Oxidation-sensitive cysteines drive IL-38 amyloid formation.

Interleukin (IL)-1 family cytokines are essential for host defense at epithelial barriers. The IL-1 family member IL-33 was recently linked to stress granules (SGs). Formation of SGs and other biomolecular condensates is promoted by proteins containing low-complexity regions (LCRs). Computational analysis predicts LCRs in six of the 11 IL-1 family members. Among these, IL-38 contains a long LCR including two amyloid cores. IL-38 localizes to intracellular granules in keratinocytes under oxidative stress (OS) and forms OS-induced amyloid aggregates in cells and in vitro. Interestingly, soluble and aggregated IL-38 are released from keratinocytes in an exosome-enriched extracellular vesicle fraction. Disulfide-bond mapping, in silico modeling, and mutational analysis suggest that oxidation-sensitive cysteines act as redox switches to alter IL-38 conformation and promote its aggregation. Finally, the presence of IL-38 granules in human epidermis facing environmental OS suggests that oxidation-induced amyloidogenesis, as an intrinsic property of IL-38, supports barrier function.

Utilization of dissolved CO2 to control methane and acetate production in methanation reactor.

This study investigated the influence of dissolved CO2 on the selection of metabolic pathway using a methanation membrane bioreactor supplied with H2/CO2. Various ratios of H2/CO2 were applied (3.3, 3.8, 4.0, 4.5, and 5.0 (v/v)) to manipulate dissolved CO2 levels in the medium. The findings revealed a correlation between the concentration of dissolved CO2 and the production of CH4 (positive) and acetate (negative). Specifically, at a dissolved concentration of CO2 above 2.0 ±â€¯0.2 mmol/L, production of CH4 was favored. At the opposite, acetate production was favored at lower dissolved CO2 concentrations, with a maximum concentration of 1.9 g/L observed at 0.9 mmol/L of dissolved CO2. This study demonstrates that the modification of dissolved CO2 levels in a methanation bioreactor can provide a strategy for the selection of metabolic pathways and microbial communities, thereby offering a promising opportunity for optimizing the conversion of CO2 into high-value products such as CH4 and acetate.

Three-Level Chirality Transfer and Amplification in Liquid Crystal Supramolecular Assembly for Achieving Full-Color and White Circularly Polarized Luminescence.

Chiral liquid crystal supramolecular assembly provides an ideal strategy for constructing excellent circularly polarized luminescence (CPL) materials. However, the chirality transfer in chiral liquid crystals normally occurs at two levels from the configurational chirality to the supramolecular phase chirality. The more precise and more levels of chirality transmission are fascinating but remain challenging. The present work reports the first success of three-level chirality transfer and amplification from configurationally point chirality of small molecules to conformationally helical chirality of helical polymers and finally to supramolecular phase chirality of cholesteric liquid crystals composed of chiral nonfluorescent polymers (P46) and nematic liquid crystals. Noticeably, the helical twisting power of P46 is five-fold larger than its monomer. Full-color and white CPL with maximum luminescence dissymmetry factor up to 1.54 and photoluminescence quantum yield up to 63.8% are realized utilizing helical supramolecular assembly combined with selective reflection mechanism. Also significantly, the electrically stimuli-responsive CPL switching device as well as anti-counterfeiting security, information encryption, and chiral logic gate applications are developed. This study deepens the understanding of chirality transfer and amplification across different hierarchical levels.

Long-Term High-Fat Diet Aggravates Absence Seizures and Neurobehavioral Disorders Without Inducing Metabolic Disorders in WAG/Rij Rats: Involvement of Systemic and Central Inflammation.

