Cobalt-electrocatalytic HAT for functionalization of unsaturated C-C bonds.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s1, for energy storage, through the reduction of protons to generate hydrogen2,3, and for organic synthesis, for the functionalization of unsaturated C-C, C-O and C-N bonds4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)7. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co-H generation that takes place through a low-valent intermediate.

Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency.

OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.

Construction of a cross-species cell landscape at single-cell level.

Individual cells are basic units of life. Despite extensive efforts to characterize the cellular heterogeneity of different organisms, cross-species comparisons of landscape dynamics have not been achieved. Here, we applied single-cell RNA sequencing (scRNA-seq) to map organism-level cell landscapes at multiple life stages for mice, zebrafish and Drosophila. By integrating the comprehensive dataset of > 2.6 million single cells, we constructed a cross-species cell landscape and identified signatures and common pathways that changed throughout the life span. We identified structural inflammation and mitochondrial dysfunction as the most common hallmarks of organism aging, and found that pharmacological activation of mitochondrial metabolism alleviated aging phenotypes in mice. The cross-species cell landscape with other published datasets were stored in an integrated online portal-Cell Landscape. Our work provides a valuable resource for studying lineage development, maturation and aging.

How many cell types are there in nature? How do they change during the life cycle? These are two fundamental questions that researchers have been trying to understand in the area of biology. In this study, single-cell mRNA sequencing data were used to profile over 2.6 million individual cells from mice, zebrafish and Drosophila at different life stages, 1.3 million of which were newly collected. The comprehensive datasets allow investigators to construct a cross-species cell landscape that helps to reveal the conservation and diversity of cell taxonomies at genetic and regulatory levels. The resources in this study are assembled into a publicly available website at http://bis.zju.edu.cn/cellatlas/.

Atomically Dispersed Zn/Co-N-C as ORR Electrocatalysts for Alkaline Fuel Cells.

Hydrogen fuel cells have drawn increasing attention as one of the most promising next-generation power sources for future automotive transportation. Developing efficient, durable, and low-cost electrocatalysts, to accelerate the sluggish oxygen reduction reaction (ORR) kinetics, is urgently needed to advance fuel cell technologies. Herein, we report on metal-organic frameworks-derived nonprecious dual metal single-atom catalysts (SACs) (Zn/Co-N-C), consisting of Co-N4 and Zn-N4 local structures. These catalysts exhibited superior ORR activity with a half-wave potential (E1/2) of 0.938 V versus RHE (reversible hydrogen electrode) and robust stability (ΔE1/2 = -8.5 mV) after 50k electrochemical cycles. Moreover, this remarkable performance was validated under realistic fuel cell working conditions, achieving a record-high peak power density of ∼1 W cm-2 among the reported SACs for alkaline fuel cells. Operando X-ray absorption spectroscopy was conducted to identify the active sites and reveal catalytic mechanistic insights. The results indicated that the Co atom in the Co-N4 structure was the main catalytically active center, where one axial oxygenated species binds to form an Oads-Co-N4 moiety during the ORR. In addition, theoretical studies, based on a potential-dependent microkinetic model and core-level shift calculations, showed good agreement with the experimental results and provided insights into the bonding of oxygen species on Co-N4 centers during the ORR. This work provides a comprehensive mechanistic understanding of the active sites in the Zn/Co-N-C catalysts and will pave the way for the future design and advancement of high-performance single-site electrocatalysts for fuel cells and other energy applications.

A Photo-induced Cross-Linking Enhanced A and B Combined Multi-Functional Spray Hydrogel Instantly Protects and Promotes of Irregular Dynamic Wound Healing.

Wounds in harsh environments can face long-term inflammation and persistent infection, which can slow healing. Wound spray is a product that can be rapidly applied to large and irregularly dynamic wounds, and can quickly form a protective film in situ to inhibit external environmental infection. In this study, a biodegradable A and B combined multi-functional spray hydrogel is developed with methacrylate-modified chitosan (CSMA1st) and ferulic acid (FA) as type A raw materials and oxidized Bletilla striata polysaccharide (OBSP) as type B raw materials. The precursor CSMA1st-FA/OBSP (CSOB-FA1st) hydrogel is formed by the self-cross-linking of dynamic Schiff base bonds, the CSMA-FA/OBSP (CSOB-FA) hydrogel is formed quickly after UV-vis light, so that the hydrogel fits with the wound. Rapid spraying and curing provide sufficient flexibility and rapidity for wounds and the hydrogel has good injectability, adhesive, and mechanical strength. In rats and miniature pigs, the A and B combined spray hydrogel can shrink wounds and promote healing of infected wounds, and promote the enrichment of fibrocyte populations. Therefore, the multifunctional spray hydrogel combined with A and B can protect irregular dynamic wounds, prevent wound infection and secondary injury, and be used for safe and effective wound treatment, which has a good prospect for development.

