SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism.

Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.

Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs.

BACKGROUND & AIMS: Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS: A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS: The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS: Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

PICKLE and HISTONE DEACETYLASE6 coordinately regulate genes and transposable elements in Arabidopsis.

Chromatin dynamics play essential roles in transcriptional regulation. The chromodomain helicase DNA-binding domain 3 chromatin remodeler PICKLE (PKL) and HISTONE DEACETYLASE6 (HDA6) are required for transcriptional gene silencing, but their coordinated function in gene repression requires further study. Through a genetic suppressor screen, we found that a point mutation at PKL could partially restore the developmental defects of a weak Polycomb repressive complex 1 (PRC1) mutant (ring1a-2 ring1b-3), in which RING1A expression is suppressed by a T-DNA insertion at the promoter. Compared to ring1a-2 ring1b-3, the expression of RING1A is increased, nucleosome occupancy is reduced, and the histone 3 lysine 9 acetylation (H3K9ac) level is increased at the RING1A locus in the pkl ring1a-2 ring1b-3 triple mutant. HDA6 interacts with PKL and represses RING1A expression similarly to PKL genetically and molecularly in the ring1a-2 ring1b-3 background. Furthermore, we show that PKL and HDA6 suppress the expression of a set of genes and transposable elements (TEs) by increasing nucleosome density and reducing H3K9ac. Genome-wide analysis indicated they possibly coordinately maintain DNA methylation as well. Our findings suggest that PKL and HDA6 function together to reduce H3K9ac and increase nucleosome occupancy, thereby facilitating gene/TE regulation in Arabidopsis (Arabidopsis thaliana).

Up-regulated novel-miR-17 promotes hypothermic reperfusion arrhythmias by negatively targeting Gja1 and mediating activation of the PKC/c-Jun signaling pathway.

BACKGROUND: Hypothermic ischemia-reperfusion arrhythmia is a common complication of cardiothoracic surgery under cardiopulmonary bypass, but few studies have focused on this type of arrhythmia. Our prior study discovered reduced myocardial Cx43 protein levels may be linked to hypothermic reperfusion arrhythmias. However, more detailed molecular mechanism research is required. METHOD: The microRNA and mRNA expression levels in myocardial tissues were detected by real-time quantitative PCR (RT-qPCR). Besides, the occurrence of hypothermic reperfusion arrhythmias and changes in myocardial electrical conduction were assessed by electrocardiography and ventricular epicardial activation mapping. Furthermore, bioinformatics analysis, applying antagonists of miRNA, western blotting, immunohistochemistry, a dual luciferase assay, and pearson correlation analysis were performed to investigate the underlying molecular mechanisms. RESULTS: The expression level of novel-miR-17 was up-regulated in hypothermic ischemia-reperfusion myocardial tissues. Inhibition of novel-miR-17 upregulation ameliorated cardiomyocyte edema, reduced apoptosis, increased myocardial electrical conduction velocity, and shortened the duration of reperfusion arrhythmias. Mechanistic studies showed that novel-miR-17 reduced the expression of Cx43 by directly targeting Gja1 while mediating the activation of the PKC/c-Jun signaling pathway. CONCLUSION: Up-regulated novel-miR-17 is a newly discovered pro-arrhythmic microRNA that may serve as a potential therapeutic target and biomarker for hypothermic reperfusion arrhythmias.

Sirtuin 6 ameliorates bleomycin-induced pulmonary fibrosis via activation of lipid catabolism.

Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6-mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single-cell sequencing database. We showed that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High-throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator-activated receptor α (PPARα) was essential for SIRT6-mediated lipid catabolism, anti-inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6-PPARα-mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.

Why is a small sample size not enough?

BACKGROUND: Clinical studies are often limited by resources available, which results in constraints on sample size. We use simulated data to illustrate study implications when the sample size is too small. METHODS AND RESULTS: Using 2 theoretical populations each with N = 1000, we randomly sample 10 from each population and conduct a statistical comparison, to help make a conclusion about whether the 2 populations are different. This exercise is repeated for a total of 4 studies: 2 concluded that the 2 populations are statistically significantly different, while 2 showed no statistically significant difference. CONCLUSIONS: Our simulated examples demonstrate that sample sizes play important roles in clinical research. The results and conclusions, in terms of estimates of means, medians, Pearson correlations, chi-square test, and P values, are unreliable with small samples.

