Bidirectional association between inflammatory bowel disease and type 1 diabetes: a nationwide matched cohort and case-control study.

Background: Co-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes, but evidence on their bidirectional associations remain scarce. This study aims to investigate their bidirectional associations. Methods: A nationwide matched cohort and case-control study with IBD patients identified between 1987 and 2017. The cohort study included 20,314 IBD patients (≤28 years; Crohn's disease [CD, n = 7277], ulcerative colitis [UC, n = 10,112], and IBD-unclassified [IBD-U, n = 2925]) and 99,200 individually matched reference individuals, with a follow-up until December 2021. The case-control study enrolled 87,001 IBD patients (no age restriction) and 431,054 matched controls. We estimated adjusted hazard ratio (aHR) of incident T1D in the cohort study with flexible parametric survival model and adjusted odds ratio (aOR) of having a prior T1D in the case-control study with conditional logistic regression model, with 95% confidence intervals (CI). Findings: During a median follow-up of 14 years, 116 IBD patients and 353 reference individuals developed T1D. Patients with IBD had a higher hazard of developing T1D (aHR = 1.58 [95% CI = 1.27-1.95]). The hazard was increased in UC (aHR = 2.02 [1.51-2.70]) but not in CD or IBD-U. In the case-control study, a total of 1018 (1.2%) IBD patients and 3496 (0.8%) controls had been previously diagnosed with T1D. IBD patients had higher odds of having prior T1D (aOR = 1.36 [1.26-1.46]). Such positive association was observed in all IBD subtypes. The sibling comparison analyses showed similar associations between IBD and T1D (aHR = 1.44 [0.97-2.15] and aOR = 1.32 [1.18-1.49]). Interpretation: Patients with IBD had a moderately increased hazard of developing T1D and higher odds of having prior T1D. Their bidirectional associations may be partially independent of shared familial factors. Funding: European Crohn's and Colitis Organisation, Stiftelsen Professor Nanna Svartz Fond, SSMF (project#: PG-23-0315-H-02), Ruth and Richard Julin Foundation; and FORTE (project#: 2016-00424).

Birth Weight, Gestational Age, and Risk of Pediatric-Onset MASLD.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide and is increasingly being diagnosed at younger ages, affecting more than one-third of young people with obesity. Objective: To evaluate associations between perinatal conditions and risk of MASLD and associated progressive liver disease. Design, Setting, and Participants: This nationwide, population-based case-control study included all biopsy-confirmed cases of MASLD in Sweden. Individuals aged 25 years or younger (hereafter, young individuals) with biopsy-proven MASLD between January 1, 1992, and December 31, 2016, were matched to up to 5 general population control individuals. Granular data on maternal and perinatal characteristics were retrieved from the Swedish Medical Birth Register. Data were analyzed from June 2023 to June 2024. Exposures: Birth weight (low [<2500 g], reference [2500 to <4000 g], or high [≥4000 g]), gestational age (GA), and birth weight for GA (small for GA [SGA; <10th percentile], appropriate for GA [10th-90th percentile], or large for GA [LGA; >90th percentile]), compared between patients and matched controls. Main Outcomes and Measures: The main outcome was odds of biopsy-proven MASLD and MASLD-associated progressive liver disease (ie, liver fibrosis or cirrhosis) according to birth weight, GA, and birth weight for GA, adjusted for matching factors. Results: In total, 165 young individuals with biopsy-proven MASLD (median age at diagnosis: 12.0 years [IQR, 4.4-16.9 years]; 100 [60.6%] male) were matched with 717 controls. There was an association between low birth weight and future development of MASLD (adjusted odds ratio [AOR], 4.05; 95% CI, 1.85-8.88) but no association between high birth weight and odds of MASLD (AOR, 0.64; 95% CI, 0.38-1.08) compared with the reference birth weight. An association was seen for SGA (AOR, 3.36; 95% CI, 2.00-5.64) compared with appropriate size for GA (reference category) but not for LGA (AOR, 0.57; 95% CI, 0.27-1.20). Progressive liver disease was more common in individuals born with low birth weight (AOR, 6.03; 95% CI, 1.66-21.87) or SGA (AOR, 4.90; 95% CI, 2.15-11.14). Conclusions and Relevance: In this nationwide study of young individuals with biopsy-proven MASLD, low birth weight and SGA were associated with development of MASLD and progressive liver disease, suggesting a need for structured screening measures to diagnose these conditions early in high-risk individuals.