CLOSE protocol versus lower ablation index value for paroxysmal atrial fibrillation: A randomized noninferior clinical trial.

INTRODUCTION: The optimized ablation index (AI) value for catheter ablation of atrial fibrillation (AF) remains to be defined. We aimed to compare the efficacy and safety of CLOSE protocol and lower AI protocol in paroxysmal AF. METHODS AND RESULTS: Patients with symptomatic, drug-resistant paroxysmal AF for first ablation were prospectively enrolled from September 2020 to January 2022. The patients were randomly divided into CLOSE group (AI ≥ 550 for anterior/roof segments and ≥400 for posterior/inferior segments) and lower AI group (AI ≥ 450 for anterior/roof segments and ≥350 for posterior/inferior segments). First-pass isolation, acute pulmonary vein (PV) reconnections, 1-year arrhythmia recurrence, and major complications were assessed. Of the 270 enrolled patients, 238 completed 1-year follow-up (118 in CLOSE group and 120 in lower AI group). First-pass isolation in left PVs was higher in CLOSE group (71.2% vs. 53.3%, p = .005). Acute PV reconnections were comparable between groups (9.3% vs. 14.2%, p = .246). At 1 year, 86.4% in CLOSE group versus 81.7% in lower AI group were free from atrial arrhythmia (log rank p = .334). The proportion difference was -4.8% (95% CI: -14.1% to 4.6%), and p = .475 for noninferiority. Stroke occurred in four patients of lower AI group, and no cardiac tamponade, atrioesophageal fistula, major bleeding or death occurred post procedure. CONCLUSION: For patients with paroxysmal AF and treated by AI-guided PV ablation, lower AI is not noninferior to CLOSE protocol.

Electrocatalysis in Alkaline Media and Alkaline Membrane-Based Energy Technologies.

Hydrogen energy-based electrochemical energy conversion technologies offer the promise of enabling a transition of the global energy landscape from fossil fuels to renewable energy. Here, we present a comprehensive review of the fundamentals of electrocatalysis in alkaline media and applications in alkaline-based energy technologies, particularly alkaline fuel cells and water electrolyzers. Anion exchange (alkaline) membrane fuel cells (AEMFCs) enable the use of nonprecious electrocatalysts for the sluggish oxygen reduction reaction (ORR), relative to proton exchange membrane fuel cells (PEMFCs), which require Pt-based electrocatalysts. However, the hydrogen oxidation reaction (HOR) kinetics is significantly slower in alkaline media than in acidic media. Understanding these phenomena requires applying theoretical and experimental methods to unravel molecular-level thermodynamics and kinetics of hydrogen and oxygen electrocatalysis and, particularly, the proton-coupled electron transfer (PCET) process that takes place in a proton-deficient alkaline media. Extensive electrochemical and spectroscopic studies, on single-crystal Pt and metal oxides, have contributed to the development of activity descriptors, as well as the identification of the nature of active sites, and the rate-determining steps of the HOR and ORR. Among these, the structure and reactivity of interfacial water serve as key potential and pH-dependent kinetic factors that are helping elucidate the origins of the HOR and ORR activity differences in acids and bases. Additionally, deliberately modulating and controlling catalyst-support interactions have provided valuable insights for enhancing catalyst accessibility and durability during operation. The design and synthesis of highly conductive and durable alkaline membranes/ionomers have enabled AEMFCs to reach initial performance metrics equal to or higher than those of PEMFCs. We emphasize the importance of using membrane electrode assemblies (MEAs) to integrate the often separately pursued/optimized electrocatalyst/support and membranes/ionomer components. Operando/in situ methods, at multiscales, and ab initio simulations provide a mechanistic understanding of electron, ion, and mass transport at catalyst/ionomer/membrane interfaces and the necessary guidance to achieve fuel cell operation in air over thousands of hours. We hope that this Review will serve as a roadmap for advancing the scientific understanding of the fundamental factors governing electrochemical energy conversion in alkaline media with the ultimate goal of achieving ultralow Pt or precious-metal-free high-performance and durable alkaline fuel cells and related technologies.

miR-200a-3p inhibits the PDGF-BB-induced proliferation of VSMCs by affecting their phenotype-associated proteins.