Neuroanatomy of lymphoid organs: Lessons learned from whole-tissue imaging studies.

Decades of extensive research have documented the presence of neural innervations of sensory, sympathetic, or parasympathetic origin in primary and secondary lymphoid organs. Such neural inputs can release neurotransmitters and neuropeptides to directly modulate the functions of various immune cells, which represents one of the essential aspects of the body's neuroimmune network. Notably, recent studies empowered by state-of-the-art imaging techniques have comprehensively assessed neural distribution patterns in BM, thymus, spleen, and LNs of rodents and humans, helping clarify several controversies lingering in the field. In addition, it has become evident that neural innervations in lymphoid organs are not static but undergo alterations in pathophysiological contexts. This review aims to update the current information on the neuroanatomy of lymphoid organs obtained through whole-tissue 3D imaging and genetic approaches, focusing on anatomical features that may designate the functional modulation of immune responses. Moreover, we discuss several critical questions that call for future research, which will advance our in-depth understanding of the importance and complexity of neural control of lymphoid organs.

Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota.

RATIONALE: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.

Time-Dependent Diffusion MRI Helps Predict Molecular Subtypes and Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Time-dependent diffusion MRI has the potential to help characterize tumor cell properties; however, to the knowledge of the authors, its usefulness for breast cancer diagnosis and prognostic evaluation is unknown. Purpose To investigate the clinical value of time-dependent diffusion MRI-based microstructural mapping for noninvasive prediction of molecular subtypes and pathologic complete response (pCR) in participants with breast cancer. Materials and Methods Participants with invasive breast cancer who underwent pretreatment with time-dependent diffusion MRI between February 2021 and May 2023 were prospectively enrolled. Four microstructural parameters were estimated using the IMPULSED method (a form of time-dependent diffusion MRI), along with three apparent diffusion coefficient (ADC) measurements and a relative ADC diffusion-weighted imaging parameter. Multivariable logistic regression analysis was used to identify parameters associated with each molecular subtype and pCR. A predictive model based on associated parameters was constructed, and its performance was assessed using the area under the receiver operating characteristic curve (AUC) and compared by using the DeLong test. The time-dependent diffusion MRI parameters were validated based on correlation with pathologic measurements. Results The analysis included 408 participants with breast cancer (mean age, 51.9 years ± 9.1 [SD]). Of these, 221 participants were administered neoadjuvant chemotherapy and 54 (24.4%) achieved pCR. The time-dependent diffusion MRI parameters showed reasonable performance in helping to identify luminal A (AUC, 0.70), luminal B (AUC, 0.78), and triple-negative breast cancer (AUC, 0.72) subtypes and high performance for human epidermal growth factor receptor 2 (HER2)-enriched breast cancer (AUC, 0.85), outperforming ADC measurements (all P < .05). Progesterone receptor status (odds ratio [OR], 0.08; P = .02), HER2 status (OR, 3.36; P = .009), and the cellularity index (OR, 0.01; P = .02) were independently associated with the odds of achieving pCR. The combined model showed high performance for predicting pCR (AUC, 0.88), outperforming ADC measurements and the clinical-pathologic model (AUC, 0.73 and 0.79, respectively; P < .001). The time-dependent diffusion MRI-estimated parameters correlated well with the pathologic measurements (n = 100; r = 0.67-0.81; P < .001). Conclusion Time-dependent diffusion MRI-based microstructural mapping was an effective method for helping to predict molecular subtypes and pCR to neoadjuvant chemotherapy in participants with breast cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Partridge and Xu in this issue.

The Polo-Like Kinase 1-Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis.

The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms in vivo and in vitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated intestinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability in vitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in intestinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.

Polycomb proteins RING1A/B promote H2A monoubiquitination to regulate female gametophyte development in Arabidopsis.

A functional female gametophyte is the basis of successful sexual reproduction in flowering plants. During female gametophyte development, the megaspore mother cell (MMC), which differentiates from a single subepidermal somatic cell in the nucellus, undergoes meiosis to produce four megaspores; only the one at the chalazal end, referred to as the functional megaspore (FM), then undergoes three rounds of mitosis and develops into a mature embryo sac. Here, we report that RING1A and RING1B (RING1A/B), two functionally redundant Polycomb proteins in Arabidopsis, are critical for female gametophyte development. Mutations of RING1A/B resulted in defects in the specification of the MMC and the FM, and in the subsequent mitosis of the FM, thereby leading to aborted ovules. Detailed analysis revealed that several genes essential for female gametophyte development were ectopically expressed in the ring1a ring1b mutant, including Argonaute (AGO) family genes and critical transcription factors. Furthermore, RING1A/B bound to some of these genes to promote H2A monoubiquitination (H2Aub). Taken together, our study shows that RING1A/B promote H2Aub modification at key genes for female gametophyte development, suppressing their expression to ensure that the development progresses correctly.

