantially. The trend of K contents under different Mg levels was dependent on the plant growth stage. Although Mg levels did not prominently affect plant K contents during the early growth stage, they were significantly negatively correlated in the leaves and positively correlated in the fruit during the late growth stage. When translocated from roots to aboveground organs, Mg and Ca were mainly distributed in the leaves, with K preferentially distributed in the fruit. The findings of this study underscore that the symptoms of Mg imbalance generally develop from middle leaves in vegetable crops, exemplified by tomato, which is different from the pattern in common grain crops. Vegetable production necessitates nutrient supply for the middle and upper parts of Mg-deficient plants, and attention should be paid to the nutritional imbalance of Ca and K in plants under excessive Mg supply.

Abstract A strong driving force for charge separation and transfer in semiconductors is essential for designing effective photoelectrodes for solar energy conversion. While defect engineering and polarization alignment can enhance this process, their potential interference within a photoelectrode remains unclear. Here we show that oxygen vacancies in bismuth vanadate (BiVO4) can create defect dipoles due to a disruption of symmetry. The modified photoelectrodes exhibit a strong correlation between charge separation and transfer capability and external electrical poling, which is not seen in unmodified samples. Applying poling at −150 Volt boosts charge separation and transfer efficiency to over 90%. A photocurrent density of 6.3 mA cm−2 is achieved on the photoelectrode after loading with a nickel-iron oxide-based cocatalyst. Furthermore, using generated holes for methane partial oxidation can produce methanol with a Faradaic efficiency of approximately 6%. These findings provide valuable insights into the photoelectrocatalytic conversion of greenhouse gases into valuable chemical products.

Abstract Microplastics (MPs) can enter the body via plastic products. Given modern plastic exposure, we seek to assess MP exposure in large populations through epidemiological tools. In this quasi-experimental study, every participant filled out a questionnaire, and those who satisfied any of the following requirements were not allowed to continue in the study: Diabetes, ulcerative colitis, Crohn’s disease, infectious diseases. Participants in the exposure and control groups were provided three hot meals in disposable plastic tableware (DPT) (n = 30) or non-DPT (n = 30), respectively. After a month of observation, individuals in the exposure group discontinued the three meals provided in DPT (n = 27) for 1 month as the post-exposure group. Each Participant in the three groups received a questionnaire survey and fecal sample collection. We compared the differences in MP levels between different groups and used the Bland–Altman analysis method to evaluate the consistency of the results obtained by different measurement methods. Statistically significant differences in the total quantity (P (0.80 matching degree) = 0.020; P (0.65 matching degree)

Abstract Background Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for upper gastrointestinal cancers (UGICs). However, durable clinical responses only existed in a minority of patients. We evaluated evidence predicting survival benefits to identify the optimal population followed by ICI-based therapy. Methods A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science to identify clinical trials for UGICs with ICI-based therapy. The outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation System (GRADE). Results Thirty-six studies comprising 12,440 patients were included for quantitative synthesis. Patients with PD-L1-positive (OR = 2.08, p

Abstract The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

In order to reduce the toxicity of inorganic arsenic and improve the bioavailability of selenium, this study used yeast to convert inorganic selenium into synthesize selenium nanoparticles (SeNPs). Through the screening of seven probiotic yeast strains, Saccharomyces cerevisiae ATCC 18824 was finally screened as the best nano-selenium synthesized strain and its optimal nano-selenium synthesized conditions were established. The synthesized nano-selenium was observed and characterized in terms of structure and morphology using field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). In addition, the safety of nano-selenium was verified by feeding experiments in mice for 30 days. ATCC 18824 synthesized nano-selenium exhibited good dispersion, presenting Se0 nano selenium monoliths of uniform size and full spherical shape, and the Na2SeO3 addition was controlled to be optimal at 0.5~1.5 mg/mL, 30 °C, and 60~72 h incubation. It was also found that nano-selenium was synthesized intracellularly and gradually released over time, ultimately excreted within 72 hours. The 30 days feeding experiment showed that nano-selenium had no significant effect on body weight change, organ index, blood routine and biochemical analysis, and major organ tissues in mice, verifying the safety of nano-selenium. Based on the results of the study, the present study successfully developed yeast-derived nano-selenium milk tablets with good sensory evaluation and rich nutritional content of 12.67 μg/g, 16.67 μg/g, and 33.33 μg/g of selenium, its nutritional value was higher than part of the commercially available milk tablets, showing its potential as a novel and safe food additive in the food processing industry application value in the food processing industry.

This study aimed to investigate the effects of Changbaishan Ganoderma lucidum seed body polysaccharide beverage on the glucose and lipid metabolism of diabetic mice. High-fat diet combined with intraperitoneal injection of streptozotocin was used to establish a diabetic mouse model. A normal control group and a model control group were also set up. Metformin hydrochloride was used as a positive control. G. lucidum polysaccharide beverage was administered at different doses of low (L-GLB), medium (M-GLB), and high (H-GLB) to investigate its improvement effects on the glucose and lipid metabolism of diabetic mice. Fasting blood glucose, insulin resistance index, triglyceride, high- and low-density lipoprotein cholesterol, superoxide dismutase activity, and malondialdehyde were measured in the mice after receiving the G. lucidum polysaccharide beverage. Compared with those of the model group, the fasting blood glucose levels of the mice in the L-GLB, M-GLB, and H-GLB groups decreased by 35.46%, 39.05%, and 42.28%, respectively, and their homeostatic model assessment of insulin resistance decreased by 43.10%, 50.25%, and 54.18%, respectively (P