Accumulating evidence shows that the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) can significantly affect the long-term prognosis of coronary artery bypass grafting. This study aimed to explore the factors affecting the proliferation, migration, and phenotypic transformation of VSMCs. First, we stimulated VSMCs with different platelet-derived growth factor-BB (PDGF-BB) concentrations, analyzed the expression of phenotype-associated proteins by Western blotting, and examined cell proliferation by scratch wound healing and the 5-ethynyl-2-deoxyuridine (EdU) assay. VSMC proliferation was induced most by PDGF-BB treatment at 20 ng/mL. miR-200a-3p decreased significantly in A7r5 cells stimulated with PDGF-BB. The overexpression of miR-200a-3p reversed the downregulation of α-SMA (p < 0.001) and the upregulation of vimentin (p < 0.001) caused by PDGF-BB. CCK8 and EdU analyses showed that miR-200a-3p overexpression could inhibit PDGF-BB-induced cell proliferation (p < 0.001). However, flow cytometric analysis showed that it did not significantly increase cell apoptosis. Collectively, the overexpression of miR-200a-3p inhibited the proliferation and migration of VSMCs induced by PDGF-BB, partly by affecting phenotypic transformation-related proteins, providing a new strategy for relieving the restenosis of vein grafts.

NADPHnet: a novel strategy to predict compounds for regulation of NADPH metabolism via network-based methods.

Identification of compounds to modulate NADPH metabolism is crucial for understanding complex diseases and developing effective therapies. However, the complex nature of NADPH metabolism poses challenges in achieving this goal. In this study, we proposed a novel strategy named NADPHnet to predict key proteins and drug-target interactions related to NADPH metabolism via network-based methods. Different from traditional approaches only focusing on one single protein, NADPHnet could screen compounds to modulate NADPH metabolism from a comprehensive view. Specifically, NADPHnet identified key proteins involved in regulation of NADPH metabolism using network-based methods, and characterized the impact of natural products on NADPH metabolism using a combined score, NADPH-Score. NADPHnet demonstrated a broader applicability domain and improved accuracy in the external validation set. This approach was further employed along with molecular docking to identify 27 compounds from a natural product library, 6 of which exhibited concentration-dependent changes of cellular NADPH level within 100 µM, with Oxyberberine showing promising effects even at 10 µM. Mechanistic and pathological analyses of Oxyberberine suggest potential novel mechanisms to affect diabetes and cancer. Overall, NADPHnet offers a promising method for prediction of NADPH metabolism modulation and advances drug discovery for complex diseases.

Association between metabolic dysfunction-associated fatty liver disease and abdominal aortic aneurysm.

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is the second most common aortic pathological manifestation. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a wide impact on the cardiovascular system and may be a risk factor for AAA. The aim of this study was to investigate whether MAFLD is associated with the risk of AAA. METHODS AND RESULTS: We used data from the prospective UK Biobank cohort study. MAFLD is defined as hepatic steatosis plus metabolic abnormality, type 2 diabetes, or overweight/obesity. AAA is collected by ICD-10 code. Cox regression was established to analyze the association between MAFLD and AAA. A total of 370203 participants were included; the average age of the participants was 56.7 ± 8.0 years, and 134649 (36.4 %) were diagnosed with MAFLD. During the 12.5 years of follow-up, 1561 (0.4 %) participants developed AAA. After fully adjusting for confounding factors, individuals with MAFLD had a significantly increased risk of AAA (HR 1.521, 95 % CI 1.351-1.712, p < 0.001). Importantly, the risk of AAA increases with the severity of MAFLD as assessed by fibrosis scores. These associations were consistent according to sex, weight, and alcohol consumption but weaker in elderly or diabetics (P for interaction <0.05). The association between the MAFLD phenotype and AAA was independent of the polygenic risk score. Additionally, MAFLD was not associated with thoracic aortic aneurysm or aortic dissection events. CONCLUSIONS: There was a significant relationship between MAFLD and AAA. These findings strongly recommend early prevention of AAA by intervening in MAFLD.