The consumption of a high-fat diet (HFD) represents a risk factor for diseases such as obesity, diabetes, insulin resistance (IR), and different brain disorders. HFD-induced obesity is linked with systemic and neuroinflammation implicated in the pathogenesis of metabolic impairment and epilepsy. In this study, we studied the negative effects of HFD consumption (16 weeks) on absence epilepsy and behavior comorbidities in WAG/Rij rats, a well-validated idiopathic model of absence epilepsy and comorbidities. Moreover, we investigated how, by restoring a normocaloric diet (NCD; 12 weeks), epileptic seizures and neuropsychiatric comorbidities could improve. We found that the HFD group showed a worsening of absence seizures, aggravation of depressive-like behavior, and performance in learning and memory than the NCD group even in the absence of hyperglycemia and/or obesity. In addition, intestinal villus rupture, inflammatory infiltrate, and intestinal permeability alteration increased after prolonged HFD intake, which could prevent weight gain. Inflammatory protein levels were found higher in the colon of the HFD group than in the NCD group, and also in the cortex and hippocampus, regions involved in absence seizures and behavioral alterations. After replacing HFD with NCD, a reduction in absence seizures and behavioral alterations was observed, and this decrease was well correlated with an improvement in inflammatory pathways. In conclusion, HFD consumption is sufficient to disrupt gut integrity resulting in systemic and brain inflammation contributing to the worsening of absence epilepsy and its comorbidities also without obesity development. These alterations can be improved by switching back the diet to NCD.

30 Years' Experience in Percutaneous Pulmonary Artery Interventions in Transposition of the Great Arteries.

Background: Pulmonary artery (PA) stenosis is common after arterial switch operation (ASO) for transposition of the great arteries (TGA). Differences between balloon angioplasty (BA) and stents on right ventricular (RV) and PA pressures are not well studied. Objectives: The purpose of this study was to analyze percutaneous PA interventions' frequency after ASO, complications, and the effects of BA and stents on RV and PA pressures. Methods: All TGA patients with ASO between 1977 and 2022 in 2 Dutch congenital heart centers were included in this multicenter retrospective study. Peri-operative ASO characteristics and pre-intervention and post-intervention invasive and echocardiographic data were analyzed. Results: ASO was performed in 960 TGA patients, of which 888 survived 30 days and had complete follow-up. Seventy-seven (9%) underwent percutaneous PA interventions. Taussig-Bing anomaly (OR: 2.8; 95% CI: 1.228-6.168; P = 0.014), ASO time era 1990 to 1999 (OR: 4.7; 95% CI: 1.762-12.780; P = 0.002), and 2000 to 2009 (OR: 4.3; 95% CI: 1.618-11.330; P = 0.003) were independently associated with percutaneous PA interventions after ASO. Invasive post-interventional pressures and gradients were lower after stent implantation compared to BA (RV pressure: 47 ± 14 vs 58 ± 11; right PA-PA gradient: 11 ± 11 vs 25 ± 12, P < 0.05; RV/left ventricle pressure ratio: 0.4 ± 0.1 vs 0.6 ± 0.2, P < 0.001). Of the patients with unilateral PA stenosis (left PA: 41%, right PA: 59%), 77% showed increased RV pressure (>30 mm Hg) and RV/left ventricle pressure ratio improved post-intervention (0.5 ± 0.2 vs 0.6 ± 0.2, P < 0.05). Seventeen complications, most minor, were reported (13%). Two post-procedural deaths were reported. Conclusions: Percutaneous PA interventions are common after ASO and can be performed safely but caution for serious complications is warranted. Unilateral PA stenosis can impact RV pressures. Stents may be more successful at treating PA stenosis compared to BA.

Persistence of subcutaneous versus intravenous infliximab in a real-life cohort: A propensity-score matched comparative analysis.