Abstract The nucleosome is one of the hallmarks of eukaryotes, a dynamic platform that supports many critical functions in eukaryotic cells. Here, we engineer the in vivo assembly of the nucleosome core in the model bacterium Escherichia coli. We show that bacterial chromosome DNA and eukaryotic histones can assemble in vivo to form nucleosome complexes with many features resembling those found in eukaryotes. The formation of nucleosomes in E. coli was visualized with atomic force microscopy and using tripartite split green fluorescent protein. Under a condition that moderate histones expression was induced at 1 µM IPTG, the nucleosome-forming bacterium is viable and has sustained growth for at least 110 divisions in longer-term growth experiments. It exhibits stable nucleosome formation, a consistent transcriptome across passages, and reduced growth fitness under stress conditions. In particular, the nucleosome arrays in E. coli genic regions have profiles resembling those in eukaryotic cells. The observed compatibility between the eukaryotic nucleosome and the bacterial chromosome machinery may reflect a prerequisite for bacteria-archaea union, providing insight into eukaryogenesis and the origin of the nucleosome.

Objective: Network analysis was used to explore the complex inter-relationships between social participation activities and depressive symptoms among the Chinese older population, and the differences in network structures among different genders, age groups, and urban-rural residency would be compared. Methods: Based on the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), 12,043 people aged 65 to 105 were included. The 10-item Center for Epidemiologic Studies Depression (CES-D) Scale was used to assess depressive symptoms and 10 types of social participation activities were collected, including housework, tai-chi, square dancing, visiting and interacting with friends, garden work, reading newspapers or books, raising domestic animals, playing cards or mahjong, watching TV or listening to radio, and organized social activities. R 4.2.1 software was used to estimate the network model and calculate strength and bridge strength. Results: 21.60% (2,601/12,043) of the participants had depressive symptoms. The total social participation score was negatively associated with depressive symptoms after adjusting for sociodemographic factors. The network of social participation and depressive symptoms showed that “D9 (Inability to get going)” and “S9 (Watching TV and/or listening to the radio)” had the highest strength within depressive symptoms and social participation communities, respectively, and “S1 (Housework)”, “S9 (Watching TV and/or listening to the radio)”, and “D5 (Hopelessness)” were the most prominent bridging nodes between the two communities. Most edges linking the two communities were negative. “S5 (Graden work) - D5 (Hopelessness)” and “S6 (Reading newspapers/books) - D4 (Everything was an effort)” were the top 2 strongest negative edges. Older females had significantly denser network structures than older males. Compared to older people aged 65–80, the age group 81–105 showed higher network global strength. Conclusions: This study provides novel insights into the complex relationships between social participation and depressive symptoms. Except for doing housework, other social participation activities were found to be protective for depression levels. Different nursing strategies should be taken to prevent and alleviate depressive symptoms for different genders and older people of different ages.

Abstract Background The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. Methods We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. Results A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). Conclusions After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. Trial registration Registration with PROSPERO for this meta-analysis is number CRD42024520509.

Abstract Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18–70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1–5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81–99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3–4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

Polycrystalline diamond compact (PDC) bit is one of the most widely used drill bits for improving the rate of penetration in deep oil and gas well and geothermal well. However, the dynamic rock fragmentation mechanics characteristics of PDC bits are still unclearly. A coupled fragmentation mechanics model of PDC cutter-rock interaction is established by combining the mixed fragmentation modes with dynamic strength. The coupling influence laws of cutter angle, cutting depth, dynamic strength ratio, breaking modes on the horizontal force coefficient (HFC), vertical force coefficient (VFC) and specific energy are analyzed. The model of this paper can optimize cutter inclination angle, cutting depth and minimum specific energy. With the increase of the cutter inclination angle, the dynamic VFC changes into two modes. The definition of the dynamic modes depends on the dynamic strength ratio. As the cutting angle increases, the cutting force increases. The cutting force increases nonlinearly with increasing cutting depth. The specific energy of rock fragmentation increases nonlinearly with increasing cutting depth. With the increase of dynamic strength, the specific energy of rock fragmentation increases nonlinearly. When the input-energy increases, the rate of penetration response is divided into three stages. The results have important guiding significance for the PDC bit design and drilling parameters optimization to increase the rate of penetration and the efficiency of exploration and development.

Abstract Background Chatbots can provide immediate assistance tailored to patients’ needs, making them suitable for sustained accompanying interventions. Nevertheless, there is currently no evidence regarding their acceptability by hypertensive patients and the factors influencing the acceptability in the real-world. Existing evaluation scales often focus solely on the technology itself, overlooking the patients’ perspective. Utilizing mixed methods can offer a more comprehensive exploration of influencing factors, laying the groundwork for the future integration of artificial intelligence in chronic disease management practices. Methods The mixed methods will provide a holistic view to understand the effectiveness and acceptability of the intervention. Participants will either receive the standard primary health care or obtain a chatbot speaker. The speaker can provide timely reminders, on-demand consultations, personalized data recording, knowledge broadcasts, as well as entertainment features such as telling jokes. The quantitative part will be conducted as a quasi-randomized controlled trial in community in Beijing. And the convergent design will be adopted. When patients use the speaker for 1 month, scales will be used to measure patients’ intention to use the speaker. At the same time, semi-structured interviews will be conducted to explore patients’ feelings and influencing factors of using speakers. Data on socio-demography, physical examination, blood pressure, acceptability and self-management behavior will be collected at baseline, as well as 1,3,6, and 12 months later. Furthermore, the cloud database will continuously collect patients’ interactions with the speaker. The primary outcome is the efficacy of the chatbot on blood pressure control. The secondary outcome includes the acceptability of the chatbot speaker and the changes of self-management behavior. Discussion Artificial intelligence-based chatbot speaker not only caters to patients’ self-management needs at home but also effectively organizes intricate and detailed knowledge system for patients with hypertension through a knowledge graph. Patients can promptly access information that aligns with their specific requirements, promoting proactive self-management and playing a crucial role in disease management. This study will serve as a foundation for the application of artificial intelligence technology in chronic disease management, paving the way for further exploration on enhancing the communicative impact of artificial intelligence technology. Trial registration Biomedical Ethics Committee of Peking University: IRB00001052-21106, 2021/10/14; Clinical Trials: ChiCTR2100050578, 2021/08/29.

