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Abstract Fructus Choerospondiatis (FC) has been utilized in Mongolian medicine for the treatment of many diseases. This investigation assessed the coloration, five active components, total phenolic and flavonol contents, as well as the antioxidant and antibacterial properties of different parts of FC from eight cultivars, and the optimal cultivar was identified to determine the anti-inflammatory capacity of all parts. The findings revealed that L* and b* values of the dried peel powder were the highest and the a* value of whole fruit powder was the highest. The concentrations of gallic acid, catechin, epicatechin, total phenols, and total flavonoids exhibited a positive correlation with antioxidant activity. A comprehensive analysis revealed that the peel contained a greater abundance of active compounds and exhibited stronger antioxidant and antibacterial properties compared to other parts. RPNO.1 can be used as the source of high-quality FC for clinical application. In vivo anti-inflammatory experiments indicated that both the flesh and peel of RPNO.1 displayed the highest anti-inflammatory effect. This research not only addressed the gap in studies regarding FC’ s anti-inflammatory properties but also proved that the peel of FC, which was often discarded, had utilization value and could be used as a medicinal herb.

Abstract This research aimed to assess the validity of ultrasound scans with new features in detecting fetal anal atresia and verify the effectiveness of these new features. Additionally, we aimed at investigating the perinatal incidence of anal atresia. This multicenter prospective study recruited 94,617 normal gravidas and 84 gravidas with anal atresia fetuses. The gold standard for diagnosing perinatal anal atresia is routine neonatal anus examinations. The incidence calculation was based on the results of the gold standard. The validity of our new approach was evaluated via a diagnostic test involving all 94,701 subjects. The effectiveness of our new features was assessed through an ablation study in a randomly established new dataset, with the ratio of anal atresia to non-anal atresia cases of 1:4. The annual perinatal incidence of anal atresia between 2019 and 2023 ranges from 0.57‰ to 1.29‰. Our new method performed great regarding the Youden index, diagnostic odds ratio (DOR), area under the curve (AUC) of the receiver operating characteristic curve (ROCC), AUC of the precision-recall curve (PRC), F1-score, and Cramer’s V. In the ablation study, our new approach surpassed its competitors concerning Youden index, DOR, AUC of the ROCC, and AUC of the PRC. Ultrasound scans show high validity and clinical value in detecting fetal anal atresia. Our new ultrasound features significantly promote the detection of fetal anal atresia.

Abstract The rapid growth of offshore wind farms (OWFs) is driven by concerns for energy security and climate change mitigation. However, their impact on marine environments remains poorly understood due to limited research. This study analyzes the effects of an OWF along China's Jiangsu Coast on seawater quality using data from different development phases. Results show the major pollutants were different across phases. Heavy metal pollution reached alert levels during construction compared to the safe levels observed in the pre-construction and operational phases, mainly due to increases in Pb, Cd, and Hg concentrations. Eutrophication was mild throughout all periods but exhibited a continuous decrease, primarily attributed to reductions in PH and COD concentrations. As a result, the comprehensive pollution level during construction was increased, but it was improved to a clean level during the operational phase. Besides, significant variations were observed in the spatial distribution patterns of major pollutant indices across different scenarios. These changes may stem from a combination effect of land-based pollution, aquaculture, OWF-induced disturbances to atmosphere and hydrodynamics, OWF-related drain and leakage contamination, and marine management policies. Understanding these effects informs OWF optimization, rational wind resource utilization, and marine ecology protection.

Abstract Background Bi-allelic variants in DNAH11 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on human sperm flagellar and their involvement in male infertility remain largely unknown. Methods A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 variants. Results In this study, we identified seven novel variants in the DNAH11 gene in four asthenoteratozoospermia subjects. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated, instead of inner dynein arms (IDA) proteins DNAH1 and DNAH6. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11, resulting in the aberrant assembly of sperm flagella and contributing to asthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.

Abstract Background Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. Methods This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. Results Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). Conclusions Sirolimus’s long-term administration is not associated with adverse effects on children’s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. Trial registration Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Introduction Involved site radiation therapy (ISRT) is a widely used treatment for primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma with control rates over 85%; however, its complications could reach 30%–50%. Intralesional rituximab injection has shown promising results with remission rates between 65% and 100% and minimal complications. This study aimed to conduct a multicentre randomised controlled clinical trial to compare the safety and efficacy of intralesional rituximab injection versus ISRT on primary ocular adnexal MALT lymphoma.Methods and analysis This is a multicentre randomised controlled trial and will be conducted at eight ophthalmic departments and institutes in China. 108 patients with primary ocular adnexal MALT lymphoma will be enrolled and randomised to undergo intralesional rituximab injection or ISRT. Comprehensive examinations will be performed before and after the treatment. The primary outcome is the cumulative occurrence rate of complications of grade ≥2 within 5 years after treatment commencement. The main secondary outcome is overall response rate, and progression-free survival, time to next treatment and overall survival will also be compared between the groups.Ethics and dissemination Ethical approval has been obtained from the Ethics Committee of the Zhongshan Ophthalmic Center (ID: 2023KYPJ125-3; V.20240818) and the ‘5010 Plan’ evaluation committee at Sun Yat-sen University, Guangzhou, China, and all subcentres. All the participants will be required to provide written informed consent. The results will be disseminated through scientific meetings and published in peer-reviewed journals.Trial registration number NCT06190301.