BACKGROUND: There is limited comparative data on patients with inflammatory bowel disease (IBD) switched from intravenous to subcutaneous infliximab and those continuing intravenously. This study aimed to compare the persistence and tolerance of subcutaneous and intravenous infliximab and the outcomes of patients resuming intravenous infliximab. METHODS: We conducted a retrospective single-centre cohort study involving IBD patients treated with maintenance intravenous infliximab. The switch to subcutaneous infliximab was offered to patients in clinical remission receiving an intravenous dose ≤ 10 mg kg-1 every ≥ 6 weeks. The switch group was compared to controls remaining on intravenous infliximab due to refusal of the switch. RESULTS: With a median follow-up of 59 (46-67) weeks, subcutaneous infliximab was discontinued in 28/282 (10 %) patients and intravenous infliximab in 1/78 (1 %) patient (p = 0.01); after propensity score-matching of the two cohorts, persistence rates at 52 weeks were respectively 91 % (95 % CI 84-98) and 100 % (95 % CI 100-100, p = 0.01). Among the 28 who discontinued subcutaneous infliximab, 27 resumed intravenous infliximab, with 4 (1 % of the switch group) who permanently stopped infliximab. CONCLUSION: Switching from intravenous to subcutaneous infliximab led to a lower treatment persistance. In cases of poor tolerance or relapse under subcutaneous infliximab, resuming intravenous infliximab is effective.

Establishing a Robust Nonlinear Targeted Switch for C1 Electroproduction in Atomic Alloy Cox/Pd Bimetallenes.

Establishing a targeted switch for CO2 conversion under electric drive is essential for achieving carbon-balance by enabling selective chemicals. However, engineering the topological assembly of active sites to precisely regulate the competing pathways for various intermediates has been plagued by unclear structure-function relationships. To tailor the CO/formate pathways, herein we established a robust nonlinear targeted switch with tunable active Cox sites integrated into Pd metallene, which involves Co1/Pd single-atom alloy (favoring CO) and Co2/Pd diatomic alloy (favoring formate). Transitioning from Co1/Pd to Co2/Pd atomic alloy bimetallenes resulted in a nonlinear, high-contrast flip in selectivity, surpassing 94% for CO and formate productions in both H-cell and flow cell. Furthermore, the superior selectivity and current efficiency for CO (> 80 %) and formate (> 88%) were consistently maintained at -150 mA cm-2 over continuous 200 h. Theoretical simulations and in-situ spectroscopy analyses unveiled that appropriate adjacent metal site combinations (Pd-Pd, Pd-Co and Co-Co) lead to tunable dz2 band center and a nonlinear shift in preferred adsorption configurations of intermediates, dictating the C1 pathways. Our finding reveals a desired switch in C1 selectivity and robust stability within Cox/Pd system, providing a new perspective for fine-tuning energy conversion processes through specific topological assembly.

3D-printing hydrogel programmed released exosomes to restore aortic medial degeneration through inhibiting VSMC ferroptosis in aortic dissection.

Aortic dissection (AD) is a devastating disease with a high mortality rate. Exosomes derived from mesenchymal stem cells (exo-MSCs) offer a promising strategy to restore aortic medial degeneration and combat ferroptosis in AD. However, their rapid degradation in the circulatory system and low treatment efficiency limit their clinical application. Methylacrylated gelatin (Gelma) was reported as a matrix material to achieve controlled release of exosomes. Herein, exo-MSCs-embedded in Gelma hydrogels (Gelma-exos) using ultraviolet light and three-dimensional (3D) printing technology. These Gelma-exos provide a sustained release of exo-MSCs as Gelma gradually degrades, helping to restore aortic medial degeneration and prevent ferroptosis. The sustained release of exosomes can inhibit the phenotypic switch of vascular smooth muscle cells (VSMCs) to a proliferative state, and curb their proliferation and migration. Additionally, the 3D-printed Gelma-exos demonstrated the ability to inhibit ferroptosis in vitro, in vivo and ex vivo experiments. In conclusion, our Gelma-exos, combined with 3D-printed technology, offer an alternative treatment approach for repairing aortic medial degeneration and ferroptosis in AD, potentially reducing the incidence of aortic dissection rupture.

Multi-functional programmable active acoustic meta-device: acoustic switch, lens, and barrier.

