Exosomal circ_0032704 confers sorafenib resistance to hepatocellular carcinoma and contributes to cancer malignant progression by modulating the miR-514a-3p/PD-L1 pathway.

Purpose: This study aims to explore the role of circ_0032704 in sorafenib-resistant hepatocellular carcinoma (HCC). Methods: The expression of circ_0032704, miR-514a-3p, and programmed death-ligand 1 (PD-L1) mRNA was detected by quantitative real-time PCR (qPCR). The expression of multidrug resistant-related proteins, migration/invasion-related proteins, exosome-related proteins, and PD-L1 protein was detected by western blot. Cell viability was detected by CCK-8 assay. Cell proliferation, migration, and invasion were assessed by EdU assay, wound healing assay, and transwell assay. The binding between miR-514a-3p and circ_0032704 or PD-L1 was verified by RIP assay, pull-down assay, and dual-luciferase reporter assay. Cell- or serum-derived exosomes were isolated and identified by TEM and NTA. Xenograft models were established to determine the effect of circ_0032704 on drug resistance in vivo. Results: Circ_0032704 was overexpressed in sorafenib-resistant HCC tissues and cells. Circ_0032704 knockdown reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells, while these effects were reversed by PD-L1 overexpression. We found that circ_0032704 positively regulated PD-L1 expression via targeting miR-514a-3p. Exosomes with circ_0032704 inhibition reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells. Exosomes with circ_0032704 inhibition also inhibited tumor growth in vivo. The expression of circ_0032704 in exosomes was stable and possessed diagnostic value. Conclusion: Circ_0032704 enhanced sorafenib resistance in HCC and promoted the malignant development of sorafenib-resistant HCC. Circ_0032704 could be transported by exosomes, and exosomal circ_0032704 had diagnostic value.

Cross-cultural experiences and self-development: a psychobiographical study of Bruce Lee.

A common challenge people face in today's cross-cultural world is how to solve a series of adaptation problems caused by cultural conflict. Exploring Bruce Lee's successful cross-cultural experiences through psychobiography offers some inspiration and thoughts. How did Bruce Lee successfully integrate martial arts, symbolising the Eastern culture, with films representing the Western culture, finally propelling kung fu films onto the international stage? Numerous publicly available materials about Bruce Lee were collected for this study, and the research data were evaluated using thematic analysis. Bruce Lee's success benefitted from reconstructing cultural environment information and exercising his initiative to shape a new cultural environment. His life experiences reflect individual cognition behaviour and social and cultural environments as two aspects of a dynamic circulation system and show that the two have reached internal and spiralling harmony through mutual integration. In the context of the Oriental collectivism culture's family narrative, Chinese adults' personality development features the unique theme of 'inheritance and innovation'. Dealing with the relationship between self-actualisation and familism is another important and challenging task in developing the Chinese personality.

Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

Dietary inflammatory index is associated with severe depression in older adults with stroke: a cross-sectional study.

Inflammation is involved in the pathogenesis of stroke and depression. We aimed to investigate the association between the dietary inflammatory index (DII) and depression in American adults with stroke. Adults with stroke were enrolled from the National Health and Nutrition Examination Survey between 2005 and 2018 in the United States. The DII was obtained from a 24-h dietary recall interview for each individual. Multivariate regression and restricted cubic spline analyses were conducted to evaluate the association between DII and depression in adults with stroke. The mean age of the 1,239 participants was 63.85 years (50.20% women), and the prevalence of depression was 18.26%. DII showed a linear and positive association with severe depression in adults with stroke (OR, 1.359; 95% CI, 1.021, 1.810; p for non-linearity=0.493). Compared with those in the lowest tertile of the DII, adults with stroke in the third tertile of the DII had a 3.222-fold higher risk of severe depression (OR, 3.222; 95% CI, 1.150, 9.026). In the stratified analyses, the association between DII score and severe depression was more significant in older adults (p for interaction=0.010) but not significant with respect to sex (p for interaction=0.184) or smoking status (p for interaction=0.396). No significant association was found between DII and moderate-to-moderately severe depression in adults with stroke. In conclusion, an increase in DII score was associated with a higher likelihood of severe depression in older adults with stroke.

The marine-derived compound TAG alleviates Parkinson's disease by restoring RUBCN-mediated lipid metabolism homeostasis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.

Efficacy and safety of piecemeal submucosal tunneling endoscopic resection for giant esophageal leiomyoma.