Tumor-derived small extracellular vesicles facilitate omental metastasis of ovarian cancer by triggering activation of mesenchymal stem cells.

BACKGROUND: Omental metastasis is the major cause of ovarian cancer recurrence and shortens patient survival, which can be largely attributed to the dynamic evolution of the fertile metastatic microenvironment driven by cancer cells. Previously, we found that adipose-derived mesenchymal stem cells (ADSCs) undergoing a phenotype shift toward cancer-associated fibroblasts (CAFs) participated in the orchestrated omental premetastatic niche for ovarian cancer. Here, we aim to elucidate the underlying mechanisms. METHODS: Small extracellular vesicles were isolated from ovarian cancer cell lines (ES-2 and its highly metastatic subline, ES-2-HM) and patient ascites using ultracentrifugation. Functional experiments, including Transwell and EdU assays, and molecular detection, including Western blot, immunofluorescence, and RT-qPCR, were performed to investigate the activation of ADSCs in vitro. High-throughput transcriptional sequencing and functional assays were employed to identify the crucial functional molecules inducing CAF-like activation of ADSCs and the downstream effector of miR-320a. The impact of extracellular vesicles and miR-320a-activated ADSCs on tumor growth and metastasis was assessed in subcutaneous and orthotopic ovarian cancer xenograft mouse models. The expression of miR-320a in human samples was evaluated using in situ hybridization staining. RESULTS: Primary human ADSCs cocultured with small extracellular vesicles, especially those derived from ES-2-HM, exhibited boosted migration, invasion, and proliferation capacities and elevated α-SMA and FAP levels. Tumor-derived small extracellular vesicles increased α-SMA-positive stromal cells, fostered omental metastasis, and shortened the survival of mice harboring orthotopic ovarian cancer xenografts. miR-320a was abundant in highly metastatic cell-derived extracellular vesicles, evoked dramatic CAF-like transition of ADSCs, targeted the 3'-untranslated region of integrin subunit alpha 7 and attenuated its expression. miR-320a overexpression in ovarian cancer was associated with omental metastasis and shorter survival. miR-320a-activated ADSCs facilitated tumor cell growth and omental metastasis. Depletion of integrin alpha 7 triggered CAF-like activation of ADSCs in vitro. Video Abstract CONCLUSIONS: miR-320a in small extracellular vesicles secreted by tumor cells targets integrin subunit alpha 7 in ADSCs and drives CAF-like activation, which in turn facilitates omental metastasis of ovarian cancer.