An infusible biologically active adhesive for chemotherapy-related heart failure in elderly rats.

Chemotherapy-induced cardiotoxicity with subsequent heart failure (HF) is a major cause of morbidity and mortality in cancer survivors worldwide. Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation. To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF, we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive (MISA) that could be delivered locally through an endoscope-guided intrapericardial injection. To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients, we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections. In vitro, we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability, but also inhibited their apoptosis. In vivo, we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation, angiogenesis, and mitochondrial respiration. Additionally, we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system. In general, our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.

Enantioselective Hydroaminoalkylation of Azaaryl Ketones through Asymmetric Photoredox Catalysis.

An enantioselective hydroaminoalkylation of azaaryl ketones under a transition-metal-free asymmetric photoredox catalysis platform is reported. A series of valuable azaarene-functionalized 1,2-amino alcohols featuring attractive quaternary carbon stereocenters have been synthesized in high yields with good to excellent enantioselectivities. The viability of readily accessible N-aryl glycines as reaction partners facilitates the conjugate modification of these products into important derivatives, thereby enhancing the synthetic utility of the current approach.

Risk of heart failure in inflammatory bowel disease: a Swedish population-based study.

BACKGROUND AND AIMS: Dysregulation of inflammatory and immune responses has been implicated in the pathogenesis of heart failure (HF). But even if inflammation is a prerequisite for inflammatory bowel disease (IBD), little is known about HF risk in IBD. METHODS: In this Swedish nationwide cohort, patients with biopsy-confirmed IBD were identified between 1969 and 2017 [n = 81 749, Crohn's disease (CD, n = 24 303), ulcerative colitis (UC, n = 45 709), and IBD-unclassified (IBD-U, n = 11 737)]. Each patient was matched with up to five general population reference individuals (n = 382 190) and IBD-free full siblings (n = 95 239) and followed until 31 December 2019. Flexible parametric survival models estimated the adjusted hazard ratio (aHR) and standardized cumulative incidence for HF, with 95% confidence intervals (CI). RESULTS: There were 5582 incident HF identified in IBD patients (incidence rate [IR]: 50.3/10 000 person-years) and 20 343 in reference individuals (IR: 37.9) during a median follow-up of 12.4 years. IBD patients had a higher risk of HF than reference individuals (aHR 1.19, 95% CI 1.15-1.23). This increased risk remained significant ≥20 years after IBD diagnosis, leading to one extra HF case per 130 IBD patients until then. The increased risk was also observed across IBD subtypes: CD (IR: 46.9 vs. 34.4; aHR 1.28 [1.20-1.36]), UC (IR: 50.1 vs. 39.7; aHR 1.14 [1.09-1.19]), and IBD-U (IR: 60.9 vs. 39.0; aHR 1.28 [1.16-1.42]). Sibling-controlled analyses showed slightly attenuated association (IBD: aHR 1.10 [1.03-1.19]). CONCLUSIONS: Patients with IBD had a moderately higher risk of developing HF for ≥20 years after IBD diagnosis than the general population.

Long-term risk of myocarditis in patients with inflammatory bowel disease: a nationwide cohort study in Sweden.