Active acoustic metamaterials (AAMM) have garnered special attention because of their potential as multi-function devices. In this direction, the present article demonstrates a novel AAMM that can be programmed as a multi-functional Active Acoustic Meta-device (AAMD) that can switch functionalities between Acoustic Switch (AS), Acoustic Lens (AL), and Acoustic Barrier (AB). Functionality: AL corresponds to the wave vector space, and AS and AB correspond to the frequency space of the proposed AAMM. Additional functionality, such as acoustic logic gates in phase space, is also envisaged. The proposed design is found to change the dispersion diagram by acquiring different configurations while keeping the basic design parameters constant. These design parameters include constituent elements, lattice constants, and filling fractions. Further, for the said functionalities, the proposed AAMM does not rely on the deformation characteristics of the constituents. It rather capitalises on the possible relative displacements of the scatterers. As an AL, AAMM demonstrates zero angle refraction, i.e., collimation, and negative refraction of the transmitted beam at a given angle of incidence over a frequency range of 200 kHz (22.22% of the applied frequency sweep, a.f.s.). AB is shown to attenuate acoustic energy over a frequency range of 700 kHz (77.78% of a.f.s.) compared to its reference and foundation design, a statically designed Phononic Crystal (PnC). Furthermore, as AS, it operates over the entire range of applied frequency sweep (100 kHz to 1000 kHz), i.e., over the frequency range of 900 kHz (100% of a.f.s.).

Effects of Switching FSH Preparations on Sperm Parameters and Pregnancy: A Prospective Controlled Study.

Objective: To study the effect of switching to a follicle-stimulating hormone (FSH) preparation other than that to which infertile male patients have not had an effective response. Patients and methods: Seventy-four normogonadotropinemic, non-obstructive, oligozoospermic patients who were poor responders to the administration of highly purified FSH (hpFSH) (Group 1 (n = 22) and Group 3 (n = 15)) or to recombinant human FSH (rhFSH) (Group 2 (n = 22) and Group 4 (n = 15)) were selected for this prospective study. After 3 months of washout from treatment with the first FSH preparation of choice, rhFSH was administered to patients in Groups 1 and 4 and hpFSH to those in Groups 2 and 3. Serum luteinizing hormone, FSH, total testosterone levels, conventional sperm parameters, testicular volume, and the number of pregnancies were evaluated at study entry and after the first and second treatment cycles. Results: Comparing treatment groups, the greatest improvement in sperm parameters was recorded in the groups of patients prescribed the switch in FSH preparation. Group 1 had the greatest benefit from therapy, with the highest pregnancy rate after the second treatment cycle. Indeed, eight couples achieved pregnancy (36.4%), compared to Groups 2 (n = 4; 18.2%), 3 (n = 1; 6.7%), and 4 (n = 2; 13.3%) (p = 0.04). Conclusions: The results of this study suggest that a therapeutic scheme involving the "switching" of the FSH preparation yields better results than a protocol using the same FSH preparation for six months. These findings, if confirmed by further studies, will help us better design a treatment strategy with FSH for infertile patients with oligozoospermia.

A Compendium of G-Flipon Biological Functions That Have Experimental Validation.

As with all new fields of discovery, work on the biological role of G-quadruplexes (GQs) has produced a number of results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly because they are different from commonly held expectations. Like other classes of flipons, those that form G-quadruplexes have a repeat sequence motif that enables the fold. The canonical DNA motif (G3N1-7)3G3, where N is any nucleotide and G is guanine, is a feature that is under active selection in avian and mammalian genomes. The involvement of G-flipons in genome maintenance traces back to the invertebrate Caenorhabditis elegans and to ancient DNA repair pathways. The role of GQs in transcription is supported by the observation that yeast Rap1 protein binds both B-DNA, in a sequence-specific manner, and GQs, in a structure-specific manner, through the same helix. Other sequence-specific transcription factors (TFs) also engage both conformations to actuate cellular transactions. Noncoding RNAs can also modulate GQ formation in a sequence-specific manner and engage the same cellular machinery as localized by TFs, linking the ancient RNA world with the modern protein world. The coevolution of noncoding RNAs and sequence-specific proteins is supported by studies of early embryonic development, where the transient formation of G-quadruplexes coordinates the epigenetic specification of cell fate.