Abstract Background Despite extensive research, the identification of effective biomarkers for early prediction of preterm birth (PTB) continues to be a challenging endeavor. This study aims to identify amniotic fluid (AF) protein biomarkers useful for the early diagnosis of PTB. Methods We initially identified the protein expression profiles in the AF of women with PTB (n = 22) and full-term birth (FTB, n = 22), from the First People’s Hospital of Yunnan Province who underwent amniocentesis from November 2019 to February 2020, using mass spectrometry employing the data-independent acquisition (DIA) technique, and then analyzed differentially expressed proteins (DEPs). Subsequently, the least absolute shrinkage and selection operator (LASSO) and random forest analysis were employed to further screen the key proteins for PTB biomarker identification. The receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analyses (DCA) were utilized to assess the discrimination and calibration of the key biomarkers. Results A total of 25 DEPs were identified between the PTB and FTB groups, comprising 13 up-regulated and 12 down-regulated proteins. Three key protein biomarkers for early PTB diagnosis were identified: IL1RL1 (interleukin-1 receptor-like 1), APOE (apolipoprotein E), and NECTIN4 (nectin cell adhesion molecule 4). The results of the ROC analysis showed that the area under the curve (AUC) of the three proteins combined as a biomarker for early diagnosis of PTB was 0.913 (95% CI: 0.823-1.000), with a sensitivity of 0.864 and a specificity of 0.955, both superior to those of the individual biomarkers. Bootstrap internal validation revealed a concordance index (C-index) of 0.878, with a sensitivity of 0.812 and a specificity of 0.773, indicating the robust predictive performance of these biomarkers. Conclusions We identified three previously unexplored yet potentially useful protein biomarkers in AF for early PTB diagnosis: IL1RL1, APOE, and NECTIN4.

Abstract Background Data are currently lacking regarding perioperative stroke recurrence in hip fracture patients with previous stroke. We aimed to analyze the incidence and risk factors of perioperative stroke recurrence in elderly patients with previous stroke who underwent hip fracture surgery. Methods We used 2019 and 2020 data from the United States National Inpatient Sample database. We identified elderly patients with previous ischemic stroke who had undergone hip fracture surgery to analyze the incidence of stroke recurrence. A 1:4 propensity score matching was used to balance confounding factors related to demographic data and matched the control group with the stroke recurrence group. Risk factors for stroke recurrence were determined using univariate and multivariate logistic analysis. Results The incidence of perioperative stroke recurrence in elderly patients with previous stroke who underwent hip fracture surgery was 5.7% (51/882). Multivariate logistic regression analysis showed that intertrochanteric fracture (odds ratio 2.24, 95% confidence interval 1.14–4.57; p = 0.021), hypertension (odds ratio 2.49, 95% confidence interval 1.26–5.02; p = 0.009), and postoperative pneumonia (odds ratio 4.35, 95% confidence interval 1.59–11.82; p = 0.004) were independently associated with stroke recurrence. Conclusions The perioperative stroke recurrence rate in elderly hip fracture patients with previous stroke was 5.7%. Intertrochanteric fracture, hypertension, and postoperative pneumonia were identified as factors significantly associated with stroke recurrence in this study. Adequate systemic support post-fracture, effective blood pressure management, and proactive infection prevention may help reduce stroke recurrence, especially in patients with intertrochanteric fractures.

Abstract Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages’ phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Abstract High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Aims: The metabolic variations between the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) remain largely unknown. Our study aimed to address this by conducting a comparative analysis of the metabolic profiles present in the cartilage of KBD and OA. Methods: Cartilage samples from patients with KBD (n = 10) and patients with OA (n = 10) were collected during total knee arthroplasty surgery. An untargeted metabolomics approach using liquid chromatography coupled with mass spectrometry (LC-MS) was conducted to investigate the metabolomics profiles of KBD and OA. LC-MS raw data files were converted into mzXML format and then processed by the XCMS, CAMERA, and metaX toolbox implemented with R software. The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the metabolites by matching the exact molecular mass data of samples with those from the database. Results: A total of 807 ion features were identified for KBD and OA, including 577 positive (240 for upregulated and 337 for downregulated) and 230 negative (107 for upregulated and 123 for downregulated) ions. After annotation, LC-MS identified significant expressions of ten upregulated and eight downregulated second-level metabolites, and 183 upregulated and 162 downregulated first-level metabolites between KBD and OA. We identified differentially expressed second-level metabolites that are highly associated with cartilage damage, including dimethyl sulfoxide, uric acid, and betaine. These metabolites exist in sulphur metabolism, purine metabolism, and glycine, serine, and threonine metabolism. Conclusion: This comprehensive comparative analysis of metabolism in OA and KBD cartilage provides new evidence of differences in the pathogenetic mechanisms underlying cartilage damage in these two conditions. Cite this article: Bone Joint Res 2024;13(7):362–371.