OBJECTIVES: Despite a suggested link between inflammatory bowel disease (IBD) and myocarditis, the association has not been well-established. This study aimed to investigate the long-term risk of myocarditis in patients with IBD. METHODS: This nationwide cohort involved all patients with biopsy-confirmed IBD in Sweden (1969-2017) (n=83,264, Crohn's disease [CD, n=24,738], ulcerative colitis [UC, n=46,409], and IBD-unclassified [IBD-U, n=12,117]), general population reference individuals (n=391,344), and IBD-free full siblings (n=96,149), and followed until 2019. Primary outcome was incident myocarditis and secondary outcome was severe myocarditis (complicated with heart failure, death, or readmission). Flexible parametric survival models were used to estimate adjusted hazard ratios (aHR) and cumulative incidence of outcomes, along with 95% confidence intervals (CIs). RESULTS: During a median follow-up of 12 years, there were 256 myocarditis cases in IBD patients (incidence rate [IR]=22.6/100,000 person-years) and 710 in reference individuals (IR=12.9), with an aHR of 1.55 (95%CI: 1.33 to 1.81). The increased risk persisted through 20 years after IBD diagnosis, corresponding to one extra myocarditis case in 735 IBD patients until then. This increased risk was observed in CD (aHR=1.48 [1.11 to 1.97]) and UC (aHR=1.58 [1.30 to 1.93]). IBD was also associated with severe myocarditis (IR: 10.1 vs. 3.5; aHR=2.44 [1.89 to 3.15]), irrespective of IBD subtypes (CD: aHR=2.39 [1.43 to 4.01], UC: aHR=2.82 [1.99 to 4.00], and IBD-U: aHR=3.14 [1.55 to 6.33]). Sibling comparison analyses yielded similar results. CONCLUSIONS: Patients with IBD had an increased risk of myocarditis, especially severe myocarditis, for ≥20 years after diagnosis, but absolute risks were low.

Catheter Ablation for Atrial Fibrillation in Patients with Left Ventricular Ejection Fraction ≤ 45%: A Meta-Analysis of Randomized Controlled Trials. / Ablação por Cateter para Fibrilação Atrial em Pacientes com Fração de Ejeção do Ventrículo Esquerdo ≤ 45%: Uma Metanálise de Ensaios Clínicos Randomizados.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) frequently coexist, resulting in adverse outcomes. However, controversies remain regarding the efficacy of catheter ablation (CA) in AF patients with severe left ventricular dysfunction. OBJECTIVES: The purpose of this study was to perform a meta-analysis of prospective randomized controlled trials to evaluate the efficacy of CA versus medical therapy (MT) in AF patients with left ventricular ejection fraction (LVEF) ≤45%. METHODS: We searched the literature for studies that compared CA to MT in AF patients with LVEF ≤45%. A meta-analysis of 7 clinical trials was performed, including 1163 patients with AF and HF. Subgroup analysis was performed based on baseline LVEF. All tests were 2-sided; only the p-value <0.05 was considered statistically significant. RESULTS: We found that CA was associated with lower all-cause mortality (risk ratio: 0.52, 95% CI: 0.37 to 0.72; p<0.01) and greater improvements in LVEF (mean difference: 4.80%, 95% CI: 2.29% to 7.31%; p<0.01) compared to MT. Patients in the CA group had a lower risk of HF hospitalization and AF recurrence and a significantly better quality of life than those in the MT group. The results of subgroup analysis indicated that patients with milder left ventricular dysfunction improved LVEF after AF ablation (mean difference: 6.53%, 95% CI: 6.18% to 6.88%; p<0.01) compared to patients with more severe disease (mean difference: 2.02%, 95% CI: 0.87% to 3.16%; p<0.01). CONCLUSIONS: Our meta-analysis demonstrated that CA was associated with significant improvements in outcomes of AF patients with LVEF ≤45%. Additionally, AF patients with milder left ventricular dysfunction could benefit more from CA.