Dissociation of the nuclear WWOX/TRAF2 switch renders UV/cold shock-mediated nuclear bubbling cell death at low temperatures.

BACKGROUND: Normal cells express functional tumor suppressor WW domain-containing oxidoreductase (WWOX), designated WWOXf. UV irradiation induces WWOXf cells to undergo bubbling cell death (BCD) - an event due to the accumulation of nuclear nitric oxide (NO) gas that forcefully pushes the nuclear and cell membranes to form one or two bubbles at room temperature (22 °C) and below. In contrast, when WWOX-deficient or -dysfunctional (WWOXd) cells are exposed to UV and/or cold shock, the cells undergo nuclear pop-out explosion death (POD). We aimed to determine the morphological and biochemical changes in WWOXf cells during BCD versus apoptosis. METHODS: WWOXf and WWOXd cells were exposed to UV followed by measuring BCD or POD by time-lapse microscopy and/or time-lapse holographic microscopy at 4, 22, or 37 °C to visualize morphological changes. Live cell stains were used to measure the kinetics of nitric oxide (NO) production and Ca2+ influx. Extent of cell death was measured by uptake of propidium iodide and by internucleosomal DNA fragmentation using agarose gel electrophoresis. RESULTS: WWOXf cells were exposed to UV and then cold shock, or cold shock and then UV, and cultured at 4, 10, and 22 °C, respectively. Initially, UV induced calcium influx and NO production, which led to nuclear bubbling and final death. Cold shock pretreatment completely suppressed UV-mediated bubbling at 37 °C, so the UV/cold shock-treated cells underwent apoptosis. Without cold shock, UV only induced bubbling at all temperatures, whereas the efficiency of bubbling at 37 °C was reduced by greater than 50%. Morphologically, the WWOXf cell height or thickness was significantly increased during cell division or apoptosis, but the event did not occur in BCD. In comparison, when WWOXd cancer cells received UV or UV/cold shock, these cells underwent NO-independent POD. UV/cold shock effectively downregulated the expression of many proteins such as the housekeeping α-tubulin (> 70%) and ß-actin (< 50%), and cortactin (> 70%) in WWOXf COS7 cells. UV/cold shock induced relocation of α-tubulin to the nucleus and nuclear bubbles in damaged cells. UV induced co-translocation of the WWOX/TRAF2 complex to the nuclei, in which the prosurvival TRAF2 blocked the proapoptotic WWOX via its zinc finger domain. Without WWOX, TRAF2 did not relocate to the nuclei. Cold shock caused the dissociation of the WWOX/TRAF2 complex in the nucleus needed for BCD. In contrast, the formation of the WWOX/TRAF2 complex, plus p53, was strengthened at 37 °C required for apoptosis. CONCLUSIONS: The temperature-sensitive nuclear WWOX/TRAF2 complex acts as a molecular switch, whose dissociation favors BCD at low temperatures, and the association supports apoptosis at 37 °C in UV-treated WWOXf cells.

Interleukin-1ß modulates lymphoid differentiation of Flt3-positive multipotent progenitors after transplantation.