Objective To investigate the safety of regular plasma donors aged 55 to 60, so as to provide reference for retention and recruitment of elderly plasma donors in China. Methods Plasma donors from 9 blood products manufacturing enterprises from 2018 to 2020 and the local general population were selected as the research objects. The total protein level, albumin and globulin ratio(ALB/GLB, A/G) and adverse reactions of plasma donation of regular plasma donors and local general population were retrospectively analyzed. Results The total protein level (g/L) and A/G of plasma donors aged 56 to 60 and the general population were 61.21±5.62 vs 60.04±6.93 and 1.610±0.299 vs 1.635±0.330, respectively, and the differences were statistically significant. The total protein level of regular plasma donors was higher than that of general population, but A/G was slightly lower than that of general population. From 2018 to 2020, there were a total of 23 056 302 plasma donations in 108 plasma stations, and adverse reactions occurred in 20 932 donations, with a total incidence of 0.09%, with no serious adverse reactions. Conclusion It is safe for regular plasma donors aged 55 to 60 to donate plasma, and the retention of them can alleviate the pressure of plasma supply.

Objective To explore the characteristics and influencing factors of adverse reactions of apheresis plasma donation in 27 domestic plasma donation stations, and put forward targeted preventive measures. Methods A total of 6 275 plasma donors with adverse reactions from 2018 to 2020 in 27 plasma donation stations in China were selected as the research objects. The types of adverse reactions, ages, time of plasma donation and other related characteristics were counted and retrospectively analyzed. Results From January 2018 to December 2020, the incidence of adverse reactions of apheresis plasma donation in 27 plasma collection stations was 1.37‰, including vasovagal reaction/hypovolemia (3 208 cases, 0.700‰), sodium citrate allergy/hypocalcemia (1 205 cases, 0.263‰), hypoglycemia (1 020 cases, 0.223‰), syncope (796 cases, 0.174‰), hematoma (8 cases, 0.002‰), other reactions (36 cases, 0.008‰), all of which were non-severe adverse reactions. There were significant differences in the incidence of different types of adverse reactions (P0.05). Conclusion The incidence of adverse reactions in plasma donation is low in China. In the process of plasma donation, attention should be paid to first-time and young (18-25 years old) donors. The incidence of adverse reactions in 56-60 years old donors is the lowest, which can provide data support for the age revision of plasma donors in China.

The zinc finger protein CTCF is ubiquitously expressed and is integral to the regulation of chromatin architecture through its interaction with cohesin. Conversely, CTCFL expression is predominantly restricted to the adult male testis but is aberrantly expressed in certain cancers. Despite their distinct expression patterns, the cooperative and competitive mechanisms by which CTCF and CTCFL regulate target gene expression in spermatocytes and cancer cells remain inadequately understood. In this review, we comprehensively examine the literature on the divergent amino acid sequences, target sites, expression profiles and functions of CTCF and CTCFL in normal tissues and cancers. We further elucidate the mechanisms by which CTCFL competitively or cooperatively binds to CTCF target sites during spermatogenesis and carcinogenesis to modulate chromatin architecture. We mainly focus on the role of CTCFL in testicular and cancer development, highlighting its interaction with CTCF at CTCF binding sites to regulate target genes. In the testis, CTCF and CTCFL cooperate to regulate the expression of testis-specific genes, essential for proper germ cell progression. In cancers, CTCFL overexpression competes with CTCF for DNA binding, leading to aberrant gene expression, a more relaxed chromatin state, and altered chromatin loops. By uncovering the roles of CTCF and CTCFL in spermatogenesis and carcinogenesis, we can better understand the implications of aberrant CTCFL expression in altering chromatin loops and its contribution to disease pathogenesis.

Troubleshooting is an important part of experimental research, but graduate students rarely receive formal training in this skill. In this article, we describe an initiative called Pipettes and Problem Solving that we developed to teach troubleshooting skills to graduate students at the University of Texas at Austin. An experienced researcher presents details of a hypothetical experiment that has produced unexpected results, and students have to propose new experiments that will help identify the source of the problem. We also provide slides and other resources that can be used to facilitate problem solving and teach troubleshooting skills at other institutions.

Metal-ion-dependent nucleases play crucial roles in cellular defense and biotechnological applications. Time-resolved crystallography has resolved catalytic details of metal-ion-dependent DNA hydrolysis and synthesis, uncovering the essential roles of multiple metal ions during catalysis. The histidine-metal (His-Me) superfamily nucleases are renowned for binding one divalent metal ion and requiring a conserved histidine to promote catalysis. Many His-Me family nucleases, including homing endonucleases and Cas9 nuclease, have been adapted for biotechnological and biomedical applications. However, it remains unclear how the single metal ion in His-Me nucleases, together with the histidine, promotes water deprotonation, nucleophilic attack, and phosphodiester bond breakage. By observing DNA hydrolysis in crystallo with His-Me I-PpoI nuclease as a model system, we proved that only one divalent metal ion is required during its catalysis. Moreover, we uncovered several possible deprotonation pathways for the nucleophilic water. Interestingly, binding of the single metal ion and water deprotonation are concerted during catalysis. Our results reveal catalytic details of His-Me nucleases, which is distinct from multi-metal-ion-dependent DNA polymerases and nucleases.

Abstract Surface defects on steel, arising from factors like steel composition and manufacturing techniques, pose significant challenges to industrial production. Efficient and precise detection of these defects is crucial for enhancing production efficiency and product quality. In accordance with these requisites, this paper elects to undertake the detection task predicated on the you only look once (YOLO) algorithm. In this study, we propose a novel approach for surface flaw identification based on the YOLOv5 algorithm, called YOLOv5-KBS. This method integrates attention mechanism and weighted Bidirectional Feature Pyramid Network (BiFPN) into YOLOv5 architecture. Our method addresses issues of background interference and defect size variability in images. Experimental results show that the YOLOv5-KBS model achieves a notable 4.2% increase in mean Average Precision (mAP) and reaches a detection speed of 70 Frames Per Second (FPS), outperforming the baseline model. These findings underscore the effectiveness and potential applications of our proposed method in industrial settings.

