USP7 promotes IgA class switching through stabilizing RUNX3 for germline transcription activation.

Class switch recombination (CSR) diversifies the effector functions of antibodies and involves complex regulation of transcription and DNA damage repair. Here, we show that the deubiquitinase USP7 promotes CSR to immunoglobulin A (IgA) and suppresses unscheduled IgG switching in mature B cells independent of its role in DNA damage repair, but through modulating switch region germline transcription. USP7 depletion impairs Sα transcription, leading to abnormal activation of Sγ germline transcription and increased interaction with the CSR center via loop extrusion for unscheduled IgG switching. Rescue of Sα transcription by transforming growth factor ß (TGF-ß) in USP7-deleted cells suppresses Sγ germline transcription and prevents loop extrusion toward IgG CSR. Mechanistically, USP7 protects transcription factor RUNX3 from ubiquitination-mediated degradation to promote Sα germline transcription. Our study provides evidence for active transcription serving as an anchor to impede loop extrusion and reveals a functional interplay between USP7 and TGF-ß signaling in promoting RUNX3 expression for efficient IgA CSR.

MEG3 in hematologic malignancies: from the role of disease biomarker to therapeutic target.

Maternally expressed gene 3 ( MEG3 ) is a noncoding RNA that is known as a tumor suppressor in solid cancers. Recently, a line of studies has emphasized its potential role in hematological malignancies in terms of tumorigenesis, metastasis, and drug resistance. Similar to solid cancers, MEG3 can regulate various cancer hallmarks via sponging miRNA, transcriptional, or posttranslational regulation mechanisms, but may regulate different key elements. In contrast with solid cancers, in some subtypes of leukemia, MEG3 has been found to be upregulated and oncogenic. In this review, we systematically describe the role and underlying mechanisms of MEG3 in multiple types of hematological malignancies. Particularly, we highlight the role of MEG3 in drug resistance and as a novel therapeutic target.

Independent associations of education, intelligence, and cognition with gastrointestinal diseases and the mediating effects of risk factors: a Mendelian randomization study.

Background: Education, intelligence and cognition affect occupational performance and socioeconomic status and may influence virous diseases development. However, the impact of these factors on gastrointestinal diseases and their mediating risk factors remains unclear. Methods: We utilized genome-wide association studies from European ancestry populations to perform two-sample Mendelian randomization analyses, aiming to estimate genetic instruments associated with education, intelligence, or cognition in relation to 24 gastrointestinal diseases Subsequently, we evaluated 14 potential mediators of this association and calculated the corresponding mediated proportions through two-step Mendelian randomization analyses. Result: As the dominant factor in gastrointestinal diseases, education had a statistically significant association with 2 gastrointestinal diseases (acute pancreatitis, gastroesophageal reflux) and a suggestive association with 6 diseases (cirrhosis, alcoholic liver disease, cholecystitis, cholelithiasis, chronic gastritis and gastric ulcer). Of the 14 mediators, smoking and adiposity traits played a major role in mediating the effects. Conclusion: The study demonstrated the causal, independent impact of education on specific gastrointestinal diseases. Smoking and adiposity traits emerged as primary mediators, illuminating potential avenues for targeted interventions for prevention of them.

Environment and social support for smoking cessation among community smokers in Beijing, China.