Obstructive Sleep Apnea Plasma-Derived Exosomes Mediate Cognitive Impairment Through Hippocampal Neuronal Cell Pyroptosis.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with impaired cognitive function. Exosomes are secreted by most cells and play a role in OSA-associated cognitive impairment (CI). The aim of this study was to investigate whether OSA plasma-derived exosomes cause CI through hippocampal neuronal cell pyroptosis, and to identify exosomal miRNAs in OSA plasma-derived. MATERIALS AND METHODS: Plasma-derived exosomes were isolated from patients with severe OSA and healthy comparisons. Daytime sleepiness and cognitive function were assessed using the Epworth Sleepiness Scale (ESS) and the Beijing version of the Montreal Cognitive Assessment Scale (MoCA). Exosomes were coincubated with mouse hippocampal neurons (HT22) cells to evaluate the effect of exosomes on pyroptosis and inflammation of HT22 cells. Meanwhile, exosomes were injected into C57BL/6 male mice via caudal vein, and then morris water maze was used to evaluate the spatial learning and memory ability of the mice, so as to observe the effects of exosomes on the cognitive function of the mice. Western blot and qRT-PCR were used to detect the expressions of Gasdermin D (GSDMD) and Caspase-1 to evaluate the pyroptosis level. The expression of IL-1ß, IL-6, IL-18 and TNF-α was detected by qRT-PCR to assess the level of inflammation. Correlations of GSDMD and Caspase-1 expression with clinical parameters were evaluated using Spearman's rank correlation analysis. In addition, plasma exosome miRNAs profile was identified, followed by Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. RESULTS: Compared to healthy comparisons, body mass index (BMI), apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and ESS scores were increased in patients with severe OSA, while lowest oxygen saturation during sleep (LSaO2), mean oxygen saturation during sleep (MSaO2) and MoCA scores were decreased. Compared to the PBS group (NC) and the healthy comparison plasma-derived exosomes (NC-EXOS), the levels of GSDMD and Caspase-1 and IL-1ß, IL-6, IL-18 and TNF-α were increased significantly in the severe OSA plasma-derived exosomes (OSA-EXOS) coincubated with HT22 cells. Compared to the NC and NC-EXOS groups, the learning and memory ability of mice injected with OSA-EXOS was decreased, and the expression of GSDMD and Caspase-1 in hippocampus were significantly increased, along with the levels of IL-1ß, IL-6, IL-18 and TNF-α. Spearman correlation analysis found that clinical AHI in HCs and severe OSA patients was positively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups, while negatively correlated with clinical MoCA. At the same time, clinical MoCA in HCs and severe OSA patients was negatively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups. A unique exosomal miRNAs profile was identified in OSA-EXOS group compared to the NC-EXOS group, in which 28 miRNAs were regulated and several KEGG and GO pathways were identified. CONCLUSIONS: The results of this study show a hypothesis that plasma-derived exosomes from severe OSA patients promote pyroptosis and increased expression of inflammatory factors in vivo and in vitro, and lead to impaired cognitive function in mice, suggesting that OSA-EXOS can mediate CI through pyroptosis of hippocampal neurons. In addition, exosome cargo from OSA-EXOS showed a unique miRNAs profile compared to NC-EXOS, suggesting that plasma exosome associated miRNAs may reflect the differential profile of OSA related diseases, such as CI.

Sleep Deprivation Promotes Endothelial Inflammation and Atherogenesis by Reducing Exosomal miR-182-5p.

BACKGROUND: Insufficient or disrupted sleep increases the risk of cardiovascular disease, including atherosclerosis. However, we know little about the molecular mechanisms by which sleep modulates atherogenesis. This study aimed to explore the potential role of circulating exosomes in endothelial inflammation and atherogenesis under sleep deprivation status and the molecular mechanisms involved. METHODS: Circulating exosomes were isolated from the plasma of volunteers with or without sleep deprivation and mice subjected to 12-week sleep deprivation or control littermates. miRNA array was performed to determine changes in miRNA expression in circulating exosomes. RESULTS: Although the total circulating exosome levels did not change significantly, the isolated plasma exosomes from sleep-deprived mice or human were a potent inducer of endothelial inflammation and atherogenesis. Through profiling and functional analysis of the global microRNA in the exosomes, we found miR-182-5p is a key exosomal cargo that mediates the proinflammatory effects of exosomes by upregulation of MYD88 (myeloid differentiation factor 88) and activation of NF-ĸB (nuclear factor kappa-B)/NLRP3 pathway in endothelial cells. Moreover, sleep deprivation or the reduction of melatonin directly decreased the synthesis of miR-182-5p and led to the accumulation of reactive oxygen species in small intestinal epithelium. CONCLUSIONS: The findings illustrate an important role for circulating exosomes in distant communications, suggesting a new mechanism underlying the link between sleep disorder and cardiovascular disease.

17ß-estradiol activates SOX6 to balance the anabolism and catabolism via estrogen receptor 2 in chondrocyte.

We investigated the influence of 17ß-estradiol (17ß-E2) on cartilage extracellular matrix (ECM) homeostasis in postmenopausal women. We focused on the roles of estrogen receptors (ESR) and SOX6 in 17ß-E2-mediated stimulation of ECM metabolism during chondrocyte (CH) degeneration. We compared the expression of anabolic genes (collagen II and aggrecan) and catabolic genes (MMPs and TIMPs) in IL-1ß-induced CH degeneration in vitro, with and without 17ß-E2 supplementation. We separately silenced the SOX6, ESR1, and ESR2 genes in CHs to determine their impact on 17ß-E2 treatment. Additionally, we used Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and luciferase assays to investigate protein-DNA interactions within ESR2 and SOX6-promoter complexes. After three days of IL-1ß treatment, ESR1/2, SOX6, collagen II, aggrecan, and TIMP1/3 were decreased, while MMP3/9/13 were increased. The addition of 17ß-E2 partially reversed these effects, but silencing SOX6, ESR1, or ESR2 weakened the protective effects of 17ß-E2. Silencing ESR2, but not ESR1, abolished the upregulation of SOX6 induced by 17ß-E2. ESR2 was found to bind the SOX6 promoter and regulate SOX6 expression. 17ß-E2 upregulates SOX6 through ESR2 mediation, and the synergistic effect of 17ß-E2 and ESR2 on SOX6 balances ECM metabolism in CHs.