BACKGROUND AND AIMS: Giant esophageal leiomyoma usually requires a thoracotomy or thoracoscopic surgery, which is more invasive than an endoscopic treatment. The purpose of this study is to evaluate the efficacy and safety of piecemeal submucosal tunneling endoscopic resection (P-STER) for giant leiomyoma originating from the muscularis propria (MP) layer of the esophagus. METHODS: This is a retrospective study. Patients with giant esophageal leiomyoma (transverse diameter ≥ 3 cm) who underwent P-STER were enrolled from November 2012 to May 2023. Clinical data and results were investigated. RESULTS: A total of 16 patients were enrolled for analysis. The lesion mean transverse diameter and longitudinal diameter were 4.22 ± 1.20 cm and 6.20 ± 1.57 cm, respectively. Our mean operation time was 195.38 ± 84.99 min. The mean number of piecemeal resected was 4.31 ± 2.36. An adverse event noted was an esophageal fistula that occurred in one case (6.25%) and was treated conservatively. The mean length of hospital stay was around 11.81 ± 7.30 days. The mean total hospitalization cost was U.S. dollars (USD) $5976.50 ± 2866.39. No recurrence or metastasis was found during the follow-up period. CONCLUSIONS: P-STER can be an effective and safe treatment for giant leiomyoma originating from the MP layer of the esophagus.

Integrated Pharmaco-Bioinformatics Approaches and Experimental Verification To Explore the Effect of Britanin on Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent global liver disorder, posing substantial health risks. Britanin, a bioactive sesquiterpene lactone extracted from Inula japonica, has demonstrated antidiabetic, hypolipidemic, and hepatoprotective attributes. Nonetheless, the precise impact of Britanin on NAFLD and the intricate biological mechanisms underpinning this interaction remain unexplored. We integrated computer-aided methods to unearth shared biological targets and signaling pathways associated with both Britanin and NAFLD. A network was constructed by compiling putative targets associated with Britanin and NAFLD, followed by a stringent screening of key targets and mechanisms through protein-protein interaction analysis along with GO and KEGG pathway enrichment analyses. Molecular docking was integrated as an evaluation tool, culminating in the identification of HO-1 as the pivotal therapeutic target, showcasing a satisfactory binding affinity. The primary mechanism was ascribed to biological processes and pathways linked to oxidative stress, as evidenced by the outcomes of enrichment analyses. Of these, the AMPK/SREBP1c pathway assumed centrality in this mechanism. Furthermore, in vivo experiments substantiated that Britanin effectively curtailed NAFLD development by ameliorating liver injury, modulating hyperlipidemia and hepatic lipid accumulation, and alleviating oxidative stress and apoptosis. In summary, this study demonstrates the potential of Britanin as a promising therapeutic drug against NAFLD.

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors.

M6A is essential for tumor occurrence and progression. The expression patterns of m6A regulators differ in various kinds of tumors. Transcriptomic expression statistics together with clinical data from a database were analyzed to distinguish patients with digestive tract tumors. Based on the expression patterns of diverse m6A regulators, patients were divided into several clusters. Survival analysis suggested significant differences in patient prognosis among the m6A clusters. The results showed overlapping of m6A expression patterns with energy metabolism and nucleotide metabolism. Functional analyses imply that m6A modifications in tumor cells probably drive metabolic reprogramming to sustain rapid proliferation of cancer cells. Our analysis highlights the m6A risk characterizes various kinds of metabolic features and predicts chemotherapy sensitivity in digestive tract tumors, providing evidence for m6A regulators as markers to predict patient outcomes.

The miR-3074/BMP7 axis regulates TGF-ß-caused activation of hepatic stellate cells in vitro and CCl4-caused murine liver fibrosis in vivo.