INTRODUCTION: This study investigated the relationship between environment support, social support and smoking cessation, to provide suggestions for the construction of environment and social support for tobacco control. METHODS: This was a secondary analysis based on two cross-sectional surveys of adult smokers who participated in the six-month community smoking cessation intervention projects in Beijing. The study subjects were divided into a successful group (n=159) and an unsuccessful group (n=253). The status of the environment support, community tobacco exposure, and social support were compared between groups. A structural equation model (SEM) was established for Confirmatory Factor Analysis. RESULTS: The univariate analysis showed that there were differences in smoking cessation outcomes among smokers with different home tobacco regulations, workplace tobacco regulations and number of smokers in the family. Differences in 6-month smoking reduction were also found with different promotion levels of anti-tobacco messaging and the frequency of smoking events at home. The logistic regression analysis indicated that home tobacco regulations (OR=1.30; 95% CI: 1.00-1.69), workplace tobacco regulations (OR=1.27; 95% CI: 1.05- 1.54), and frequency of smoking events at home (OR=1.15; 95% CI: 1.02-1.29), were associated with smoking cessation. The results of the SEM showed that environment support (ß=0.39; 95% CI: 0.05-0.73, p=0.026) and social support (ß=0.37; 95% CI: 0.05-0.68, p=0.022) had influence on smoking cessation. CONCLUSIONS: Environment support and social support are related to smoking cessation. Attention should be paid to the smoking regulations at home and workplace, anti-tobacco messaging, and social support by the family. TRIAL REGISTRATION: The study was registered on the official website of the China Clinical Trial Registration Center. Identifier: ChiCTR1900024991.

The Effect of Annealing on the Soft Magnetic Properties and Microstructure of Fe82Si2B13P1C3 Amorphous Iron Cores.

This research paper investigated the impact of normal annealing (NA) and magnetic field annealing (FA) on the soft magnetic properties and microstructure of Fe82Si2B13P1C3 amorphous alloy iron cores. The annealing process involved various methods of magnetic field application: transverse magnetic field annealing (TFA), longitudinal magnetic field annealing (LFA), transverse magnetic field annealing followed by longitudinal magnetic field annealing (TLFA) and longitudinal magnetic field annealing followed by transverse magnetic field annealing (LTFA). The annealed samples were subjected to testing and analysis using techniques such as differential scanning calorimetry (DSC), transmission electron microscopy (TEM), X-ray diffraction (XRD), magnetic performance testing equipment and magneto-optical Kerr microscopy. The obtained results were then compared with those of commercially produced Fe80Si9B11. Fe82Si2B13P1C3 demonstrated the lowest loss of P1.4T,2kHz = 8.1 W/kg when annealed in a transverse magnetic field at 370 °C, which was 17% lower than that of Fe80Si9B11. When influenced by the longitudinal magnetic field, the magnetization curve tended to become more rectangular, and the coercivity (B3500A/m) of Fe82Si2B13P1C3 reached 1.6 T, which was 0.05 T higher than that of Fe80Si9B11. During the 370 °C annealing process of the Fe82Si2B13P1C3 amorphous iron core, the internal stress in the strip gradually dissipated, and impurity domains such as fingerprint domains disappeared and aligned with the length direction of the strip. Consequently, wide strip domains with low resistance and easy magnetization were formed, thereby reducing the overall loss of the amorphous iron core.

Mechanism of community quitters' psychological traits on their smoking cessation effects: Based on a study of community intervention.

INTRODUCTION: We study the relationship between psychological traits of smokers and their smoking cessation effects, and provide more scientific evidence for smoking cessation intervention. METHODS: The study was conducted as a nested case-control study. Smokers who participated in the community smoking cessation intervention projects in Beijing in 2018-2020, were selected as the research participants and divided into two groups: a successful smoking cessation and unsuccessful smoking cessation group, according to their smoking cessation effects at 6 months. Psychological traits of quitters including smoking abstinence self-efficacy, willingness to quit smoking, and trait coping style, were compared between the two groups, and a structural equation model was established for confirmatory factor analysis to analyze their mechanisms. RESULTS: There were differences in smoking cessation results between the successful smoking cessation group and the unsuccessful smoking cessation group in terms of smoking abstinence self-efficacy and willingness to quit smoking. Willingness to quit smoking (OR=1.06; 95% CI: 1.008-1.118) is a risk factor, while smoking abstinence self-efficacy in habit/addiction situations (OR=0.77; 95% CI: 0.657-0.912) is a protective factor. The results of the structural equation model showed that smoking abstinence self-efficacy (ß=0.199, p=0.002) and trait coping style (ß= -0.166, p=0.042) could influence smoking cessation effects. The structural equation model was well fitted, which showed that smoking abstinence self-efficacy (ß=0.199, p=0.002) and trait coping style (ß= -0.166, p=0.042) might have influenced the effect of smoking cessation among smokers. CONCLUSIONS: Willingness to quit smoking has a positive impact on the smoking cessation effect, while smoking abstinence self-efficacy in habit/addiction situations and negative trait coping style have a negative impact. Smoking abstinence self-efficacy and trait coping styles can significantly affect smoking cessation outcomes.