FUNDAMENTO: A fibrilação atrial (FA) e a insuficiência cardíaca (IC) coexistem frequentemente, resultando em desfechos adversos. No entanto, permanecem controvérsias quanto à eficácia da ablação por cateter (AC) em pacientes com FA com disfunção ventricular esquerda grave. OBJETIVOS: O objetivo deste estudo foi realizar uma metanálise de ensaios prospectivos randomizados e controlados para avaliar a eficácia da AC versus terapia médica (TM) em pacientes com FA com fração de ejeção do ventrículo esquerdo (FEVE) ≤45%. MÉTODOS: Procuramos na literatura estudos que comparassem AC com TM em pacientes com FA com FEVE ≤45%. Foi realizada uma metanálise de 7 ensaios clínicos, incluindo 1.163 pacientes com FA e IC. A análise de subgrupo foi realizada com base na FEVE basal. Todos os testes foram bilaterais; apenas o valor p <0,05 foi considerado estatisticamente significativo. RESULTADOS: Descobrimos que a AC estava associada a menor mortalidade por todas as causas (taxa de risco: 0,52, IC 95%: 0,37 a 0,72; p<0,01) e maiores melhorias na FEVE (diferença média: 4,80%, IC 95%: 2,29% a 7,31%; p<0,01) em comparação com TM. Os pacientes do grupo AC apresentaram menor risco de hospitalização por IC e recorrência de FA e qualidade de vida significativamente melhor do que aqueles do grupo TM. Os resultados da análise de subgrupo indicaram que pacientes com disfunção ventricular esquerda mais leve melhoraram a FEVE após a ablação de FA (diferença média: 6,53%, IC 95%: 6,18% a 6,88%; p<0,01) em comparação com pacientes com doença mais grave (diferença média : 2,02%, IC 95%: 0,87% a 3,16%; p<0,01). CONCLUSÕES: Nossa metanálise demonstrou que a AC foi associada a melhorias significativas nos resultados de pacientes com FA com FEVE ≤45%. Além disso, pacientes com FA com disfunção ventricular esquerda mais leve poderiam se beneficiar mais com a AC.

Ablação por Cateter para Fibrilação Atrial em Pacientes com Fração de Ejeção do Ventrículo Esquerdo ≤ 45%: Uma Metanálise de Ensaios Clínicos Randomizados / Catheter Ablation for Atrial Fibrillation in Patients with Left Ventricular Ejection Fraction ≤ 45%: A Meta-Analysis of Randomized Controlled Trials

Resumo Fundamento A fibrilação atrial (FA) e a insuficiência cardíaca (IC) coexistem frequentemente, resultando em desfechos adversos. No entanto, permanecem controvérsias quanto à eficácia da ablação por cateter (AC) em pacientes com FA com disfunção ventricular esquerda grave. Objetivos O objetivo deste estudo foi realizar uma metanálise de ensaios prospectivos randomizados e controlados para avaliar a eficácia da AC versus terapia médica (TM) em pacientes com FA com fração de ejeção do ventrículo esquerdo (FEVE) ≤45%. Métodos Procuramos na literatura estudos que comparassem AC com TM em pacientes com FA com FEVE ≤45%. Foi realizada uma metanálise de 7 ensaios clínicos, incluindo 1.163 pacientes com FA e IC. A análise de subgrupo foi realizada com base na FEVE basal. Todos os testes foram bilaterais; apenas o valor p <0,05 foi considerado estatisticamente significativo. Resultados Descobrimos que a AC estava associada a menor mortalidade por todas as causas (taxa de risco: 0,52, IC 95%: 0,37 a 0,72; p<0,01) e maiores melhorias na FEVE (diferença média: 4,80%, IC 95%: 2,29% a 7,31%; p<0,01) em comparação com TM. Os pacientes do grupo AC apresentaram menor risco de hospitalização por IC e recorrência de FA e qualidade de vida significativamente melhor do que aqueles do grupo TM. Os resultados da análise de subgrupo indicaram que pacientes com disfunção ventricular esquerda mais leve melhoraram a FEVE após a ablação de FA (diferença média: 6,53%, IC 95%: 6,18% a 6,88%; p<0,01) em comparação com pacientes com doença mais grave (diferença média : 2,02%, IC 95%: 0,87% a 3,16%; p<0,01). Conclusões Nossa metanálise demonstrou que a AC foi associada a melhorias significativas nos resultados de pacientes com FA com FEVE ≤45%. Além disso, pacientes com FA com disfunção ventricular esquerda mais leve poderiam se beneficiar mais com a AC.