Myeloablative pre-conditioning facilitates the differentiation of transplanted hematopoietic stem and progenitor cells (HSPCs). However, the factors in the stress environment that regulate HSPC behavior remain elusive. Here, we investigated the mechanisms that shaped the cell fates of transplanted murine multipotent progenitors (MPPs) expressing the Fms-related receptor tyrosine kinase 3 gene (Flt3). Using lineage tracing, clonal analysis, and single-cell RNA sequencing (RNA-seq), we showed that the myeloablative environment increased lymphoid priming of Flt3+ MPPs and that their efficient B cell output required intact interleukin 1 (IL-1) signaling. The Flt3+ MPPs with short-term exposure to IL-1ß underwent a myeloid-biased to lymphoid-biased cell fate switch and produced more lymphoid-biased progeny with a stronger B lymphopoiesis capacity in vitro. Correspondingly, a brief exposure to IL-1ß facilitated the B cell output of transplanted Flt3+ MPPs in vivo. Together, our study demonstrated an unrecognized function of IL-1ß in promoting B lymphopoiesis and highlighted a latent effect of IL-1ß in regulating MPP cell fate dynamics.

Insights into the distinct membrane targeting mechanisms of WDR91 family proteins.

WDR91 and SORF1, members of the WD repeat-containing protein 91 family, control phosphoinositide conversion by inhibiting phosphatidylinositol 3-kinase activity on endosomes, which promotes endosome maturation. Here, we report the crystal structure of the human WDR91 WD40 domain complexed with Rab7 that has an unusual interface at the C-terminus of the Rab7 switch II region. WDR91 is highly selective for Rab7 among the tested GTPases. A LIS1 homology (LisH) motif within the WDR91 N-terminal domain (NTD) mediates self-association and may contribute partly to the augmented interaction between full-length WDR91 and Rab7. Both the Rab7 binding site and the LisH motif are indispensable for WDR91 function in endocytic trafficking. For the WDR91 orthologue SORF1 lacking the C-terminal WD40 domain, a C-terminal amphipathic helix (AH) mediates strong interactions with liposomes containing acidic lipids. During evolution the human WDR91 ancestor gene might have acquired a WD40 domain to replace the AH for endosomal membrane targeting.

Has Ghana's Rotavirus Vaccine Switch Met Programmatic Expectations? An Analysis of National Surveillance Data; 2018-2022.

Background: Ghana introduced a 2-dose schedule rotavirus vaccine, Rotarix, into childhood immunization in 2012 but switched to a 3-dose schedule vaccine, Rotavac, in 2020 on account of programmatic advantages offered by the latter, including lower cost per fully immunized child and lower cold chain volume requirement. The objective of the study was to assess the effect of the vaccine switch on the trends of rotavirus vaccine uptake and health facility outpatient department (OPD) attendance due to diarrhea among children aged 1-11 months. Methods: A retrospective analysis was conducted on childhood immunization and diarrhea surveillance data for 2018-2022. The uptake of the different rotavirus vaccine products and the proportion of health facility OPD attendance attributed to diarrhea, respectively, were compared between the pre- and postswitch study periods. Results: The uptake of rotavirus vaccine was sustained following the switch. There were no significant differences in vaccination coverages (rota1, Rotarix coverage [94.3%], vs rota1, Rotavac coverage [95.3%]; P = .757; rota2, Rotarix coverage [91.3%], vs rota2, Rotavac coverage [92.7%]; P = .789). The proportions of health facility OPD attendance due to diarrhea were comparable (preswitch [12.4%] vs postswitch [12.1%]; P = .838). Conclusions: Ghana's rotavirus vaccine switch yielded expected programmatic benefits without any untoward effects. The trends of vaccine uptake and reduction in diarrhea morbidity were sustained. These experiences and lessons from the rotavirus vaccine switch are vital for potential switches for other vaccines in the current immunization schedule to mitigate the annual vaccine expenditure.

Characterization of Interchanging Incretin Analogs in Clinical Practice: A Descriptive Report.