BackgroundArsenic, cobalt, barium, and other individual metal exposure have been confirmed to be associated with the incidence of kidney stones. However, there are few studies on the association between mixed metal exposure and kidney stones, especially in occupational groups. ObjectiveTo investigate the association between mixed metal exposure and kidney stones in an occupational population from a metal smelting plant. MethodsA questionnaire survey was conducted to collect sociodemographic characteristics, medical history, and lifestyle information of 1158 mixed metal-exposed workers in a metal smelting plant in Guangdong Province from July 2021 to January 2022. Midstream morning urine samples were collected from the workers, the concentrations of 18 metals including lithium, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, strontium, molybdenum, cadmium, cesium, barium, tungsten, titanium, and lead were measured by inductively coupled plasma mass spectrometry, and the urinary mercury levels were measured by cold atomic absorption spectroscopy. Based on predetermined inclusion criteria, a total of 919 mixed metal-exposed workers were included in the study, including 117 workers in the kidney stone group and 802 workers in the non-kidney stone group. With a detection rate of urinary metals greater than 80% as entry criterion, 16 eligible metals were finally included for further analysis. Parametric or non-parametric methods were used to compare the differences between continuous or categorical variables of the non-kidney stone group and the kidney stone group. Logistic regression models were constructed to explore the association between individual metal exposures and kidney stones. Weighted quantile sum (WQS) regression models were used to evaluate the association between mixed metal exposure and kidney stones, as well as the weights of each metal on kidney stones. Then Bayesian kernel machine regression (BKMR) models were used to explore the overall effect of mixed metal exposure on renal calculi and the potential interactions between metals. ResultsWe found that there were significant differences in sex, age, length of service, and body mass Index (BMI) between the non-kidney stone group and the kidney stone group (P

Abstract Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.

Abstract Background Cervical cancer is one of the most common gynecological malignancies. Previous studies have shown that the ethanol extract of Sophora moorcroftiana seeds (EESMS) possesses an antiproliferative effect on several tumors in vitro. Therefore, in this study, we assessed the impact of EESMS on human cervical carcinoma (HeLa) cell proliferation. Methods The proliferation and apoptotic effects of HeLa cells treated with EESMS were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay, dual acridine orange/ethidium bromide double staining, flow cytometry, and western blotting. Single-cell level atomic force microscopy (AFM) was conducted to detect the mechanical properties of HeLa cells, and proteomics and bioinformatics methods were used to elucidate the molecular mechanisms of EESMS. Results EESMS treatment inhibited HeLa cell proliferation by blocking the G0/G1 phase, increasing the expression of Caspase-3 and affecting its mechanical properties, and the EESMS indicated no significant inhibitory effect on mouse fibroblasts L929 cell line. In total, 218 differentially expressed proteins were identified using two-dimensional electrophoresis, and eight differentially expressed proteins were successfully identified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The differentially expressed proteins were involved in various cellular and biological processes. Conclusion This study provides a perspective on how cells change through biomechanics and a further theoretical foundation for the future application of Sophora moorcroftiana as a novel low-toxicity chemotherapy medication for treating human cervical cancer.

Abstract Background Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. Methods We collected a prospective study cohort of 110 stage I–II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. Results Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942–0.982) in the study cohort, 0.972 (95% CI: 0.953–0.992) in the first validation cohort and 0.937 (95% CI: 0.890–0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. Conclusions We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. Trial registration This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

Ikigai, a Japanese term often referred to as “purpose in life” or “the feeling that life is worthwhile”, is a commonly used indicator of well-being in studies focused on the elderly population in Japan. It can be identified within the different realms like family, work, and friendship. However, as individuals age, their sense of ikigai is prone to diminish. Teachable agents (TAs) have been employed in educational settings for decades to facilitate learning by teaching students. Previous research has indicated that TAs can have a positive impact on self-esteem which is an important aspect of ikigai. TAs may hold the potential to address issues related to declining ikigai that are often associated with aging. By engaging in the act of teaching the agent, elderly individuals may experience a sense of being needed, consequently enhancing their self-esteem and potentially leading to an improvement in their ikigai levels. In this paper, we introduce a TA designed around the concept of ikigai, aiming at assisting the elderly in maintaining a high level of ikigai to support healthy aging. Based on a user study conducted using the phenomenographical approach, we demonstrate the effectiveness of our proposed TA design.