Abstract Background Atrial fibrillation (AF) and heart failure (HF) frequently coexist, resulting in adverse outcomes. However, controversies remain regarding the efficacy of catheter ablation (CA) in AF patients with severe left ventricular dysfunction. Objectives The purpose of this study was to perform a meta-analysis of prospective randomized controlled trials to evaluate the efficacy of CA versus medical therapy (MT) in AF patients with left ventricular ejection fraction (LVEF) ≤45%. Methods We searched the literature for studies that compared CA to MT in AF patients with LVEF ≤45%. A meta-analysis of 7 clinical trials was performed, including 1163 patients with AF and HF. Subgroup analysis was performed based on baseline LVEF. All tests were 2-sided; only the p-value <0.05 was considered statistically significant. Results We found that CA was associated with lower all-cause mortality (risk ratio: 0.52, 95% CI: 0.37 to 0.72; p<0.01) and greater improvements in LVEF (mean difference: 4.80%, 95% CI: 2.29% to 7.31%; p<0.01) compared to MT. Patients in the CA group had a lower risk of HF hospitalization and AF recurrence and a significantly better quality of life than those in the MT group. The results of subgroup analysis indicated that patients with milder left ventricular dysfunction improved LVEF after AF ablation (mean difference: 6.53%, 95% CI: 6.18% to 6.88%; p<0.01) compared to patients with more severe disease (mean difference: 2.02%, 95% CI: 0.87% to 3.16%; p<0.01). Conclusions Our meta-analysis demonstrated that CA was associated with significant improvements in outcomes of AF patients with LVEF ≤45%. Additionally, AF patients with milder left ventricular dysfunction could benefit more from CA.

A novel machine learning-derived four-gene signature predicts STEMI and post-STEMI heart failure.

High mortality and morbidity rates associated with ST-elevation myocardial infarction (STEMI) and post-STEMI heart failure (HF) necessitate proper risk stratification for coronary artery disease (CAD). A prediction model that combines specificity and convenience is highly required. This study aimed to design a monocyte-based gene assay for predicting STEMI and post-STEMI HF. A total of 1,956 monocyte expression profiles and corresponding clinical data were integrated from multiple sources. Meta-results were obtained through the weighted gene co-expression network analysis (WGCNA) and differential analysis to identify characteristic genes for STEMI. Machine learning models based on the decision tree (DT), support vector machine (SVM), and random forest (RF) algorithms were trained and validated. Five genes overlapped and were subjected to the model proposal. The discriminative performance of the DT model outperformed the other two methods. The established four-gene panel (HLA-J, CFP, STX11, and NFYC) could discriminate STEMI and HF with an area under the curve (AUC) of 0.86 or above. In the gene set enrichment analysis (GSEA), several cardiac pathogenesis pathways and cardiovascular disorder signatures showed statistically significant, concordant differences between subjects with high and low expression levels of the four-gene panel, affirming the validity of the established model. In conclusion, we have developed and validated a model that offers the hope for accurately predicting the risk of STEMI and HF, leading to optimal risk stratification and personalized management of CAD, thereby improving individual outcomes.

Alcohol consumption and atrial fibrillation risk: An updated dose-response meta-analysis of over 10 million participants.