The impact of His bundle location and direction on the efficacy and safety of ablation.

BACKGROUND: The impact of the His bundle location and distance from the ablation site on ablation efficacy and complication risk remains unexplored. We determined the correlation between age, height, body mass index (BMI), and the His bundle location, and whether the distance between the His bundle and ablation target (DHIS-ABL) affects ablation safety and efficacy. METHODS: Overall, 346 patients with atrioventricular nodal re-entrant tachycardia (AVNRT) and 96 with atrioventricular re-entrant tachycardia (AVRT) were retrospectively analyzed. The distance between the His bundle and the coronary sinus ostium (DHis-CS), the height of the His bundle (HHIS), and DHIS-ABL were measured. Electrocardiograms were obtained 3 months post-ablation to assess recurrence and complications. RESULTS: Multiple linear regression showed that HHIS was negatively correlated with age in both groups. In AVNRT patients, DHIS-ABL was associated with age, height, and BMI; DHIS-CS was only negatively correlated with age. In AVRT patients, there was no significant correlation between the DHIS-ABL and age, height, or BMI. The recurrence rates in the AVNRT and AVRT groups were 0.9% and 8.7%, respectively. Subgroup analysis showed that patients with DHIS-ABL ≤ 10 mm had a higher recurrence rate than those with DHIS-ABL > 10 mm (p = .013). The incidence of third-degree atrioventricular block (AVB) complications was 0.2%. CONCLUSIONS: HHIS was negatively correlated with age but not with height and BMI. The DHIS-ABL correlated with age, height, and BMI in AVNRT patients. A short DHIS-ABL led to a higher rate of supraventricular tachycardia recurrence; whether this affects AVB risk warrants further studies with larger sample sizes.

Transforming growth factor-ß receptors: versatile mechanisms of ligand activation.

Transforming growth factor-ß (TGF-ß) signaling is initiated by activation of transmembrane TGF-ß receptors (TGFBR), which deploys Smad2/3 transcription factors to control cellular responses. Failure or dysregulation in the TGF-ß signaling pathways leads to pathological conditions. TGF-ß signaling is regulated at different levels along the pathways and begins with the liberation of TGF-ß ligand from its latent form. The mechanisms of TGFBR activation display selectivity to cell types, agonists, and TGF-ß isoforms, enabling precise control of TGF-ß signals. In addition, the cell surface compartments used to release active TGF-ß are surprisingly vibrant, using thrombospondins, integrins, matrix metalloproteinases and reactive oxygen species. The scope of TGFBR activation is further unfolded with the discovery of TGFBR activation initiated by other signaling pathways. The unique combination of mechanisms works in series to trigger TGFBR activation, which can be explored as therapeutic targets. This comprehensive review provides valuable insights into the diverse mechanisms underpinning TGFBR activation, shedding light on potential avenues for therapeutic exploration.

Characteristic and mechanism of biological nitrogen and phosphorus removal facilitated by biogenic manganese oxides (BioMnOx) at various concentrations of Mn(II).

Biogenic manganese oxides (BioMnOx) have attracted considerable attention as active oxidants, adsorbents, and catalysts. However, characteristics and mechanisms of nitrification-denitrification in biological redox reactions mediated by different concentrations of BioMnOx are still unclear. Fate of nutrients (e.g., NH4+-N, TP, NO3--N) and COD were investigated through different concentrations of BioMnOx produced by Mn(II) in the moving bed biofilm reactor (MBBR). 34% and 89.2%, 37.8% and 89.8%, 57.3% and 88.9%, and 62.1% and 90.4% of TN and COD by MBBR were synchronously removed in four phases, respectively. The result suggested that Mn(II) significantly improved the performance of simultaneous nitrification and denitrification (SND) and TP removal based on manganese (Mn) redox cycling. Characteristics of glutathione peroxidase (GSH-Px), reactive oxygen species (ROS), and electron transfer system activity (ETSA) were discussed, demonstrating that ROS accumulation reduced the ETSA and GSH-Px activities when Mn(II) concentration increased. Extracellular polymeric substance (EPS) function and metabolic pathway of Mn(II) were explored. Furthermore, effect of cellular components on denitrification was evaluated including BioMnOx performances, indicating that Mn(II) promoted the non-enzymatic action of cell fragments. Finally, mechanism of nitrification and denitrification, denitrifying phosphorus and Mn removal was further elucidated through X-ray photoelectron spectroscopy (XPS), high throughput sequencing, and fourier transform infrared reflection (FTIR). This results can bringing new vision for controlling nutrient pollution in redox process of Mn(II).