Background: Intravenous vitamin C (IVC, ascorbate [Asc]) and alpha-lipoic acid (ALA) are frequently coadministered in integrative oncology clinics, with limited understanding of combination effects or drug-drug interactions. As high-dose IVC has anticancer activity through peroxide (H 2 O 2 ), it is hypothesized that IV ALA, a thiol antioxidant, might have untoward effects when combined with IVC. Methods: In vitro combination index (CI) was investigated in 6 types of human cancer cells, using clinically relevant concentrations of Asc (0.625-20 mM) and ALA (0.25, 0.5, and 1 mM) evaluated by nonconstant ratio metrics. Cellular H 2 O 2 was measured using HeLa cells expressing a fluorescent probe HyPer. Mouse xenografts of the metastatic breast cancer MDA-MB-231 were treated with intraperitoneal injections of ALA (10, 20, and 50 mg/kg) and Asc (0.2, 0.5, and 4 g/kg) at various dose levels. Results: Cancer cell lines were sensitive to Asc treatment but not to ALA. There is no evidence ALA becomes a prooxidant at higher doses. The CIs showed a mixture of synergistic and antagonistic effects with different ALA and Asc combination ratios, with a “U” shape response to Asc concentrations. The ALA concentrations did not influence the CIs or cellular H 2 O 2 formation. Adding ALA to Asc dampened the increase of H 2 O 2 . Toxicity was observed in mice receiving prolonged treatment of ALA at all doses. The Asc at all doses was nontoxic. The combination of ALA and Asc increased toxicity. The ALA at all doses did not inhibit tumor growth. The Asc at 4 g/kg inhibited tumor growth. Adding ALA 50 mg/kg to Asc 4 g/kg did not enhance the effect, but lower doses of ALA (10 or 20 mg/kg) dampened the inhibitory effect of Asc. Conclusions: These data do not support the concurrent or relative concurrent use of high-dose intravenous ALA with prooxidative high-dose IVC in clinical oncology care with potentially increased toxicity.

Mucormycosis is an aggressive fungal disease. Gastrointestinal mucormycosis is rare, but its clinical symptoms lack specificity and mortality is high. Here, we report a case of intestinal mucormycosis caused by Lichtheimia ramosa in a 65-year-old woman with diabetes mellitus. The patient exhibited extensive mucosal tissue damage in the colon, with broad, undivided filamentous fungal hyphae present in the intestinal tissue. Therefore, the patient was suspected to have a filamentous fungal infection. Colonic tissue samples were obtained for fungal culture, and the fungus was identified as L. ramosa based on morphology and DNA sequencing. This case highlights the importance of pathologists and microbiologists in identifying pathogenic fungi and the significance of screening for mucormycosis in high-risk patient populations.

Rheumatoid arthritis is a chronic autoimmune disease of undetermined etiology characterized by symmetric synovitis with predominantly destructive and multiple joint inflammation. Cytoplasmic DNA sensors that recognize protein molecules that are not themselves or abnormal dsDNA fragments play an integral role in the generation and perpetuation of autoimmune diseases by activating different signaling pathways and triggering innate immune signaling pathways and host defenses. Among them, melanoma deficiency factor 2 (AIM2) recognizes damaged DNA and double-stranded DNA and binds to them to further assemble inflammasome, initiating the innate immune response and participating in the pathophysiological process of rheumatoid arthritis. In this article, we review the research progress on the source of cytoplasmic DNA, the mechanism of assembly and activation of AIM2 inflammasome, and the related roles of other cytoplasmic DNA sensors in rheumatoid arthritis.

Summary: Exploration of efficient Ru-based catalysts is significant for advancing the production of hydrogen from ammonia decomposition, which depends predominantly on the rational regulation of the metal-support interaction of Ru-based catalysts. Herein, highly dispersed Ru nanoparticles (NPs) on Gd2O3 (Ru/Gd2O3) are developed and applied for the NH3 decomposition reaction. By varying the reduction temperature, the activity of the Ru/Gd2O3 catalyst can be remarkably improved. Characterization results reveal that the enhanced activity is associated with the strong metal‒support interaction (SMSI) induced formation of Gd2O3 overlayer on the Ru NPs. With a relatively low reduction temperature, the exposed Ru NPs possess relatively low activity toward NH3 decomposition. After high temperature activation treatment, the Gd2O3 overlayer coated Ru NPs show much enhanced intrinsic activity than that of the exposed Ru NPs. This study brings a facile strategy to modulate the catalytic performance of oxide supported Ru catalysts by regulating the SMSI of catalysts.

The presence of inactive components in siliceous and calcareous wastes tends to cause a misunderstanding in their mix design for hydrothermal solidification. The contents of typical reactive elements (i.e. Caact, Siact and Alact) in raw materials are quickly determined by simulating hydrothermal conditions. A generic mix design framework is proposed, which utilizes the molar ratio of Caact/Siact as the controlling parameter. The framework was demonstrated through a series of studies, which involved the production of granular materials using a mixture of clayey soil with slaked lime, as well as the production of compacted cylinders using a mixture of clayey soil with either slaked lime or calcium carbide slag. Experimental results showed that the hydrothermal samples achieved their maximum strength when the molar ratio of Caact/Siact in raw materials approached the theoretical Ca/Si molar ratio (i.e. 0.83) in tobermorite, provided that the molar ratio of Alact/(Alact + Siact) remained below 21%.