Background: The treatment of atrial fibrillation (AF) has made significant progress, but the prevention of AF has not received the attention it deserves. A few recent large-sized studies have conducted dose response analysis and reported different conclusions from previous studies on alcohol consumption and AF risk. Objectives: The aim of this study is to examine the potential non-linear association between alcohol consumption and risk of AF and explore the potential differences of gender. Methods: In this updated dose-response meta-analysis, PubMed, Embase and Cochrane databases were searched until June 2022. Risk estimates were reported as relative risk (RR) with 95% confidence intervals (CIs). The random-effects restricted cubic spline models are used to evaluate the potential non-linear association between alcohol consumption and AF risk. Results: A total of 10,151,366 participants with 214,365 cases of AF enrolled in 13 prospective studies. The overall meta-analysis showed that a 1 drink/day increase in alcohol consumption increased the risk of AF by 6% (RR: 1.06; 95% CI: 1.03-1.08). In gender subgroup analysis, pooled results were different between men (RR: 1.08; 95% CI: 1.05-1.11) and women (RR: 1.05; 95% CI: 0.96-1.14). A linear relationship between alcohol consumption and risk of AF was found in men (p = 0.87) while a J-shaped curve was observed in women (p = 0.00). Regional subgroup analysis yielded broadly comparable results in Americas (RR: 1.07; 95% CI: 1.03-1.12), Europe (RR: 1.04; 95% CI: 0.99-1.1) and Asia (RR: 1.07; 95% CI: 0.99-1.14). Conclusion: The relationship between AF risk and alcohol consumption is linear in men, while a potential non-linear J-shaped relationship is shown in women. Condensed abstract: We conducted a dose-response meta-analysis on the relationship between alcohol consumption and risk of atrial fibrillation. We merged the data of over 10 million participants and found gender differences in the pattern of association with AF and alcohol consumption. The relationship between AF risk and alcohol consumption is linear in men, while a potential non-linear J-shaped relationship is shown in women. In summary, this research is vital in furthering our understanding of the role of alcohol consumption in new-onset AF, especially among different genders.

Identification of QTL under Brassinosteroid-Combined Cold Treatment at Seedling Stage in Rice Using Genotyping-by-Sequencing (GBS).

Cold stress is a major threat to the sustainability of rice yield. Brassinosteroids (BR) application can enhance cold tolerance in rice. However, the regulatory mechanism related to cold tolerance and the BR signaling pathway in rice has not been clarified. In the current study, the seedling shoot length (SSL), seedling root length (SRL), seedling dry weight (SDW), and seedling wet weight (SWW) were used as the indices for identifying cold tolerance under cold stress and BR-combined cold treatment in a backcross recombinant inbred lines (BRIL) population. According to the phenotypic characterization for cold tolerance and a high-resolution SNP genetic map obtained from the GBS technique, a total of 114 QTLs were identified, of which 27 QTLs were detected under cold stress and 87 QTLs under BR-combined cold treatment. Among them, the intervals of many QTLs were coincident under different treatments, as well as different traits. A total of 13 candidate genes associated with cold tolerance or BR pathway, such as BRASSINAZOLE RESISTANT1 (OsBZR1), OsWRKY77, AP2 domain-containing protein, zinc finger proteins, basic helix-loop-helix (bHLH) protein, and auxin-induced protein, were predicted. Among these, the expression levels of 10 candidate genes were identified under different treatments in the parents and representative BRIL individuals. These results were helpful in understanding the regulation relationship between cold tolerance and BR pathway in rice.

Quantitative Trait Loci Mapping Analysis for Cold Tolerance Under Cold Stress and Brassinosteroid-Combined Cold Treatment at Germination and Bud Burst Stages in Rice.