An intervention study on a hospital-community integrated management model of tobacco dependence based on a community intervention trial.

Objective: To assess the effect of the hospital-community integrated management model of tobacco dependence on smoking cessation among community residents compared with a brief smoking cessation intervention. Methods: Our study recruited 651 smokers who were willing to quit in 19 communities in Beijing and conducted a 6-month smoking cessation intervention. The control group receiving a brief smoking cessation intervention and the pilot group receiving an integrated smoking cessation intervention. Intention-to-treat analysis (ITT) and generalized estimating equations were used to assess the effects of the integrated intervention and smoking cessation medication on average number of cigarettes smoked per day (ACSD) and smoking cessation rate. Results: Simple effects analysis showed that smokers taking medication had significantly lower ACSD than those not taking medication at follow-up, the control group reduced smoking by 3.270, 4.830, and 4.760 cigarettes in the first, third and sixth months, respectively, while the pilot group reduced by 6.230, 5.820, and 4.100 cigarettes. The integrated intervention significantly reduced ACSD among medication-taking smokers at 1st month (reduced by 3.420, P < 0.05) and 3rd month (reduced by 2.050, P < 0.05), but had no significant effect among non-medication taking smokers. The 3rd month smoking cessation rate among medication-taking smokers was 27.0%, which was significantly higher than the smokers with brief smoking cessation intervention. Conclusion: The integrated hospital-community intervention can significantly promote smoking cessation among smokers taking medication, but the issue of payment for medication and additional labor compensation for medical staff should be addressed before its popularization.

A Cost-Effectiveness Analysis of Comprehensive Smoking-Cessation Interventions Based on the Community and Hospital Collaboration.

Background: The prevalence of cigarette smoking in China is high and the utilization of smoking cessation clinics is very low. Multicomponent smoking cessation interventions involving community and hospital collaboration have the potential to increase the smoking cessation rate. However, the cost-effectiveness of this intervention model is unknown. Methods: We conducted a smoking cessation intervention trial in 19 community health service centers in Beijing, China. A cost-effectiveness analysis was performed from a societal perspective to compare three strategies of smoking cessation: no intervention (NI), pharmacological intervention (PI), and comprehensive intervention (CI) (PI plus online health promotion). A Markov model, with a time horizon of 20 years, was used to simulate the natural progression of estimated 10,000 male smokers. A cross-sectional survey was conducted to obtain data on costs and quality-adjusted life years (QALYs) by using the five-level EuroQol-5-dimension (EQ-5D-5L) questionnaire. Probabilistic sensitivity analysis was performed to explore parameters of uncertainty in the model. Results: A total of 680 participants were included in this study, including 283 in the PI group and 397 in the CI group. After 6 months of follow-up, the smoking cessation rate reached 30.0% in the CI group and 21.2% in the PI group. Using the Markov model, compared with the NI group, the intervention strategies of the PI group and the CI group were found to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of $535.62/QALY and $366.19/QALY, respectively. The probabilistic sensitivity analysis indicated that the CI strategy was always the most cost-effective intervention. Conclusion: CI for smoking cessation, based in hospital and community in China, is more cost-effective than PI alone. Therefore, this smoking cessation model should be considered to be implemented in healthcare settings.

Alternative end-joining in BCR gene rearrangements and translocations.