IntroductionLow skeletal muscle mass and high adipose tissue coexist across the body weight spectrum and independently predict the survival ratio of colorectal cancer (CRC) patients. This combination may lead to a mutually exacerbating vicious cycle. Tumor-associated metabolic conditions primarily affect subcutaneous adipose tissue, but the nature and direction of its relationship with skeletal muscle are unclear. This study aims to examine the bidirectional causal relationship between skeletal muscle index (SMI) and subcutaneous fat index (SFI) during the perioperative period in CRC patients; as well as to validate the association between perioperative SMI, SFI, and CRC prognosis.MethodsThis population-based retrospective cohort study included patients with stage I-III colorectal cancer who underwent radical resection at the Third Affiliated Hospital of Kunming Medical University between September 2012 and February 2019. Based on inclusion and exclusion criteria, 1,448 patients were analyzed. Preoperative (P1), 2 months postoperative (P2), and 5 months postoperative (P3) CT scans were collected to evaluate the skeletal muscle index (SMI; muscle area at the third lumbar vertebra divided by height squared) and subcutaneous fat index (SFI; subcutaneous fat area at the third lumbar vertebra divided by height squared). A random intercept cross-lagged panel model (RI-CLPM) was used to examine the intra-individual relationship between SMI and SFI, and Cox regression was employed to assess the association between SMI, SFI, recurrence-free survival (RFS), and overall survival (OS).ResultsThe median age at diagnosis was 59.00 years (IQR: 51.00–66.00), and 587 patients (40.54%) were female. RI-CLPM analysis revealed a negative correlation between SFI and subsequent SMI at the individual level: P1-P2 (β = −0.372, p = 0.038) and P2-P3 (β = −0.363, p = 0.001). SMI and SFI showed a negative correlation during P1-P2 (β = −0.363, p = 0.001) but a positive correlation during P2-P3 (β = 0.357, p = 0.006). No significant correlation was found between the random intercepts of SFI and SMI at the between-person level (r = 0.157, p = 0.603). The Cox proportional hazards multivariate regression model identified that patients with elevated SFI had poorer recurrence-free survival (HR, 1.24; 95% CI: 1.00–1.55). Compared to patients with normal preoperative SMI and SFI, those with low SMI or high SFI had poorer recurrence-free survival (HR, 1.26; 95% CI: 1.03–1.55) and overall survival (HR, 1.39; 95% CI: 1.04–1.87). However, no significant association between SMI and SFI and the prognosis of colorectal cancer patients was observed postoperatively.ConclusionIn CRC patients, preoperative muscle loss leads to postoperative fat accumulation, exacerbating muscle loss in a feedback loop. Elevated preoperative SFI predicts poorer survival outcomes. Monitoring SMI and SFI is crucial as prognostic indicators, despite non-significant postoperative associations. Further research is needed to improve patient outcomes.

Summary: The development of efficient catalysts for ammonia synthesis under mild conditions is critical for establishing a carbon-neutral society powered by renewable ammonia. While significant effort has been focused on Fe and Ru-based catalysts, there have been very limited studies on manganese-based catalysts for ammonia synthesis because of their low intrinsic catalytic activity. Herein, we report that the synergy between manganese nitride (Mn4N) and europium nitride (EuN) yields an ammonia synthesis rate that is 41 and 25 times higher than that of neat Mn4N and EuN, respectively. Detailed studies suggest that a [Eu-N-Mn] species at the interface of Mn4N and EuN plays a pivotal role in ammonia synthesis. Compositing of Mn4N with other rare earth metal nitrides such as LaN, PrN, and CeN also leads to a significant enhancement in catalytic activity. This work broadens the scope of advanced nitride catalysts for ammonia synthesis.

Background: Patients with gastric cancer (GC) who underwent radical surgery require long-term follow-up (usually 5 years). The purpose of this study was to explore individualized follow-up strategies for patients with GC. Methods: This is a retrospective cohort study that established a clinicopathologic database of patients who underwent gastrectomy from January 2010 to December 2020 at Ningbo No. 2 Hospital. Follow-up was performed until March 2023. The rate of new-onset recurrence of patients with GC was explored annually according to different pTNM stages, defining a recurrence rate of less than 1% as adequate follow-up time. Results: Of the 1606 patients who were eligible, the total number of patients who completed the 5- and 10-year follow-up was 1107 and 586, respectively. A total of 444 cases were diagnosed with recurrence. The recurrence rate for stage IA patients was consistently less than 1% during the follow-up time. The adequate follow-up time (the rate of new-onset recurrence less than 1%) was 5 years for stage IB and IIA patients, and 8 years for stage IIB and IIIA patients, respectively. In contrast, stage IIIB patients were always at risk of recurrence during the follow-up time (>1%). Time to a new recurrence rate for stage IIIC patients was 6 years. Conclusion: Among patients who underwent radical gastrectomy, the rate of new-onset recurrence varied among patients with different pTNM stages. This study suggests that the follow-up of GC can be individualized and refer to pTNM stage.

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10-11), RIC8A (FDR = 7.05 × 10-4), and SOX12 (FDR = 1.43 × 10-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients. Cite this article: Bone Joint Res 2024;13(5):237–246.

In recent years, exploration breakthroughs have been successively achieved in the strata deeper than the fifth member of the Lower Ordovician Majiagou Formation in the Ordos Basin, revealing its tremendous exploration potential. With the deployment of high-precision 3D seismic data and the deepening of oil and gas exploration, the control exerted by faults on the gas reservoirs in the deeper layers of the fifth member has become increasingly prominent. Based on high-precision 3D seismic data, this study systematically characterized the geometric features of faults in the Gaojiabao area, dissected typical fault structural patterns, established fault formation and evolution models, and, in conjunction with drilling and testing data, discussed the control of faults on the differential enrichment of gas reservoirs in the deeper layers of the Majiagou Formation. The study yielded the following insights: Faults in the Lower Paleozoic of the Gaojiabao area in the Ordos Basin exhibit distinct stratified deformation characteristics, with the two sets of gypsum-salt rocks in the third and fifth members being major contributors to fault stratification. The Lower Paleozoic in the Gaojiabao area mainly develops strike-slip faults with compressional and torsional properties and thrust faults. Through studying the structural morphology and fault patterns of the Gaojiabao area, it is inferred that the Yanshan tectonic movement was the most significant phase of reformation affecting the faults formed during the Caledonian tectonic movement. The coupling of the structural uplift period with the oil-gas charging period in the Gaojiabao area means that faults play multiple roles, including improving reservoirs, connecting source rocks, and controlling traps.