Low temperature is one of the major abiotic stresses limiting seed germination and early seedling growth in rice. Brassinosteroid (BR) application can improve cold tolerance in rice. However, the regulatory relationship between cold tolerance and BR in rice remains undefined. Here, we constructed a population of 140 backcross recombinant inbred lines (BRILs) derived from a cross between a wild rice (Dongxiang wild rice, DXWR) and a super rice (SN265). The low-temperature germination rate (LTG), survival rate (SR), plant height (PH), and first leaf length (FLL) were used as indices for assessing cold tolerance under cold stress and BR-combined cold treatment at seed germination and bud burst stages. A high-resolution SNP genetic map, covering 1,145 bin markers with a distance of 3188.33 cM onto 12 chromosomes, was constructed using the GBS technique. A total of 73 QTLs were detected, of which 49 QTLs were identified under cold stress and 24 QTLs under BR-combined cold treatment. Among these, intervals of 30 QTLs were pairwise coincident under cold stress and BR-combined cold treatment, as well as different traits including SR and FLL, and PH and FLL, respectively. A total of 14 candidate genes related to cold tolerance or the BR signaling pathway, such as CBF/DREB (LOC_Os08g43200), bHLH (LOC_Os07g08440 and LOC_Os07g08440), WRKY (LOC_Os06g30860), MYB (LOC_Os01g62410 and LOC_Os05g51160), and BRI1-associated receptor kinase 1 precursor (LOC_Os06g16300), were located. Among these, the transcript levels of 10 candidate genes were identified under cold stress and BR-combined cold treatment by qRT-PCR. These findings provided an important basis for further mining the genes related to cold tolerance or the BR signaling pathway and understanding the molecular mechanisms of cold tolerance in rice.

Rab35 GTPase positively regulates endocytic recycling of cardiac KATP channels.

ATP-sensitive K+ (KATP) channel couples membrane excitability to intracellular energy metabolism. Maintaining KATP channel surface expression is key to normal insulin secretion, blood pressure and cardioprotection. However, the molecular mechanisms regulating KATP channel internalization and endocytic recycling, which directly affect the surface expression of KATP channels, are poorly understood. Here we used the cardiac KATP channel subtype, Kir6.2/SUR2A, and characterized Rab35 GTPase as a key regulator of KATP channel endocytic recycling. Electrophysiological recordings and surface biotinylation assays showed decreased KATP channel surface density with co-expression of a dominant negative Rab35 mutant (Rab35-DN), but not other recycling-related Rab GTPases, including Rab4, Rab11a and Rab11b. Immunofluorescence images revealed strong colocalization of Rab35-DN with recycling Kir6.2. Rab35-DN minimized the recycling rate of KATP channels. Rab35 also regulated KATP channel current amplitude in isolated adult cardiomyocytes by affecting its surface expression but not channel properties, which validated its physiologic relevance and the potential of pharmacologic target for treating the diseases with KATP channel trafficking defects.

Crystal structures of the SARS-CoV-2 nucleocapsid protein C-terminal domain and development of nucleocapsid-targeting nanobodies.

The ongoing outbreak of COVID-19 caused by SARS-CoV-2 has resulted in a serious public health threat globally. Nucleocapsid protein is a major structural protein of SARS-CoV-2 that plays important roles in the viral RNA packing, replication, assembly, and infection. Here, we report two crystal structures of nucleocapsid protein C-terminal domain (CTD) at resolutions of 2.0 Å and 3.1 Å, respectively. These two structures, crystallized under different conditions, contain 2 and 12 CTDs in asymmetric unit, respectively. Interestingly, despite different crystal packing, both structures show a similar dimeric form as the smallest unit, consistent with its solution form measured by the size-exclusion chromatography, suggesting an important role of CTD in the dimerization of nucleocapsid proteins. By analyzing the surface charge distribution, we identified a stretch of positively charged residues between Lys257 and Arg262 that are involved in RNA-binding. Through screening a single-domain antibodies (sdAbs) library, we identified four sdAbs targeting different regions of nucleocapsid protein with high affinities that have future potential to be used in viral detection and therapeutic purposes.

Effect of rs4646994 polymorphism of angiotensin-converting enzyme on the risk of nonischemic cardiomyopathy.