Continuously progressive hepatic fibrosis might cause chronic liver diseases, resulting in hepatic failure. The activation of hepatic stellate cells (HSCs) residing in the liver might induce and influence hepatic fibrosis. In the present study, microRNA 3074 (miR-3074) was found increased within transforming growth factor-ß (TGF-ß)-activated HSCs and enriched within the TGF-ß signaling. In activated HSCs by TGF-ß, miR-3074 overexpression aggravated TGF-ß-induced fibrotic changes, whereas miR-3074 inhibition exerted opposite effects. miR-3074 directly targeted bone morphogenetic protein 7 (BMP7) and inhibited BMP7 expression. Under TGF-ß induction, overexpressed BMP7 notably attenuated the promotive roles of miR-3074 overexpression in TGF-ß-activated HSCs. Within carbon tetrachloride (CCl4)-caused liver fibrosis murine model, miR-3074 agomir administration promoted, while LV-BMP7 administration alleviated CCl4-induced fibrotic changes; LV-BMP7 significantly attenuated the effects of miR-3074 agomir. Lastly, mmu-miR-3074 also targeted mouse BMP7 and inhibited mouse BMP7 expression. In conclusion, the miR-3074/BMP7 axis regulates TGF-ß-caused activation of HSCs in vitro and CCl4-caused murine liver fibrosis in vivo. BMP7-mediated Smad1/5/8 activation might be involved.

The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study.

BACKGROUND: Interindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy. METHODS: IBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations. RESULTS: Approximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients. CONCLUSION: The gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment. TRIAL REGISTRATION: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

Feasibility of using chest computed tomography (CT) imaging at the first lumbar vertebra (L1) level to assess skeletal muscle mass: a retrospective study.

Background: Skeletal muscle mass is an essential parameter for diagnosing sarcopenia. The gold standard for assessing skeletal muscle mass is using computed tomography (CT) to measure skeletal muscle area at the third lumbar vertebra (L3) level. This study aims to investigate whether skeletal muscle mass could be evaluated at the first lumbar vertebra (L1) level using images obtained from routine chest CT scans. Methods: Skeletal muscle index (SMI, cm2/m2) and skeletal muscle density (SMD, HU) are commonly used to measure relative muscle mass and the degree of fat infiltration. This study used CT images at the L1 level to measure the skeletal muscle area (SMA, cm2) in 815 subjects from the health examination center. Linear regression analysis was used to explore the association between L1 and L3 measurements. The receiver operating characteristic (ROC) analysis was used to assess the predictive performance of L1 SMI for sarcopenia. The sex-specific cut-off values for low skeletal muscle mass in patients under the age of 60 were determined using the following formula: "mean - 1.28 × standard deviation." A multivariate linear regression model was established. Results: A significantly higher SMI at the L1 level was found in males than in females (43.88 ± 6.33 cm2/m2 vs 33.68 ± 5.03 cm2/m2; P < 0.001). There were strong correlations between measures at the L1 and L3 levels in both the total subject and sex-specific analyses. A negative association was found between age and L3 SMI in males (r = -0.231, P = 0.038). Both body mass index (BMI) and body surface area (BSA) were positively associated with L1 SMI in both males and females. A multivariate analysis was used to establish a prediction rule to predict SMI at the L3 level. The assessment of consistency and interchangeability between predicted and actual SMI at the L3 level yielded moderately good results. Considering the significant differences observed between male and female participants, the sex-specific cut-off values of the L1 SMI for defining low skeletal muscle mass were 36.52 cm2/m2 in males and 27.29 cm2/m2 in females. Conclusions: Based on a population from central China, the correlated indicators obtained at the L1 level from routine chest CT scans may serve as effective surrogate markers for those at the L3 level in assessing overall skeletal muscle mass.

Inhibition of ATM with KU-55933 Sensitizes Endometrial Cancer Cell Lines to Olaparib.

Background: Endometrial cancer (EC) is one of the most prevalent gynecologic cancers, which poses a serious threat to women's health worldwide. Olaparib, the first FDA-approved PARP inhibitor for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers, triggers apoptosis of cancer cells through synthetic lethality by inhibiting PARP1/2 enzymatic activity and BRCA1/2-dependent homologous recombination (HR) repair deficiency. However, the synergistic lethal effects between Olaparib and inhibitors of other DNA damage response proteins, such as ATM, PTEN and RAD51, are still unknown. Aim: Exploring the synergistic lethal effect between Olaparib and KU-55933 on EC. Methods: The GEPIA database was used to test EC patient survival rate. CCK8 was used for cell viability assays. Western blot was used for examining gene levels. The wound healing assay was used to detect cell migration ability. Flow cytometry was used for detecting the apoptosis rate. All experimental conditions were repeated independently in triplicate and analyzed in three separate experiments. Results: In this study, we discovered that the frequency of ATM alterations in endometrial cancer reaches nearly 20% and that there is a positive correlation between ATM alterations and prognosis. Furthermore, we discovered that endometrial cells with low expression levels of ATM are sensitive to Olaparib. Treatment with KU-55933, a specific inhibitor of ATM, significantly enhanced the sensitivity of endometrial cancer cells to Olaparib, as evidenced by colony formation, cell migration and apoptosis assay. Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation. Conclusion: Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.