Abstract Background Flexible hybrid teaching has become the new normal of basic medical education in the postepidemic era. Identifying ways to improve the quality of curriculum teaching and achieve high-level talent training is a complex problem that urgently needs to be solved. Over the course of the past several semesters, the research team has integrated design thinking (DT) into undergraduate teaching to identify, redesign and solve complex problems in achieving curriculum teaching and professional talent training objectives. Methods This study is an observational research. A total of 156 undergraduate stomatology students from Jining Medical University in 2021 were selected to participate in two rounds of online flipped teaching using the design thinking EDIPT (empathy, definition, idea, prototype, and test) method. This approach was applied specifically to the chapters on the respiratory system and female reproductive system. Data collection included student questionnaires, teacher-student interviews, and exam scores. GraphPad Prism software was used for data analysis, and the statistical method was conducted by multiple or unpaired t test. Results According to the questionnaire results, the flipped classroom teaching design developed using design thinking methods received strong support from the majority of students, with nearly 80% of students providing feedback that they developed multiple abilities during the study process. The interview results indicated that teachers generally believed that using design thinking methods to understand students' real needs, define teaching problems, and devise instructional design solutions, along with testing and promptly adjusting the effectiveness through teaching practices, played a highly positive role in improving teaching and student learning outcomes. A comparison of exam scores showed a significant improvement in the exam scores of the class of 2021 stomatology students in the flipped teaching chapters compared to the class of 2020 stomatology students, and this difference was statistically significant. However, due to the limitation of the experimental chapter scope, there was no significant difference in the overall course grades. Conclusion The study explores the application of design thinking in histology and embryology teaching, revealing its positive impact on innovative teaching strategies and students' learning experience in medical education. Online flipped teaching, developed through design thinking, proves to be an effective and flexible method that enhances student engagement and fosters autonomous learning abilities.

Abstract Objective We aimed to evaluate the ability of Adult Comorbidity Evaluation 27 (ACE-27) to predict perioperative outcomes and survival in elderly women with advanced epithelial ovarian cancer (AEOC) undergoing cytoreductive surgery. Methods We collected patients with AEOC in our hospital between January 1, 2012 and January 1, 2021. Patients younger than 65 years old or those with non-epithelial ovarian cancer were excluded. ACE-27 was applied retrospectively to assess comorbidities in the selected patients, who were then classified into two groups based on their ACE-27 scores: low ACE-27 score group (none to mild) and high ACE-27 score group (moderate to severe). Results A total of 222 elderly women with AEOC were included, of whom 164 patients accepted debulking surgery. Among those who have undergone surgery, Clavien–Dindo grade III + perioperative complications or unintended intensive care unit (ICU) admission occurred more often in patients of high ACE-27 score group, with statistically significant difference (odds ratio [OR]: 4.21, 95% confidence interval [CI], 1.28–14.35, p = 0.018). Further stratified analyses by age, BMI, FIGO stage and pathology also prove that OS of patients graded severe was shorter than patients graded none to moderate in cohort of age

Abstract Systemic immune monitoring is a crucial clinical tool for disease early diagnosis, prognosis and treatment planning by quantitative analysis of immune cells. However, conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing, especially in mass health screenings, because of time-consuming, technical-sensitive and high-cost features. However, the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology. To address this bottleneck, we constructed a generally applicable DNA framework signal amplification platform (DSAP) based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells, including CD4+, CD8+ T-lymphocytes, and monocytes (down to 1/100 μl). Based on this advanced detection platform, we present a novel high-throughput immune-cell phenotyping system, DSAP, achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost. As a proof-of-concept, DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients (AUC > 0.97) within 30 min, which can be applied in HIV infection monitoring and screening. Therefore, we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.

Summary: Background: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. Methods: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. Findings: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. Interpretation: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. Funding: The funding details can be found in the Acknowledgements section.

Summary: Background: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Methods: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). Findings: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. Interpretation: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. Funding: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Objective To examine the current prevalence and cost of paediatric off-label drug prescriptions in Gansu, China, and the potential influencing factors.Design The prevalence of off-label prescriptions in paediatrics was evaluated according to the National Medical Products Administration drug instructions in the China Pharmaceutical Reference (China Pharmaceutical Reference, MCDEX) database. The evidence of the prescription was determined by existing clinical practice guidelines and the Thomson Grade in the Micromedex 2021 compendium. We used logistic regression to investigate the characteristics that influence paediatric off-label drug use after single-factor regression analysis.Setting A multicentre cross-sectional study of outpatient paediatric prescriptions in 196 secondary and tertiary hospitals in Gansu Province, China, in March and September 2020.Results We retrieved 104 029 paediatric prescriptions, of which 39 480 (38.0%) contained off-label use. The most common diseases treated by off-label drugs were respiratory system diseases (n=15 831, 40.1%). A quarter of off-label prescriptions had adequate evidence basis (n=10 130, 25.6%). Unapproved indications were the most common type of off-label drug use (n=25 891, 65.6%). A total of 1177 different drugs were prescribed off-label, with multienzyme tablets being the most common drug (n=1790, 3.5%). The total cost of the prescribed off-label drugs was ¥106 116/day. Off-label prescriptions were less frequent in tertiary than in secondary hospitals. Topical preparations were more commonly prescribed off-label than other types of drugs. Senior-level clinicians prescribed drugs off-label more often than intermediate and junior clinicians.Conclusion Off-label drug use is widespread in paediatric practice in China. Three-quarters of the prescriptions may potentially include inappropriate medication use, resulting in a daily economic burden of about ¥81 000 in 2020 in Gansu Province with 25 million inhabitants. The management of off-label drug use in paediatrics in China needs improvement.