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphisms have recently been shown to be associated with risk of developing left ventricular hypertrophy (LVH). However, the results were controversial. We aimed to conduct this meta-analysis to further confirm the association between ACE rs4646994 polymorphism and hypertrophic cardiomyopathy (HCM)/dilated cardiomyopathy (DCM). METHODS: PubMed, Embase, the Chinese National Knowledge Information, and Wanfang databases were searched for eligible studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Then we evaluated the association between ACE gene mutation and HCM/DCM by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analysis was further performed to explore situations in specialized subjects. Sensitivity analysis and publication bias was assessed to confirm the study reliability. RESULTS: There were 13 studies on DCM (2004 cases and 1376 controls) and 16 studies on HCM (2161 controls and 1192 patients). ACE rs4646994 polymorphism was significantly associated with DCM in all genetic models. However, in HCM, four genetic models (allele model, homozygous model, heterozygous model, and dominant model) showed significant association between ACE rs4646994 polymorphism and DCM. In subgroup analysis, we found that ACE rs4646994 polymorphism was significantly associated with DCM/HCM in Asian population. Finally, we also conducted a cumulative meta-analysis, which indicates that the results of our meta-analysis are highly reliable. CONCLUSION: ACE rs4646994 polymorphism increases the risk of DCM/HCM in Asians, but not in Caucasians. More case-control studies are needed to strengthen our conclusions and to assess the gene-gene and gene-environment interactions between ACE rs4646994 polymorphism and DCM/HCM.

Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer.

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance. Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC. Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression. Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.

The potential role of abnormal angiotensin-converting enzyme 2 expression correlated with immune infiltration after SARS-CoV-2 infection in the prognosis of breast cancer.

The potential role of abnormal ACE2 expression after SARS-CoV-2 infection in the prognosis of breast cancer is still ambiguous. In this study, we analyzed ACE2 changes in breast cancer and studied the correlation between ACE2 and the prognosis and further analyzed the relationship between immune infiltration and the prognosis of different breast cancer subtypes. Finally, we inferred the prognosis of breast cancer patients after SARS-CoV-2 infection. We found that ACE2 expression decreased significantly in breast cancer, except for basal-like subtype. Decreased ACE2 expression level was correlated with abnormal immune infiltration and poorer prognosis of luminal B breast cancer (RFS: HR 0.76, 95%CI=0.63-0.92, p=0.005; DMFS: HR 0.70, 95%CI=0.49-1.00, p=0.046). The expression of ACE2 was strongly positively correlated with the immune infiltration level of CD8+ T cell (r=0.184, p<0.001), CD4+ T cell (r=0.104, p=0.02) and neutrophils (r=0.101, p=0.02). ACE2 expression level in the luminal subtype was positively correlated with CD8A and CD8B markers in CD8+ T cells, and CEACAM3, S100A12 in neutrophils. In conclusion, breast tumor tissues might undergo a further decrease in the expression level of ACE2 after SARS-CoV-2 infection, which could contribute to further deterioration of immune infiltration and worsen the prognosis of luminal B breast cancer after SARS-CoV-2 infection.

A Minimally Invasive Exosome Spray Repairs Heart after Myocardial Infarction.

Myocardial infarction (MI) remains the most common cause of death worldwide. Many MI survivors will suffer from recurrent heart failure (HF), which has been recognized as a determinant of adverse prognosis. Despite the success of improved early survival after MI by primary percutaneous coronary intervention, HF after MI is becoming the major driver of late morbidity, mortality, and healthcare costs. The development of regenerative medicine has brought hope to MI treatment in the past decade. Mesenchymal stem cell (MSC)-derived exosomes have been established as an essential part of stem cell paracrine factors for heart regeneration. However, its regenerative power is hampered by low delivery efficiency to the heart. We designed, fabricated, and tested a minimally invasive exosome spray (EXOS) based on MSC exosomes and biomaterials. In a mouse model of acute myocardial infarction, EXOS improved cardiac function and reduced fibrosis, and promoted endogenous angiomyogenesis in the post-injury heart. We further tested the feasibility and safety of EXOS in a pig model. Our results indicate that EXOS is a promising strategy to deliver therapeutic exosomes for heart repair.