Associations between homocysteine, vitamin B12, and folate and the risk of all-cause mortality in American adults with stroke.

Objective: Associations between plasma homocysteine (Hcy), vitamin B12, and folate and the risk of all-cause mortality are unclear. This study aimed to examine whether plasma Hcy, vitamin B12, and folate levels independently predict the risk of all-cause mortality in American adults with stroke. Methods: Data from the United States National Health and Examination Survey (NHANES; 1999-2006) were used and linked with the latest (2019) National Death Index (NDI). Cox proportional hazards models and restricted cubic splines were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of all-cause mortality for Hcy, folate, and B12 levels in adults with stroke. Sample weights were calculated to ensure the generalizability of the results. Results: A total of 431 participants were included (average age: 64.8 years). During a median follow-up of 10.4 years, 316 deaths occurred. Hcy was positively associated with all-cause mortality in adults with stroke (HR, 1.053; 95% CI: 1.026-1.080). Stroke patients with plasma Hcy levels in the fourth quartile had a 1.631-fold higher risk of all-cause mortality (HR, 1.631; 95% CI: 1.160-2.291) than those in the first quartile. The association between plasma Hcy and all-cause mortality was strong significant in older patients (p for interaction = 0.020). Plasma folate and vitamin B12 concentrations were inversely correlated with Hcy concentrations [B-value (95% CI): -0.032 (-0.056- -0.008), -0.004 (-0.007- -0.002), respectively]. No significant associations were observed between folate, vitamin B12 levels, and all-cause mortality in adults with stroke. Conclusion: Plasma Hcy levels were positively associated with all-cause mortality in older adults with stroke. Folate and vitamin B12 levels were inversely correlated with Hcy. Plasma Hcy may serve as a useful predictor in mortality risk assessment and targeted intervention in adults with stroke.

Efficacy of a basal insulin dose management smartphone application for controlling fasting blood glucose in patients with type-2 diabetes mellitus: A single-centre, randomised clinical study.

OBJECTIVE: To explore the efficacy and safety of the 'Walk with you' application for titrating basal insulin (BI) doses in type-2 diabetes mellitus (T2DM) hospitalised patients. METHODS: This was a randomised, single-centre, open-label, controlled clinical trial to compare the changes in fasting blood glucose (FBG) and postprandial blood glucose (PBG), time to reach target FBG (FBG-TRT), incidence of hypoglycaemia events and FBG coefficient of variation in the application group (weight-based titration of BI dose regimen) and control group (typical adjustment regimen). PATIENTS: This study selected 173 patients with T2DM using basal-prandial insulin therapy who were admitted to Binhaiwan Central Hospital of Dongguan between December 2021 and December 2022. Patients were randomised to the control group or the application group (App group) and then titrated to achieve an FBG concentration of less than 7.0 mmol/L. RESULTS: There were 86 patients in the control group and 87 patients in the App group. The FBG concentrations in the control and App groups were decreased by 6.77 ± 4.75 and 5.95 ± 4.06 mmol/L, respectively. The FBG-TRTs in the control and App groups were 3.80 ± 1.52 and 2.82 ± 1.34 days, respectively (p < .001). Fewer patients in the control group reached the FBG-TRT within 3 days than in the App group, with 46.5% and 71.3% of patients reaching that target, respectively. There was no significant between-group difference in hypoglycaemia incidence. CONCLUSION: The use of this weight-based insulin dose titration protocol for BI app is effective and safe for achieving the target FBG in noncritically ill patients with T2DM and is free, easy to use and user friendly.

Challenges of delivering care to older persons in the intensive care unit: A qualitative study based on the third wave of COVID-19 in China.