Objective To analyze the influence of plasma donation on human total protein level and the impact of different blood collection tubes on total protein level detection. Methods A total of 1 373 plasma donors from 11 apheresis plasma stations in 6 provinces/autonomous regions from March to April, 2021 were selected. Whole blood was collected by ordinary blood collection tube without anticoagulant, heparin anticoagulant tube and sodium citrate anticoagulant tube, and then respectively divided into serum group, heparin anticoagulant group, and sodium citrate anticoagulant group. After separating serum and plasma, the samples were subjected to total protein detection using the biuret method. Kruskal-Wallis test was used to compare the total protein levels among different tubes. The plasma donors were divided into male group (n=597) and female group (n=776), and the total protein levels between different genders were compared by t test. The plasma donors were divided into Sichuan group, Hubei group and Gansu group according to the region, and the Games-Howell test was used for comparison. Results The median serum total protein level of 1 373 donors was 73.1g/L, which was consistent with the reference range of 65-85 g/L. The median total protein levels of the serum group, heparin anticoagulant group and sodium citrate anticoagulant group were 73.1g/L, 73.3g/L and 63.8g/L, respectively, with statistically significant difference (P 0.05). The serum total protein levels of male group and female group were (72.41±5.40)g/L and (73.67±4.95)g/L, reseectively, and the difference was statistically significant (P0.05). Conclusion Plasma donors who meet the donation criteria will not experience abnormal total protein levels due to regular plasma donation. There were differences in total protein levels among different blood collection tubes, different genders and different regions. The total protein level of females was higher than that of males. The total protein level was the highest in Hubei province, followed by Sichuan and Gansu.Heparin anticoagulant group was the highest, followed by serum group and sodium citrate anticoagulant group.

Abstract Monitoring extent and severity is vital in the ulcerative colitis (UC) follow-up, however, current assessment is complex and low cost-effectiveness. We aimed to develop a routine blood-based clinical decision support tool, Jin’s model, to investigate the extent and severity of UC. The multicentre retrospective cohort study recruited 975 adult UC inpatients and sub-grouped into training, internal validation and external validation set. Model was developed by logistics regression for the extent via Montreal classification and for the severity via Mayo score, Truelove and Witts score (TWS), Mayo endoscopic score (MES) and Degree of Ulcerative colitis Burden of Luminal Inflammation (DUBLIN) score. In Montreal classification, left-sided and extensive versus proctitis model achieved area under the receiver operating characteristic curve (AUROC) of 0.78 and 0.81 retrospectively. For severity, Mayo score model, TWS model, MES model and DUBLIN score model achieved an AUROC of 0.81, 0.70, 0.74 and 0.70 retrospectively. The models also were evaluated with satisfactory calibration and clinical unity. Jin’s model was free with open access at http://jinmodel.com:3000/ . Jin’s model is a noninvasive, convenient, and efficient approach to assess the extent and severity of UC.

Abstract Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age‐dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age‐gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β‐amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age‐dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age‐dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age‐dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age‐gradient changes in the autophagy–lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state.

Objective To explore the effects of acute normovolemic hemodilution (ANH) combined with intraoperative recycled autotransfusion on blood transfusion volume and coagulation function in elderly patients undergoing cardiac surgery. Methods A total of 94 elderly patients undergoing cardiac surgery in the hospital were enrolled and randomly divided into observation group (n=47) and control group (n=47) between March 2020 and March 2022. The observation group was given ANH combined with intraoperative recycled autotransfusion, while control group was given routine allogeneic transfusion. The blood transfusion volume, oxygenation status, immune function, inflammatory indexes and adverse reactions in the two groups were compared. Results The banked blood transfusion volume was less in observation group than control group [(1.73±0.43) U vs (5.71±1.71) U, P

Objective To investigate the effects of platelet activation pathways on the characterization of platelet-derived extracellular vesicles(PEVs). Methods Whole blood from healthy donors was prepared into platelet suspension by centrifugation. Platelets were randomly divided into six groups, the ctrl group added no extra stimulus, and the other five groups were treated with collagen, adenosine diphosphate(ADP), thrombin, Ca2+ ionophore and freeze-thaw cycles (F-T) to activate platelets. Platelet-derived exosomes(PEXOs) and microvesicles(PMVs) were isolated by differential centrifugations, and then were determined by nano-flow cytometry and electron microscopy. The protein markers of PEXOs also were identified by western-blot. The protein concentration and content of PEXOs were also detected. Results CD9, CD81, TSG101 proteins were detected in all of the PEXOs, which had no calnexin. Both PEXOs and PMVs had CD41; PEXOs were cup-holder-like bilayer membrane vesicles under a transmission electron microscope, while PMVs were irregular membranous structure; 85%-95% of PEXOs were