Introduction Cigarette smoking is one of the most important causes of COPD and could induce the apoptosis of pulmonary microvascular endothelial cells (PMVECs). The conditional knockout of LRG1 from endothelial cells reduced emphysema in mice. However, the mechanism of the deletion of LRG1 from endothelial cells rescued by cigarette smoke (CS) induced emphysema remains unclear. This research aimed to demonstrate whether LRG1 promotes the apoptosis of PMVECs through KLK10 in COPD. Methods Nineteen patients were divided into three groups: control non-COPD (n=7), smoker non-COPD (n=7), and COPD (n=5). The emphysema mouse model defined as the CS exposure group was induced by CS exposure plus cigarette smoke extract (CSE) intraperitoneal injection for 28 days. Primary PMVECs were isolated from the mouse by magnetic bead sorting method via CD31-Dynabeads. Apoptosis was detected by western blot and flow cytometry. Results LRG1 was increased in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. KLK10 was over-expressed in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. LRG1 promoted apoptosis in PMVECs. LRG1 knockdown reversed CSE-induced apoptosis in PMVECs. The mRNA and protein expression of KLK10 were increased after over-expressed LRG1 in PMVECs isolated from mice. Similarly, both the mRNA and protein levels of KLK10 were decreased after LRG1 knockdown in PMVECs. The result of co-immunoprecipitation revealed a protein-protein interaction between LRG1 and KLK10 in PMVECs. KLK10 promoted apoptosis via the down-regulation of Bcl-2/Bax in PMVECs. KLK10 knockdown could reverse CSE-induced apoptosis in PMVECs. Conclusions LRG1 promotes apoptosis via up-regulation of KLK10 in PMVECs isolated from mice. KLK10 promotes apoptosis via the down-regulation of Bcl-2/ Bax in PMVECs. There was a direct protein-protein interaction between LRG1 and KLK10 in PMVECs. Our novel findings provide insights into the understanding of LRG1/KLK10 function as a potential molecule in COPD.

Abstract Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm2 chip in a device measuring 23 × 16 × 3.5 cm3. We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease.

Abstract Background Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application. Methods We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro. Results In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them. Conclusions We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density.

An edge-coloring of a graph $ G $ is an assignment of colors to its edges so that no two edges incident to the same vertex receive the same color. The chromatic index of $ G $, denoted by $ \chi'(G) $, is the least $ k $ for which $ G $ has a $ k $ edge-coloring. Graphs with $ \chi'(G) = \Delta(G) $ are said to be Class 1, and graphs with $ \chi'(G) = \Delta(G)+1 $ are said to be Class 2. Let $ G $ be a graph with $ V(G) = \{t_1, t_2, \ldots, t_n\} $, $ n\geq2 $, and $ h_n = (H_i)_{i\in\{1, 2, \ldots, n\}} $ be a sequence of vertex-disjoint graphs with $ V(H_i) = \{(t_i, y_1), (t_i, y_2), \ldots, (t_i, y_{m_i})\} $, $ m_i\geq1 $. The generalized lexicographic product $ G[h_n] $ of $ G $ and $ h_n = (H_i)_{i\in\{1, 2, \ldots, n\}} $ is a simple graph with vertex set $ \bigcup_{i = 1}^{n}V(H_i) $, in which $ (t_i, y_p) $ is adjacent to $ (t_j, y_q) $ if and only if either $ t_i = t_j $ and $ (t_i, y_p)(t_i, y_q)\in E(H_i) $ or $ t_it_j\in E(G) $. If $ G $ is a complete graph with order 2, then $ G[h_2] $ denotes a join $ H_1+H_2 $ of vertex-disjoint graphs $ H_1 $ and $ H_2 $. If $ H_i\cong H $ for $ i = 1, 2, \ldots, n $, then $ G[h_n] = G[H] $, where $ G[H] $ denotes the lexicographic product of two graphs $ G $ and $ H $. In this paper, we provide sufficient conditions for the generalized lexicographic product $ G[h_n] $ of $ G $ and $ h_n = (H_i)_{i\in\{1, 2, \ldots, n\}} $ to be Class 1, where all graphs in $ h_n $ have the same number of vertices.

Abstract With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

Abstract Background Chronic shoulder and neck pain is one of the most common chronic occupational disorders, with an average incidence rate of 48.5%, severely affecting patients’ quality of life and ability to work. According to epidemiological research, the prevalence of chronic neck, shoulder, and low back pain in adults over the age of 45 ranges from 40 to 80%. According to reports, medical staff have a higher incidence rate than other populations, and there is a positive correlation between the grade of the medical institution and the incidence rate, making medical staff a priority group for the prevention of chronic neck, shoulder, and low back pain. By the end of 2022, China has been fully opened to epidemic prevention and control, the total number of patients in domestic hospitals has increased significantly, and resulting in medical personnel shoulting great pressure, which seriously affects the physical and mental health of medical personnel. The aim of this study was to explore the risk factors of chronic neck, shoulder and lumbar back pain in medical staff. To provide guidelines for medical staff to improve cervical and lumbar subacute pain and reduce the emergence of spinal lesions. Methods From January to February 2023, 602 staff members of a third-grade hospital in Zunyi City were studied by Questionnaire star. Univariate and multivariate Logistic regression were used to analyze the independent risk factors of chronic neck, shoulder and lumbar back pain in medical staff, with stepwise regression utilized to choose the optimum model. The model was selected using Akaike’s information criterion (AIC) and the Hosmer-Lemeshow goodness-of-fit test. Results A total of 602 medical staff were polled, and the findings revealed that 588 cases of chronic neck, shoulder, and low back pain of varied severity had occurred in the previous 1 to 2 years, with a 97.7% incidence rate; logistic regression analysis revealed that anxiety level, frequency of bending over in the previous 1 to 2 years, whether related preventive measures were taken at work, gender, positive senior title, daily ambulation time, and whether the department they worked in organized independent influencing factors. Conclusion The incidence of chronic neck, shoulder, and lumbar back pain among medical staff is high; its influencing factors are different and have not been systematically identified. Hospitals should take effective measures tailored to local conditions to improve the physical and mental health of medical staff.