The complete chloroplast genome sequence and phylogenetic relationship analysis of Eomecon chionantha, one species unique to China.

Eomecon chionantha Hance, an endemic species in China, has a long medical history in Chinese ethnic minority medicine and is known for its anti-inflammatory and analgesic effects. However, studies of E. chionantha are lacking. In this study, we investigated the characteristics of the E. chionantha chloroplast genome and determined the taxonomic position of E. chionantha in Papaveraceae via phylogenetic analysis. In addition, we determined molecular markers to identify E. chionantha at the molecular level by comparing the chloroplast genomes of E. chionantha and its closely related species. The complete chloroplast genomic information indicated that E. chionantha chloroplast DNA (178,808 bp) contains 99 protein-coding genes, 8 rRNAs, and 37 tRNAs. Meanwhile, we were able to identify a total of 54 simple sequence repeats through our analysis. Our findings from the phylogenetic analysis suggest that E. chionantha shares a close relationship with four distinct species, namely Macleaya microcarpa, Coreanomecon hylomeconoides, Hylomecon japonica, and Chelidonium majus. Additionally, using the Kimura two-parameter model, we successfully identified five hypervariable regions (ycf4-cemA, ycf3-trnS-GGA, trnC-GCA-petN, rpl32-trnL-UAG, and psbI-trnS-UGA). To the best of our knowledge, this is the first report of the complete chloroplast genome of E. chionantha, providing a scientific reference for further understanding of E. chionantha from the perspective of the chloroplast genome and establishing a solid foundation for the future identification, taxonomic determination and evolutionary analysis of this species.

CUX1 attenuates the apoptosis of renal tubular epithelial cells induced by contrast media through activating the PI3K/AKT signaling pathway.

OBJECTIVE: Contrast media (CM) is a commonly applied drug in medical examination and surgery. However, contrast-induced acute kidney injury (CIAKI) poses a severe threat to human life and health. Notably, the CUT-like homeobox 1 (CUX1) gene shows protective effects in a variety of cells. Therefore, the objective of this study was to provide a new target for the treatment of CIAKI through exploring the role and possible molecular mechanism of CUX1 in CIAKI. METHOD: Blood samples were collected from 20 patients with CIAKI and healthy volunteers. Human kidney 2 (HK-2) cells were incubated with 200 mg/mL iohexol for 6 h to establish a contrast-induced injury model of HK-2 cells. Subsequently, qRT-PCR was used to detect the relative mRNA expression of CUX1; CCK-8 and flow cytometry to assess the proliferation and apoptosis of HK-2 cells; the levels of IL(interleukin)-1ß, tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) in cells and lactate dehydrogenase (LDH) activity in cell culture supernatant were detect; and western blot to observe the expression levels of CUX1 and the PI3K/AKT signaling pathway related proteins [phosphorylated phosphoinositide 3-kinase (p-PI3K), PI3K, phosphorylated Akt (p-AKT), AKT]. RESULTS: CUX1 expression was significantly downregulated in blood samples of patients with CIAKI and contrast-induced HK-2 cells. Contrast media (CM; iohexol) treatment significantly reduced the proliferation of HK-2 cells, promoted apoptosis, stimulated inflammation and oxidative stress that caused cell damage. CUX1 overexpression alleviated cell damage by significantly improving the proliferation level of HK-2 cells induced by CM, inhibiting cell apoptosis, and reducing the level of LDH in culture supernatant and the expression of IL-1ß, TNF-α and MDA in cells. CM treatment significantly inhibited the activity of PI3K/AKT signaling pathway activity. Nevertheless, up-regulating CUX1 could activate the PI3K/AKT signaling pathway activity in HK-2 cells induced by CM. CONCLUSION: CUX1 promotes cell proliferation, inhibits apoptosis, and reduces inflammation and oxidative stress in CM-induced HK-2 cells to alleviate CM-induced damage. The mechanism of CUX1 may be correlated with activation of the PI3K/AKT signaling pathway.