OBJECTIVE: To characterize the tolerability associated with incretin analog interchanges to equipotent or higher strengths based on an interchange process in an adult outpatient setting. METHODS: This was a retrospective chart review of adult patients receiving care through a participating family medicine or endocrinology clinic between January 1, 2022, and November 30, 2022 at a major academic medical center. An incretin analog equivalency table and protocol for interchange was created in response to on-going shortages and need for therapy adjustments to different medications within the same class. Patients were included if a recommended incretin analog interchange was initiated, and a tolerability assessment was conducted. Patients were excluded if they did not meet inclusion criteria or if they were unreachable for tolerability assessments for interchanged agents. RESULTS: There were 156 patients included for characterization and response to tolerability of interchange. It was determined that 96% of patients tolerated the incretin analog interchange. A dose escalation occurred in 58% of patients, 41% were transitioned to an equipotent dose, and 1 patient was considered a dose decrease. Prior authorizations were required 74% of the time for the new therapy. The most common interchanges were dulaglutide 4.5 mg to tirzepatide 7.5 mg, dulaglutide 4.5 mg to tirzepatide 10 mg, and dulaglutide 3 mg to tirzepatide 7.5 mg. These interchanges made up 37.3% of the total population and were observed to have 93% tolerability. Seven patients did not tolerate incretin analog interchange. Five experienced gastrointestinal effects and two experienced injection site reactions. The interchange of incretin analog was estimated to reduce time to maximum dose by a median of three months. During this study, no patients experienced interruption of therapy defined as missing a dose of incretin analog. CONCLUSIONS: This characterization report demonstrates an effective approach to addressing incretin analog interchanges. A high level of tolerability is evident with the defined interchange process. Future studies should continue to confirm effective and safe interchanges of incretin analogs from outcomes and tolerability reports.

Qianyang Yuyin granules alleviate hypertension-induced vascular remodeling by inhibiting the phenotypic switch of vascular smooth muscle cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Qianyang Yuyin granules (QYYY) have been used clinically to treat hypertension for over two decades. Previous clinical trials have shown that QYYY can improve vascular elastic function in hypertensive patients. However, the underlying pharmacological mechanism is unclear. AIM OF THE STUDY: To elucidate the effects and mechanisms of QYYY on vascular remodeling using a multidisciplinary approach that includes network pharmacology, proteomics, and both in vitro and in vivo experiments. MATERIALS AND METHODS: The main components of QYYY were identified using ultra-high-performance liquid chromatography and high-resolution mass spectrometry. Network pharmacology and molecular docking were employed to predict QYYY's primary active ingredients, potential therapeutic targets and intervention pathways in hypertensive vascular remodeling. We induced hypertension in male C57BL/6 mice by infusing angiotensin II (Ang II) via osmotic minipumps, and performed pre-treatment with QYYY or Sacubitril/valsartan (Entresto). Blood pressure was monitored in vivo, followed by the extraction of aortas to examine pathological structural changes and alterations in protein expression patterns. The expression and location of proteins involved in the HIF-1α/TWIST1/P-p65 signaling pathway were investigated, as well as markers of vascular smooth muscle cells (VSMCs) phenotypic switch. In vitro, we studied the effects of QYYY water extract on Ang II-stimulated human aortic VSMCs. We investigated whether QYYY could affect the HIF-1α/TWIST1/P-p65 signaling pathway, thereby ameliorating apoptosis, autophagy, and phenotype switch in VSMCs. RESULTS: We identified 62 main compounds in QYYY, combined with network pharmacology, speculated 827 potentially active substances, and explored 1021 therapeutic targets. The KEGG pathway analysis revealed that the mechanisms of action associated with QYYY therapy potentially encompass various biological processes, including metabolic pathways, TNF signaling pathways, apoptosis, Ras signaling pathways, HIF-1 signaling pathways, autophagy-animal pathways. In hypertensive mice, QYYY restored abnormally elevated blood pressure, vascular remodeling, and inflammation with a dose-response relationship while altering abnormal protein patterns. In vitro, QYYY could inhibit abnormal proliferation, migration, intracellular Ca2+ accumulation and cytoskeletal changes of VSMCs. It improved mitochondrial function, reduced ROS levels, stabilized membrane potential, prevented cell death, and reduced overproduction of TGF-ß1, TNF-a, and IL-1ß. CONCLUSION: QYYY may be able to inhibit the overactivation of the HIF-1α/TWIST1/P-p65 signaling pathway, improve the phenotypic switch, and balance apoptosis and autophagy in VSMCs, thereby effectively improving vascular remodeling caused by hypertension.