Abstract Background Advanced cancer patients with good Eastern Cooperative Oncology Group (ECOG) performance status (score 0–1) are underrepresented in current qualitative reports compared with their dying counterparts. Aim To explore the experiences and care needs of advanced cancer patients with good ECOG. Design A qualitative phenomenological approach using semi-structured interview was employed. Data was analyzed using the Colaizzi’s method. Setting/Participants Purposive sample of terminal solid cancer patients on palliative care aged 18–70 years with a 0–1 ECOG score were recruited from a tertiary general hospital. Results Sixteen participants were interviewed. Seven themes were generated from the transcripts, including experiencing no or mild symptoms; independence in self-care, decision-making, and financial capacity; prioritization of cancer growth suppression over symptom management; financial concerns; hope for prognosis and life; reluctance to discuss death and after-death arrangements; and use of complementary and alternative medicine (CAM) and religious coping. Conclusions Advanced cancer patients with good ECOG have distinct experiences and care needs from their dying counterparts. They tend to experience no or mild symptoms, demonstrate a strong sense of independence, and prioritize cancer suppression over symptom management. Financial concerns were common and impact their care-related decision-making. Though being hopeful for their prognosis and life, many are reluctant to discuss death and after-death arrangements. Many Chinese patients use herbal medicine as a CAM modality but need improved awareness of and accessibility to treatment options. Healthcare professionals and policy-makers should recognize their unique experiences and needs when tailoring care strategies and policies.

Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Abstract Congenital infection caused by vertical transmission of microsporidia N. bombycis can result in severe economic losses in the silkworm-rearing industry. Whole-transcriptome analyses have revealed non-coding RNAs and their regulatory networks in N. bombycis infected embryos and larvae. However, transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae remains unclear. Here, we simultaneously compared the transcriptomes of N. bombycis and its host B. mori embryos of 5-day and larvae of 1-, 5- and 10-day during congenital infection. For the transcriptome of N. bombycis, a comparison of parasite expression patterns between congenital-infected embryos and larva showed most genes related to parasite central carbon metabolism were down-regulated in larvae during infection, whereas the majority of genes involved in parasite proliferation and growth were up-regulated. Interestingly, a large number of distinct or shared differentially expressed genes (DEGs) were revealed by the Venn diagram and heat map, many of them were connected to infection related factors such as Ricin B lectin, spore wall protein, polar tube protein, and polysaccharide deacetylase. For the transcriptome of B. mori infected with N. bombycis, beyond numerous DEGs related to DNA replication and repair, mRNA surveillance pathway, RNA transport, protein biosynthesis, and proteolysis, with the progression of infection, a large number of DEGs related to immune and infection pathways, including phagocytosis, apoptosis, TNF, Toll-like receptor, NF-kappa B, Fc epsilon RI, and some diseases, were successively identified. In contrast, most genes associated with the insulin signaling pathway, 2-oxacarboxylic acid metabolism, amino acid biosynthesis, and lipid metabolisms were up-regulated in larvae compared to those in embryos. Furthermore, dozens of distinct and three shared DEGs that were involved in the epigenetic regulations, such as polycomb, histone-lysine-specific demethylases, and histone-lysine-N-methyltransferases, were identified via the Venn diagram and heat maps. Notably, many DEGs of host and parasite associated with lipid-related metabolisms were verified by RT-qPCR. Taken together, simultaneous transcriptomic analyses of both host and parasite genes lead to a better understanding of changes in the microsporidia proliferation and host responses in embryos and larvae in N. bombycis congenital infection.

Abstract Background and purpose The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in directing folate species towards nucleotide synthesis or DNA methylation. The MTHFR polymorphisms C677T and A1298C have been linked to cancer susceptibility, but the evidence supporting this association has been equivocal. To investigate the individual and joint associations between MTHFR C677T, A1298C, and digestive system cancer in a Chinese hypertensive population, we conducted a population-based case–control study involving 751 digestive system cancer cases and one-to-one matched controls from the China H-type Hypertension Registry Study (CHHRS). Methods We utilized the conditional logistic regression model to evaluate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of digestive system cancer. Results The analysis revealed a significantly lower risk of digestive system cancer in individuals with the CT genotype (adjusted OR: 0.71; 95% CI 0.52, 0.97; P = 0.034) and TT genotype (adjusted OR: 0.57; 95% CI 0.40, 0.82; P = 0.003; P for trend = 0.003) compared to those with the 677CC genotype. Although A1298C did not show a measurable association with digestive system cancer risk, further stratification of 677CT genotype carriers by A1298C homozygotes (AA) and heterozygotes (AC) revealed a distinct trend within these subgroups. Conclusion These findings indicate a potential protective effect against digestive system cancer associated with the T allele of MTHFR C677T. Moreover, we observed that the presence of different combinations of MTHFR polymorphisms may contribute to varying susceptibilities to digestive system cancer.