Abstract Tomato (Solanum lycopersicum L.) is a major Solanaceae crop worldwide and is vulnerable to bacterial wilt (BW) caused by Ralstonia solanacearum during the production process. BW has become a growing concern that could enormously deplete the tomato yield from 50 to 100% and decrease the quality. Research on the molecular mechanism of tomato regulating BW resistance is still limited. In this study, two tomato inbred lines (Hm 2–2, resistant to BW; and BY 1–2, susceptible to BW) were used to explore the molecular mechanism of tomato in response to R. solanacearum infection by RNA-sequencing (RNA-seq) technology. We identified 1923 differentially expressed genes (DEGs) between Hm 2–2 and BY 1–2 after R. solanacearum inoculation. Among these DEGs, 828 were up-regulated while 1095 were down-regulated in R-3dpi (Hm 2–2 at 3 days post-inoculation with R. solanacearum) vs. R-mock (mock-inoculated Hm 2–2); 1087 and 2187 were up- and down-regulated, respectively, in S-3dpi (BY 1–2 at 3 days post-inoculation with R. solanacearum) vs. S-mock (mock-inoculated BY 1–2). Moreover, Gene Ontology (GO) enrichment analysis revealed that the largest amount of DEGs were annotated with the Biological Process terms, followed by Cellular Component and Molecular Function terms. A total of 114, 124, 85, and 89 regulated (or altered) pathways were identified in R-3dpi vs. R-mock, S-3dpi vs. S-mock, R-mock vs. S-mock, and R-3dpi vs. S-3dpi comparisons, respectively, by Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. These clarified the molecular function and resistance pathways of DEGs. Furthermore, quantitative RT-PCR (qRT-PCR) analysis confirmed the expression patterns of eight randomly selected DEGs, which suggested that the RNA-seq results were reliable. Subsequently, in order to further verify the reliability of the transcriptome data and the accuracy of qRT-PCR results, WRKY75, one of the eight DEGs was silenced by virus-induced gene silencing (VIGS) and the defense response of plants to R. solanacearum infection was analyzed. In conclusion, the findings of this study provide profound insight into the potential mechanism of tomato in response to R. solanacearum infection, which lays an important foundation for future studies on BW.

Abstract Stool characteristics are of great value to assess diseases, but patients knew little. E-learning applied in health popularization and patient education is booming. In China, WeChat applets has advantages of abundant users, convenient access and low cost, which may be a great media in patient education on stool. This preliminary study aims to develop and evaluate a stool card WeChat applet. We collected stools images during 2020 to 2022 in the Department of Gastroenterology and Hepatology in the Second Affiliated Hospital of Harbin Medical University, constructed a stool card applet named the Doctor Friend Primary Screening Stool Card (DFPSSC) and evaluated it. Eligible participants were divided into the applet, traditional paper media and control group. We implement a series of tests to evaluate the effectiveness. 20 clinicians and participants using the DFPSSC completed a questionnaire to evaluate the usability. We developed the DFPSSC for an E-learning approach. Of 108 volunteers, 97 completed the DFPSSC learning. No significant pretest differences were found among the three groups (P = 0.303). Applet group had significantly higher posttest scores than pretest scores in intervention (P

Abstract This study aimed to examine the effects of an adapted physical activity (APA) intervention on health-related physical fitness (HRPF) in adolescents with intellectual disability (ID). With a randomized controlled trial design, adolescents aged 12–18 years, with mild and moderate ID, and being overweight and obese were recruited and randomly assigned to either an intervention or a control group. The APA intervention consisted of overall moderate intensity aerobic and resistance exercise, with a duration of 45 min/session, a frequency of 2 sessions/week, and lasting for 9 months. A negative control was involved, in which participants received no treatment. Changes in four fitness tests, including the 9-min run/walk, handgrip strength, 30-s sit-ups, and sit-and-reach tests, were assessed between the groups using general linear models. A total of 57 participants (39 in the intervention group and 18 in the control group) completed the study. Significant mean differences in changes in the 9-min run/walk test (413.6 m [95% CI 146.72 m, 680.41 m], p = 0.003) and the right-side sit-and-reach test (2.2 cm [95% CI 0.37 cm, 4.09 cm], p = 0.020) respectively were observed in the intervention group, compared to the control group. No significant between-group improvement was observed for the handgrip strength and the 30-s sit-ups tests. The APA intervention induced beneficial effects on cardiorespiratory fitness and potential beneficial effects on flexibility for adolescents with ID. However, no significant effects of this intervention on muscular strength and endurance were observed in this study. Future studies should consider involving effective exercises in interventions to improve muscular strength and endurance.

Objective To investigate the matrix effect on the determination of potency in Recombinant Human Coagulation Factor Ⅷ for Injection (rFⅧ). Methods Two different detection matrices were used to establish two methods for detecting the potency in Recombinant Human Coagulation Factor Ⅷ for Injection. And the matrix effect on the determination of potency was determined, including specificity, linearity, repeatability, accuracy and intermediate precision. Results As to the specificity, the recoveries of the two substrates at high vs low concentration level were 112% and 110% vs 104% and 109%, respectively. As to the linearity, in the range of (0.125-1.000) IU/mL, the correlation coefficient between concentration and coagulation time of standard/ sample was higher than 0.99. As to the accuracy/repeatability, the recoveries of two matrices was 104% and 102%, and RSD was 2.4% and 1.9%. As to the intermediate precision, personnel factor of two matrices was 0.72 and 0.23, date factor was 0.79 and 0.85, and RSD(for 12 times) was 4.2% and 3.0%. Comparison of two matrices was as follows: Deviation in test results of 6 batches of rFⅧ was all lower than 5%. There was no significant difference between two matrices. Conclusion The two matrices for potency detection show good performance including specificity, linearity, repeatability, accuracy, and intermediate precision. They are suitable for the determination of potency in rFⅧ products.

Activated platelets secrete bioactive molecules and extracellular vesicles. Platelet-derived extracellular vesicles(PEVs), which are rich in proteins, have become important mediators of intercellular communication and cargo exchange, being involved in not only hemostasis and thrombosis, but also in immunity and tissue repair. In past decades, many advances have been made in the isolation, characterization and application of PEVs. Platelet activation modes influence the proteomic features of formed extracellular vesicles. The activation ways may be closely related to functional differences. This review summarized the proteomics and functions of PEVs induced by different platelet activation pathways.

Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.