Learning curve for the combined trans-oral and chest approach to endoscopic selective neck dissection: a cumulative sum (CUSUM) analysis.

BACKGROUND: The combined trans-oral and chest approach is a novel technique for endoscopic selective neck dissection (SND), with satisfactory oncological safety and cosmetic results. However, this hybrid approach is difficult, and the learning curve remains unclear. In this study, we aimed to evaluate the short-term outcomes for this hybrid approach, and to define the associated learning curve. METHOD: Clinical data and surgical outcomes of 58 PTC patients who underwent endoscopic SND via combined trans-oral and chest approach between September 2020 and April 2023 were retrospectively reviewed. The cumulative sum (CUSUM) sequential analysis technique is used to detect change, and has been applied for the evaluation of learning curves. RESULTS: The study population included 58 patients (40 females, 18 males), with mean age of 38.9 ± 12.7 years and average body mass index of 22.6 ± 4.8 kg/m2. In all cases, the same surgical team performed endoscopic SND via combined trans-oral and chest approach. The numbers of positive/retrieved lymph nodes were 4.3 ± 3.2/27.8 ± 8.4 in the lateral compartment and 4.0 ± 3.5/8.4 ± 5.1 in the central compartment. The learning curve was evaluated in terms of an initial phase (20 cases) and a mature phase (38 cases). Operative time was longer during the initial phase, compared to the mature phase (375.2 vs. 274.6 min, p = 0.002). The frequency of operative complications was higher during the initial phase, compared to the mature phase (85% vs. 55.3%, p = 0.048). CONCLUSIONS: After the experience acquired using endoscopic SND via combined trans-oral and chest approach to treat PTC in 20 patients, the number of complications decreased significantly. Compared to data collected for the initial phase, data collected for the mature phase showed trends toward decreased operating time.

Serum uric acid and mortality in metabolic dysfunction-associated steatotic liver disease: Subgroup differences.

BACKGROUND AND AIMS: This study aims to investigate the association between serum uric acid (SUA) and both the risk and long-term mortality of dysfunction-associated steatotic liver disease (MASLD), and to explore differences between the pure MASLD and metabolic and alcohol related/associated liver disease (MetALD) subgroups. METHODS AND RESULTS: We included 11,675 participants from the Third National Health and Nutrition Examination Survey, with matched mortality data up to 2019. Logistic regression and Cox proportional hazards regression evaluated the relationship between SUA and both the risk and mortality of MASLD. Non-linear correlations and threshold effects were explored using restricted cubic splines and a two-piecewise Cox proportional hazards model. We found that SUA was positively associated with the risk of MASLD [odds ratio (OR): 1.19, 95 % confidence interval (CI) 1.12-1.27]. For pure MASLD, SUA showed a positive association with all-cause mortality [<4.7 mg/dL: hazard ratio (HR): 1.34, 95 % CI 1.04-1.73; ≥4.7 mg/dL: HR: 1.08, 95 % CI 1.02-1.15] and cardiovascular mortality (HR: 1.12, 95 % CI 1.02-1.22). For MetALD, there was an inverse J-shaped relationship (threshold: 6.6 mg/dL) between SUA and all-cause mortality. Below the threshold, SUA was negatively correlated with all-cause mortality (HR: 0.42, 95 % CI 0.19-0.93), but no association was found above it (HR: 0.81, 95 % CI 0.54-1.21). Additionally, no association was observed between SUA and cardiovascular mortality. CONCLUSIONS: SUA serves as an independent predictor of the risk and all-cause mortality of MASLD. The relationship between SUA and both all-cause and cardiovascular mortality differs between the pure MASLD and MetALD subgroups.