BACKGROUND: With the aging population and the ongoing pandemic, older persons account for a large proportion of ICU admissions. Despite numerous studies on the impact of COVID-19 on older persons, there has been a small body of research investigating nursing practice with critically ill older patients admitted to ICU for COVID-19. AIMS: To explore current challenges in the nursing care of older persons with severe COVID-19 through the experience of frontline nurses. STUDY DESIGN: A qualitative descriptive design was used. In-depth and semi-structured interviews with 18 ICU nurses were conducted to explore the experience of providing care for older persons with severe COVID-19 in the Omicron wave. A content analysis approach was adopted to analyse qualitative data. FINDINGS: Three themes emerged as follows: (1) no plan survives first contact with the enemy, (2) expectations versus Reality and (3) difficulty in providing holistic care. CONCLUSIONS: Challenges could be encountered in different stages of providing care for older persons with severe COVID-19, including the preparation and training of knowledge and skills in the early stage, the challenges posed by old age in the diagnostic and treatment stage and the challenges of psychological care and rehabilitation care. RELEVANCE TO CLINICAL PRACTICE: With the regular prevention and control of COVID-19, our study provides guidance for establishing measures (training courses of ICU nurses) to improve the nursing quality of older persons with severe COVID-19.

Associations between homocysteine and B vitamins and stroke: a cross-sectional study.

Objective: Homocysteine (Hcy) is a predictor for stroke. B vitamins are required for the metabolism of Hcy. We designed a study to investigate the associations of plasma Hcy and B vitamins with the prevalence of stroke in adults. Methods: A total of 8,371 adults were included in the National Health and Examination Survey (NHANES) between 2003-2006 in the United States. Multivariate regression analysis and smooth curve fitting were conducted to evaluate the associations of stroke prevalence with Hcy, folate, vitamin B6, and B12. A segmented regression model was used to analyze the threshold effects. Sample weights were calculated to ensure the results' generalizability. Results: The mean age of all participants was 46.43 years (51.8% women), and the prevalence of stroke was 2.72%. A nonlinear and positive association was found between plasma Hcy levels and the prevalence of stroke. Furthermore, L-shaped associations were found between plasma vitamin B6 and folate levels and stroke, with the turning point at 65.2 nmol/L for vitamin B6 and 26 nmol/L for folate, respectively. Vitamin B12 revealed a U-shaped relationship with stroke, with the turning points at 492.98 pmol/L for vitamin B12. Conclusion: Non-linear associations of plasma Hcy and B vitamins levels with stroke prevalence were found in American adults. These associations may have an implication that higher plasma Hcy levels should be reduced, and plasma vitamin B6, vitamin B12 and folate levels should be moderately improved in stroke prevention. Future studies are needed to verify the causality of these associations and elucidate the underlying mechanisms.

Development and external validation of a prognostic tool for nonsevere COVID-19 inpatients.

To develop a machine learning model and nomogram to predict the probability of persistent virus shedding (PVS) in hospitalized patients with coronavirus disease 2019 (COVID-19), the clinical symptoms and signs, laboratory parameters, cytokines, and immune cell data of 429 patients with nonsevere COVID-19 were retrospectively reviewed. Two models were developed using the Akaike information criterion (AIC). The performance of these two models was analyzed and compared by the receiver operating characteristic (ROC) curve, calibration curve, net reclassification index (NRI), and integrated discrimination improvement (IDI). The final model included the following independent predictors of PVS: sex, C-reactive protein (CRP) level, interleukin-6 (IL-6) level, the neutrophil-lymphocyte ratio (NLR), monocyte count (MC), albumin (ALB) level, and serum potassium level. The model performed well in both the internal validation (corrected C-statistic = 0.748, corrected Brier score = 0.201) and external validation datasets (corrected C-statistic = 0.793, corrected Brier score = 0.190). The internal calibration was very good (corrected slope = 0.910). The model developed in this study showed high discriminant performance in predicting PVS in nonsevere COVID-19 patients. Because of the availability and accessibility of the model, the nomogram designed in this study could provide a useful prognostic tool for clinicians and medical decision-makers.

Successful surgical repair in an older adult with supracardiac total anomalous pulmonary venous connection: A case report.

Total anomalous pulmonary venous connection (TAPVC) is a rare, cyanotic and critical congenital heart disease where the entire left and right pulmonary veins fail to drain into the left atrium directly. Also, TAPVC-induced tissue hypoxia gradually worsens after birth. Thus, timely surgical repairs are recommended once diagnosed, particularly with pulmonary venous drainage obstruction(s). Nonetheless, in sporadic cases, patients with TAPVC survive to adulthood with no surgical treatment. Herein, we report a 46-year-old female with TAPVC, where the four pulmonary veins drain into to the innominate vein (IV) via the vertical vein. The patient developed palpitations and non-anginal chest pain following routine activities for over three months. The patient had a successful surgical correction with excellent postoperative recovery.

Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation.

Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.