Abstract CAR T-cell therapy is well tolerated and effective in patients with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). However, even second- generation anti-CD30 CAR T-cells with CD28 (28z) costimulatory domains failed to achieve the desired rate of complete responses. In the present study, we developed second-generation (CD28z) and third-generation (CD28BBz) CAR T-cells targeting CD30 and investigated their efficacy in vitro and in vivo. Both of CD28z and CD28BBz anti-CD30 CAR T cells were similar regarding amplification, T cell subsets distribution, T cell activity, effector/memory and exhaustion. However, we found that the 28BBz anti-CD30 CAR T-cells persist long-term, specifically homing to the tumor and mediating powerful antitumor activity in tumor xenograft models. Subsequently, we also demonstrated that the third generation anti-CD30 CAR T-cells have miner side effects or potential risks of tumorigenesis. Thus, anti-CD30 CAR T-cells represent a safe and effective treatment for Hodgkin lymphoma.

Objective To optimize the preparation conditions of platelets as biomarkers to ensure the preparation of platelet samples with low activation and good stability. Methods The platelet count, platelet activation rate and the count of residual leukocytes were compared among the control and four experimental groups with different centrifugation conditions (120g 10 min vs. 120g 15 min vs.120g 20 min vs.240g 20 min)and different formulations of protective solution, i.e.apyrase, dipyridamole, cilostazol and L-arginine (experimental group 1) vs.apyrase, dipyridamole, cilostazol and adenosine (experimental group 2) vs.apyrase, cilostazol, L-Arginine and adenosine (experimental group 3) vs. apyrase, dipyridamole, L-arginine and adenosine (experimental group 4). Results Platelets obtained by centrifugation at 120 g for 15 min(73.88±5.36) and centrifugation at 120 g for 10 min(77.65±3.07) had higher recovery rates than other experimental groups(52.77±7.86 and 37.71±13.82)(P0.05). The residual leukocytes in the experimental group centrifuged at 120g for 15 min was slightly lower than that in the experimental group centrifuged at 120 g for 10 min, with no statistical differences (P>0.05). The platelet activation rates of four experimental groups were all significantly lower than that of the control within 72 hours (P0.05). Conclusion For preparing platelets as biomarker samples, the group with solution including apyrase, dipyridamole, cilostazol and L-arginine, and centrifugation at 120 g for 15min, showed the minimum residual leukocytes and the optimum stability within 72 hours.

Objective To establish and optimize a method for the determination of aluminum (Al) residue by inductively coupled plasma mass spectrometry (ICP-MS). Methods Nitric acid solution was used to treat samples and standards. The concentration of nitric acid solution and equipment parameters were optimized, and the specificity, linearity, repeatability, accuracy, detection limit, quantitative limit and intermediate precision of the optimized detection method were investigated to confirm whether it was suitable for the determination of Al residue in human serum albumin. Results The concentration of nitric acid was 5%, and digest time was 4 h. The equipment condition of ICP-MS was as follows: RF power: 1600 W, sampling depth: 10 mm, atomizer / carrier gas flow rate: 1.0 L/ min, compensation flow rate: 0.5 L/ min, experimental mode: standard mode, integration time: 0.2 s, data acquisition: 3 times. Specificity: The recoveries of Al: 92% (high concentration, RSD=3.5%), 98% (low concentration, RSD=4.9%). Linearity: In the range of (0~40) μg/L, the correlation coefficient between concentration and optical energy signal (CPS) of standard / sample were higher than 0.999 0. Accuracy/ Repeatability: The recoveries of sample (3 concentration): 108% (RSD=4.7%), 110% (RSD=4.9%) and 110% (RSD=2.8%). The detection limit was 0.006 μg/L, and the quantitation limit was 0.019 μg/L. Intermediate precision: personnel factor and date factor, P>0.05, RSD (12 times)=2%. Comparison between ICP-MS and atomic absorption spectrometry (AAS): the deviation between ICP-MS and AAS was 8%, and that of samples was 3%, with no significant difference noticed between the two methods. Conclusion After optimization, ICP-MS method has shown good performance in terms of specificity, linearity, repeatability, accuracy, detection limit, quantitative limit and intermediate precision, and is suitable for the determination of Al residue in human albumin products of our company.

Abstract Complete mitochondrial genomes (mitogenomes) can provide useful information for phylogenetic relationships, gene rearrangement, and molecular evolution. In this study, the complete mitogenomes of two hermit crabs, Dardanus arrosor and Dardanus aspersus, were sequenced for the first time and compared with other published mitogenomes of Paguroidea. Each of the two mitogenomes contains an entire set of 37 genes and a putative control region, but they display different gene arrangements. The different arrangements of the two mitogenomes might be the result of transposition, reversal, and tandem duplication/random loss events from the ancestral pancrustacean pattern. Genome sequence similarity analysis reveals the gene rearrangement in 15 Paguroidea mitogenomes. After synteny analysis between the 15 Paguroidea mitogenomes, an obvious rearranged region is found in D. aspersus mitogenome. Across the 13 protein-coding genes (PCGs) tested, COI has the least and ND6 has the largest genetic distances among the 15 hermit crabs, indicating varied evolution rates of PCGs. In addition, the dN/dS ratio analysis shows that all PCGs are evolving under purifying selection. The phylogenetic analyses based on both gene order and sequence data present the monophyly of three families (Paguridae, Coenobitidae, and Pylochelidae) and the paraphyly of the family Diogenidae. Meanwhile, the phylogenetic tree based on the nucleotide sequences of 13 PCGs shows that two Dardanus species formed a sister group with five Coenobitidae species. These findings help to better understand the gene rearrangement and phylogeny of Paguroidea, as well as provide new insights into the usefulness of mitochondrial gene order as a phylogenetic marker.