Programmed DNA double-strand breaks (DSBs) occur during antigen receptor gene recombination, namely V(D)J recombination in developing B lymphocytes and class switch recombination (CSR) in mature B cells. Repair of these DSBs by classical end-joining (c-NHEJ) enables the generation of diverse BCR repertoires for efficient humoral immunity. Deletion of or mutation in c-NHEJ genes in mice and humans confer various degrees of primary immune deficiency and predisposition to lymphoid malignancies that often harbor oncogenic chromosomal translocations. In the absence of c-NHEJ, alternative end-joining (A-EJ) catalyzes robust CSR and to a much lesser extent, V(D)J recombination, but the mechanisms of A-EJ are only poorly defined. In this review, we introduce recent advances in the understanding of A-EJ in the context of V(D)J recombination and CSR with emphases on DSB end processing, DNA polymerases and ligases, and discuss the implications of A-EJ to lymphoid development and chromosomal translocations.

Pituitary stalk interruption syndrome: A rare case report and literature review.

RATIONALE: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe, and hypoplastic or aplastic anterior lobe. Moreover, this condition is considered rare. PATIENT CONCERNS: A 23-year-old male patient presented with a history of short stature and hypogonadism. Laboratory assessment revealed low thyroxine, cortisol, and adrenocorticotropic hormone levels, which are consistent with adrenal insufficiency without hypoglycemia. The insulin-induced hypoglycemia tolerance test finding indicated growth hormone (GH) deficiency. Moreover, magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. This triad of symptoms was indicative of PSIS. DIAGNOSIS: INTERVENTIONS:: The patient was deficient in adrenaline, thyroxine, gonadal steroid, and GH. Thus, glucocorticoid replacement therapy was initiated, followed by euthyrox, androgen, and human chorionic gonadotropin treatment. Calcium tablets, calcitriol, and alendronate sodium were used for the management of osteoporosis. The patient was 164 cm tall, and his bone age was approximately 15 years old. However, owing to a poor economic condition, the family did not proceed with GH therapy. OUTCOMES: The patient did not present with adrenal or hypothyroidism crisis after receiving poly-hormonal replacement therapy. His secondary sexual characteristics began to develop. However, owing to a short treatment window period, the patient could not receive the required treatment. Hence, whether the patient would have a normal fertility function needs to be confirmed. LESSONS: PSIS is a rare disease with various clinical characteristics. During the neonatal period and infancy, the signs and symptoms of PSIS are often not evident. Therefore, diagnosis is delayed. The early detection of hormone deficiency and treatment initiation can affect both the quality of life and the prognosis of patients with PSIS. Thus, the diagnosis and treatment of this disease must be improved to help patients achieve a better quality of life and to prevent reproductive health problems.

Spexin alleviates insulin resistance and inhibits hepatic gluconeogenesis via the FoxO1/PGC-1α pathway in high-fat-diet-induced rats and insulin resistant cells.