National trends in using revisional surgeries post-sleeve gastrectomy due to reflux and weight recurrence: a matched case-control analysis.

BACKGROUND: Several options exist for surgical conversion after sleeve gastrectomy (SG), but a definitive safety profile for each option by indication for conversion remains unclear. OBJECTIVES: To determine and compare 30-day risk profiles of SG conversion to Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), and single-anastomosis duodenoileostomy (SADI). METHODS: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database entries from 2020 to 2022 were used to identify 25,760 adult patients who underwent SG conversion to RYGB, BPD-DS, or SADI. Subgroup analyses were performed among 6106 conversions completed for weight-related complications (RYGB: 3053 patients; BPD-DS: 1826 patients; SADI: 1227 patients). Multivariable analysis and 1:1 nearest-neighbor matching were used to further characterize the 30-day risk profile of each conversion. RESULTS: Patients with RYGB conversions had a lower preoperative body mass index compared with those with BPD-DS + SADI conversions (39.8 versus 46.1, P < .001) and significantly lower rates of medical comorbidities. The distribution of conversion indication for each MBS configuration varied, where most RYGB conversions were for reflux (56.1%) whereas most BPD-DS + SADI conversions were for weight-related complications (87.3%; P < .001). On 1:1 matched analysis of conversions for weight recurrence, odds of 30-day complications (odds ratio .73, P = .019) and readmission (odds ratio .77, P = .031) were lower in BPD-DS + SADI conversions compared with RYGB. There were no significant differences in odds of 30-day reintervention or reoperation between conversion to RYGB and BPD-DS + SADI. Major differing drivers of complications between conversion types included hemorrhage (RYGB 1.98% versus BPD-DS + SADI .87%; P = .001). CONCLUSIONS: For weight recurrence after SG, conversion to BPD-DS + SADI does not have greater 30-day complications than RYGB and may be a safe conversion option.

Rbm3 deficiency leads to transcriptome-wide splicing alterations.

Rbm3 (RNA-binding motif protein 3) is a stress responsive gene, which maintains cellular homeostasis and promotes survival upon various harmful cellular stimuli. Rbm3 protein shows conserved structural and molecular similarities to heterogeneous nuclear ribonucleoproteins (hnRNPs), which regulate all steps of the mRNA metabolism. Growing evidence is pointing towards a broader role of Rbm3 in various steps of gene expression. Here, we demonstrate that Rbm3 deficiency is linked to transcriptome-wide pre-mRNA splicing alterations, which can be reversed through Rbm3 co-expression from a cDNA. Using an MS2 tethering assay, we show that Rbm3 regulates splice site selection similar to other hnRNP proteins when recruited between two competing 5 ' splice sites. Furthermore, we show that the N-terminal part of Rbm3 encompassing the RNA recognition motif (RRM), is sufficient to elicit changes in splice site selection. On the basis of these findings, we propose a novel, undescribed function of Rbm3 in RNA splicing that contributes to the preservation of transcriptome integrity.

Unique Tachycardia Recorded on a Cardiac Implantable Electronic Device: What is the Mechanism?

In a 55-year-old man with nonischemic cardiomyopathy, a unique tachycardia was recorded on a dual-chamber implantable cardioverter defibrillator (St. Jude Medical [Abbott]) as an automatic mode switch episode. This case report discusses the mechanism of tachycardia, how it can be differentiated from similar rhythms, and its clinical implications. The report explores device limitations in managing such tachycardias and presents reprograming strategies to prevent recurrence. This case emphasizes the importance of careful analysis of device-mediated arrhythmias and appropriate programming.