Background Despite the potential detrimental consequences for individuals’ health and discrimination from covid-19 symptoms, the outcomes have received little attention. This study examines the relationships between having personally experienced discrimination based on the symptoms of covid-19 (during the first wave of the pandemic), mental health, and emotional responses (anger and sadness). It was predicted that covid-19 discrimination would be positively related to poor mental health and that this relationship would be mediated by the emotions of anger and sadness. Methods The study was conducted using an online questionnaire from January to June 2020 (the Covistress network; including 44 countries). Participants were extracted from the COVISTRESS database (Ntotal = 280) with about a half declaring having been discriminated due to covid-19 symptoms (N = 135). Discriminated participants were compared to non-discriminated participants using ANOVA. A mediation analysis was conducted to examine the indirect effect of emotional responses and the relationships between perceived discrimination and self-reported mental health. Results The results indicated that individuals who experienced discrimination based on the symptoms of covid-19 had poorer mental health and experienced more anger and sadness. The relationship between covid-19 personal discrimination and mental health disappeared when the emotions of anger and sadness were statistically controlled for. The indirect effects for both anger and sadness were statistically significant. Discussion This study suggests that the covid-19 pandemic may have generated discriminatory behaviors toward those suspected of having symptoms and that this is related to poorer mental health via anger and sadness.

Abstract Absence of bilateral internal carotid arteries is a rare congenital vascular dysplasia. We reported the case and present some typical and exquisite neuroimges for teaching.

IntroductionReasons for drug shortages are multi-factorial, and patients are greatly injured. So we needed to reduce the frequency and risk of drug shortages in hospitals. At present, the risk of drug shortages in medical institutions rarely used prediction models. To this end, we attempted to proactively predict the risk of drug shortages in hospital drug procurement to make further decisions or implement interventions.ObjectivesThe aim of this study is to establish a nomogram to show the risk of drug shortages.MethodsWe collated data obtained using the centralized procurement platform of Hebei Province and defined independent and dependent variables to be included in the model. The data were divided into a training set and a validation set according to 7:3. Univariate and multivariate logistic regression were used to determine independent risk factors, and discrimination (using the receiver operating characteristic curve), calibration (Hosmer-Lemeshow test), and decision curve analysis were validated.ResultsAs a result, volume-based procurement, therapeutic class, dosage form, distribution firm, take orders, order date, and unit price were regarded as independent risk factors for drug shortages. In the training (AUC = 0.707) and validation (AUC = 0.688) sets, the nomogram exhibited a sufficient level of discrimination.ConclusionsThe model can predict the risk of drug shortages in the hospital drug purchase process. The application of this model will help optimize the management of drug shortages in hospitals.

Abstract Platelets may serve as a perfect peripheral source for exploring diagnostic biomarkers for Alzheimer's disease (AD); however, the molecular linkage between platelet and the brain is missing. To find the common altered and driving molecules in both brain and the platelet, we performed an integrated analysis of our platelet omics and brain omics reported in the literature, and analyzed their correlations with AD‐specific pathology and cognitive impairment. By integrating the gene and protein expression profiles from 269 AD patients, we deduced 239 differentially expressed proteins (DEPs) appeared in both brain and the platelet, and 70.3% of them had consistent changes. Further analysis demonstrated that the altered brain and peripheral regulations were pinpointed into 10 imbalanced pathways. We also found that 117 DEPs, including ADAM10, were closely associated to the AD‐specific β‐amyloid and tau pathologies; and the changes of IDH3B and RTN1 had a potential diagnostic value for cognitive impairment analyzed by machine learning. Finally, we identified that HMOX2 and SERPINA3 could serve as driving molecules in neurodegeneration, and they were increased and decreased in AD patients, respectively. Together, this integrated brain and platelet omics provides a valuable resource for establishing efficient peripheral diagnostic biomarkers and potential therapeutic targets for AD.

Summary: Background: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). Methods: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. Findings: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. Interpretation: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. Funding: This study was supported by The National Natural Science Foundation of China.

Background and objectives The adverse effects of plasma donation on the body has lowered the odds of donation. The aim of this study was to investigate the prevalence of abnormal serum calcium and total serum protein related to plasma donation, identify the influencing factors, and come up with suggestions to make plasma donation safer. Methods Donors from 10 plasmapheresis centers in five provinces of China participated in this study. Serum samples were collected before donation. Serum calcium was measured by arsenazo III colorimetry, and the biuret method was used for total serum protein assay. An automatic biochemical analyzer was used to conduct serum calcium and total serum protein tests. Results The mean serum calcium was 2.3 ± 0.15 mmol/L and total serum protein was 67.75 ± 6.02 g/L. The proportions of plasma donors whose serum calcium and total serum protein were lower than normal were 20.55% (815/3,966) and 27.99% (1,111/3,969), respectively. There were significant differences in mean serum calcium and total serum protein of plasma donors with different plasma donation frequencies, gender, age, regions, and body mass index (BMI), (all p

Abstract The aim of this study was to analyze the role of blood biomarkers regarding preoperative inflammation and coagulation in predicting the postoperative in-hospital mortality of patients with type A acute aortic dissection (AAD). A total of 206 patients with type A AAD who had received surgical treatment were enrolled in this study. Patients were divided into two groups: the death group (28 patients who died during hospitalization) and the survival group (178 patients). Peripheral blood samples were collected before anesthesia induction. Preoperative levels of D-dimer, fibrinogen (FIB), platelet (PLT), white blood cells (WBC) and neutrophil (NEU) were compared between the two groups. Univariable and multivariable logistic regression analysis were utilized to identify the independent risk factors for postoperative in-hospital deaths of patients with type A AAD. Receiver operating characteristic (ROC) curve were used to analyze the predictive value of these indices in the postoperative in-hospital mortality of the patients. Univariable logistic regression analysis showed that the P values of the five parameters including D-dimer, FIB, PLT, WBC and NEU were all less than 0.1, which may be risk factors for postoperative in-hospital deaths of patients with type A AAD. Further multivariable logistic regression analysis indicated that higher preoperative D-dimer and WBC levels were independent risk factors for postoperative in-hospital mortality of patients with type A AAD. ROC curve analysis indicated that application of combining FIB and PLT could improve accuracy in prediction of postoperative in-hospital mortality in patients with type A AAD. Both preoperative D-dimer and WBC in patients with type A AAD may be used as independent risk factors for the postoperative in-hospital mortality of such patients. The combination of FIB and PLT may improve the accuracy of clinical prognostic assessment.