Objective: Recent studies demonstrate circulating serum spexin levels are reduced in obesity or type 2 diabetes mellitus (T2DM) patients and may play a role in glucose metabolism. The mechanism underlying is not known. In this study, we explore whether spexin has a role in insulin resistance and hepatic glucose metabolism. Methods: The correlation between serum spexin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) was studied in newly diagnosed T2DM patients. After intraperitoneal injection of exogenous spexin for 8 weeks, the effect of spexin on exogenous glucose infusion rates (GIR), and hepatic glucose production (HGP) were assessed by extended hyperinsulinemic-euglycemic clamp in high-fat-diet (HFD)-induced rats. Glucose concentration with CRISPR/Cas9-mediated disruption of spexin expression in HepG2 cells culture was observed. Expression of transcription factors (Forkhead box O1, FoxO1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α) and key enzymes (G-6-Pase and PEPCK) of gluconeogenesis pathway were observed in vitro and in vivo. Results: The serum spexin level was significantly low in newly diagnosed T2DM patients as compared with healthy patients and significantly negatively correlated with the HOMA-IR values. Exogenous spexin treatment resulted in weight loss and decrease of HOMA-IR value in high-fat-diet (HFD)-induced rats. The exogenous glucose infusion rates (GIR) were higher in the HFD + spexin group than that in the HFD group (358 ± 32 vs. 285 ± 24 µmol/kg/min, P < 0.05). Steady-state hepatic glucose production (HGP) was also suppressed by ~50% in the HFD + spexin group as compared with that in the HFD group. Furthermore, spexin inhibited gluconeogenesis in dose-dependent and time-dependent manner in the insulin-resistant cell model. CRISPR/Cas9-mediated knockdown of spexin in HepG2 cells activated gluconeogenesis. Moreover, spexin was shown regulating gluconeogenesis by inhibiting FoxO1/PGC-1α pathway, and key gluconeogenic enzymes, (PEPCK and G-6-Pase) in both HFD-induced rats and insulin-resistant cells. Conclusions: Spexin plays an important role in insulin resistance in HFD-induced rats and insulin-resistant cells. Regulation of the effects of spexin on insulin resistance may hold therapeutic value for metabolic diseases.

Increased Serum ANGPTL8 Concentrations in Patients with Prediabetes and Type 2 Diabetes.

The objectives of the study were to investigate serum ANGPTL8 concentrations in different glucose metabolic statuses and to explore the correlations between serum ANGPTL8 levels and various metabolic parameters. Serum ANGPTL8 levels were determined using ELISA in 22 subjects with NGT (normal glucose tolerance), 74 subjects with IGR (impaired glucose regulation), and 33 subjects with T2DM (type 2 diabetes mellitus). Subjects with IFG, IGT, CGI, and T2DM had higher levels of serum ANGPTL8 than subjects with NGT. Serum ANGPTL8 was positively correlated with FPG, fasting C-peptide, and postprandial C-peptide and negatively correlated with BETA/IR when adjusted for age and BMI. Multivariate analysis suggested FPG and fasting C-peptide as independent factors associated with serum ANGPTL8 levels. Serum ANGPTL8 concentrations were significantly increased in IGR and T2DM. Serum ANGPTL8 might play a role in the pathological mechanism of glucose intolerance.

Gender Disparity in the Relationship between Prevalence of Thyroid Nodules and Metabolic Syndrome Components: The SHDC-CDPC Community-Based Study.

The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required.

Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.

Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.

The interplay between surfaces and soluble factors define the immunologic and angiogenic properties of myeloid dendritic cells.

BACKGROUND: Dendritic cells (DCs) are antigen presenting cells capable of inducing specific immune responses against microbial infections, transplant antigens, or tumors. Interestingly, microenvironment conditions such as those present in tumor settings might induce a DC phenotype that is poorly immunogenic and with the capability of promoting angiogenesis. We hypothesize that this plasticity may be caused not only by the action of specific cytokines or growth factors but also by the properties of the surfaces with which they interact, such as extracellular matrix (ECM) components. RESULTS: Herewith we studied the effect of different surfaces and soluble factors on the biology of DCs. To accomplish this, we cultured murine myeloid(m) DCs on surfaces coated with fibronectin, collagen I, gelatin, and Matrigel using poly-D-lysine and polystyrene as non-biological surfaces. Further, we cultured these cells in the presence of regular DC medium (RPMI 10% FBS) or commercially available endothelial medium (EGM-2). We determined that mDCs could be kept in culture up to 3 weeks in these conditions, but only in the presence of GM-CSF. We were able to determine that long-term DC cultures produce an array of angiogenic factors, and that some of these cultures still retain the capability to induce T cell responses. CONCLUSIONS: Altogether these data indicate that in order to design DC-based vaccines or treatments focused on changing the phenotype of DCs associated with diseases such as cancer or atherosclerosis, it becomes necessary to fully investigate the microenvironment in which these cells are present or will be delivered.