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.

Abstract Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer’s disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

Abstract The 2019 Ridgecrest, California seismic sequence, including an Mw6.4 foreshock and Mw7.1 mainshock, represent the largest regional seismic events within the past 20 years. To obtain accurate coseismic fault-slip distribution, we used precise positioning data of small earthquakes from January 2019 to October 2020 to determine the dip parameters of the eight fault geometry, and used the Interferometric Synthetic Aperture Radar (InSAR) data processed by Xu et al. (Seismol Res Lett 91(4):1979–1985, 2020) at UCSD to constrain inversion of the fault-slip distribution of both earthquakes. The results showed that all faults were sinistral strike-slips with minor dip-slip components, exception for dextral strike-slip fault F2. Fault-slip mainly occurred at depths of 0–12 km, with a maximum slip of 3.0 m. The F1 fault contained two slip peaks located at 2 km of fault S4 and 6 km of fault S5 depth, the latter being located directly above the Mw7.1hypocenter. Two slip peaks with maximum slip of 1.5 m located 8 and 20 km from the SW endpoint of the F2 fault were also identified, and the latter corresponds to the Mw6.4 earthquake. We also analyzed the influence of different inversion parameters on the fault slip distribution, and found that the slip momentum smoothing condition was more suitable for the inversion of the earthquakes slip distribution than the stress-drop smoothing condition.

Abstract Background Cholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment. Methods Immunoblotting and immunohistochemistry were used to assess the expression profiling of USP9X and EGLN3 in cholangiocarcinoma patients. ShRNA was used to silence gene expression. Cell apoptosis, cell cycle, CCK8, clone formation, shRNA interference and xenograft mouse model were used to explore biological function of USP9X and EGLN3. The underlying molecular mechanism of USP9X in cholangiocarcinoma was determined by immunoblotting, co-immunoprecipitation and quantitative real time PCR (qPCR). Results Here we demonstrated that USP9X is downregulated in cholangiocarcinoma which contributes to tumorigenesis. The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo. Clinical data demonstrated that expression levels of USP9X were positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that USP9X was involved in the deubiquitination of EGLN3, a member of 2-oxoglutarate and iron-dependent dioxygenases. USP9X elicited tumor suppressor role by preventing degradation of EGLN3. Importantly, knockdown of EGLN3 impaired USP9X-mediated suppression of proliferation. USP9X positively regulated the expression level of apoptosis pathway genes de through EGLN3 thus involved in apoptosis of cholangiocarcinoma. Conclusion These findings help to understand that USP9X alleviates the malignant potential of cholangiocarcinoma through upregulation of EGLN3. Consequently, we provide novel insight into that USP9X is a potential biomarker or serves as a therapeutic or diagnostic target for cholangiocarcinoma.

Abstract In this study, a wearable multichannel human magnetocardiogram (MCG) system based on a spin exchange relaxation-free regime (SERF) magnetometer array is developed. The MCG system consists of a magnetically shielded device, a wearable SERF magnetometer array, and a computer for data acquisition and processing. Multichannel MCG signals from a healthy human are successfully recorded simultaneously. Independent component analysis (ICA) and empirical mode decomposition (EMD) are used to denoise MCG data. MCG imaging is realized to visualize the magnetic and current distribution around the heart. The validity of the MCG signals detected by the system is verified by electrocardiogram (ECG) signals obtained at the same position, and similar features and intervals of cardiac signal waveform appear on both MCG and ECG. Experiments show that our wearable MCG system is reliable for detecting MCG signals and can provide cardiac electromagnetic activity imaging.

Abstract Background In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. Methods Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes. Results Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P

Introduction Circulating microRNAs (miRNAs) are widely identified as promi­sing and novel biomarkers for the diagnosis of human diseases. This study investigated the clinical value of miR-532-5p for asymptomatic carotid artery stenosis (CAS) patients and detected its predictive value for the occurrence of future cerebral ischaemic events (CIE). Material and methods Serum expression of miR-532-5p was measured using qRT-PCR. A receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of miR-532-5p in asymptomatic CAS patients, and the area under the curve (AUC) was calculated. The predictive value of miR-532-5p for the occurrence of CIE was evaluated by using Kaplan-Meier methods and Cox regression analysis. Results Serum expression of miR-532-5p was identified to be significantly decreased in CAS patients compared with healthy controls. The ROC curve with an AUC of 0.903 indicated high diagnostic accuracy of serum miR-532-5p expression in asymptomatic CAS patients. As Kaplan-Meier analysis results suggested, more CIE events were observed in cases with low miR-532-5p expression. Low miR-532-5p and high degree of carotid stenosis were independent factors for the occurrence of CIE in asymptomatic CAS patients. Conclusions The study suggests the potential clinical value of miR-532-5p for the early diagnosis of asymptomatic CAS patients. MiR-532-5p might have predictive value for the risk of future CIE in asymptomatic CAS patients.