Cervical vertebral Hounsfield units are a better predictor of Zero-P subsidence than the T-score of DXA in patients following single-level anterior cervical discectomy and fusion with zero-profile anchored spacer.

OBJECTIVES: To determine the predictive effect of Hounsfield unit (HU) values in the cervical vertebral body measured by computed tomography (CT) and T-scores measured by dual-energy X-ray absorptiometry (DXA) on Zero-P subsidence after anterior cervical discectomy and fusion (ACDF)with Zero-P. In addition, we evaluated the most reliable measurement of cervical HU values. METHODS: We reviewed 76 patients who underwent single-level Zero-P fusion for cervical spondylosis. HU values were measured on CT images according to previous studies. Univariate analysis was used to screen the influencing factors of Zero-P subsidence, and then, logistic regression was used to determine the independent risk factors. The area under the receiver operating characteristic curve (AUC) was used to evaluate the ability to predict Zero-P subsidence. RESULTS: Twelve patients (15.8%) developed Zero-P subsidence. There were significant differences between subsidence group and non-subsidence group in terms of age, axial HU value, and HU value of midsagittal, midcoronal, and midaxial (MSCD), but there were no significant differences in lowest T-score and lowest BMD. The axial HU value (OR = 0.925) and HU value of MSCD (OR = 0.892) were independent risk factors for Zero-P subsidence, and the lowest T-score was not (OR = 1.186). The AUC of predicting Zero-P subsidence was 0.798 for axial HU value, 0.861 for HU value of MSCD, and 0.656 for T-score. CONCLUSIONS: Lower cervical HU value indicates a higher risk of subsidence in patients following Zero-P fusion for single-level cervical spondylosis. HU values were better predictors of Zero-P subsidence than DXA T-scores. In addition, the measurement of HU value in the midsagittal, midcoronal, and midaxial planes of the cervical vertebral body provides an effective method for predicting Zero-P subsidence.

Investigating Facial Muscle Physiology Following Soft Tissue Filler Injections-A Surface-derived Electromyographic and Skin Vector Displacement Analytic Study.

The use of hyaluronic acid-based soft tissue fillers has often been reported to modulate the muscle, that is, to cause myomodulation. To our knowledge, there has been so far no scientific study investigating the potential of hyaluronic acid-based soft tissue fillers to modulate or actually alter the function of facial muscles. To further assess this three-dimensional (3D) surface imaging and electromyography (EMG)-based prospective study investigated the changes of facial muscle contraction after injection of strategically placed hyaluronic acid-based soft tissue fillers to assess the actual validity of the term myomodulation. A total of 13 subjects with a mean age of 37.8 years (12 females, 1 male) were injected according to a predefined injection protocol. Surface EMG and 3D surface imaging were performed prior to the injection and 5 days after the injection. The results showed no significant change in the strength of the muscles (measured in µV) after injection of hyaluronic acid-based soft tissue fillers. However, horizontal and vertical skin displacement upon contraction of the zygomaticus major muscle changed significantly between baseline and follow-up, with a mean horizontal skin displacement increase from 3.2 to 4.1 mm. Upon contraction of the depressor anguli oris muscle, the horizontal skin displacement did not change significantly (2.15 vs. 2.05 mm), while vertical skin displacement increased significantly from 2.9 to 4.3 mm. The modification of the surrounding tissue caused an alteration of the vectorial skin displacement upon contraction of the muscle. A potential explanation could be the increased distance between the origin and insertion of the muscle due to the material deposition in the proximity of the relevant facial muscles, leading to a change of contraction vector.

The Influence of Scar Patterns After Reduction Mammoplasty on Eye Movement and Gaze Pattern: An Eye-Tracking Investigation.

BACKGROUND: Given that scars are acknowledged as the primary cause of postoperative dissatisfaction following reduction mammoplasty, it is imperative to comprehend the patient's visual perception of different scar patterns in order to enhance patient satisfaction. To achieve this, eye-tracking technology provides an unbiased method of evaluating how observers assess breast scars. METHODS: 58 participants (32 females and 26 males) between the ages of 19 and 82 years (mean age of 29.47 ± 10.98 years) were shown 18 color photographs, taken at 3 viewing angles (right 45° oblique, frontal and frontal view with arms raised), from 6 patients undergone reduction mammoplasty with the inverted T-scar technique (3 patients) or no-vertical-scar technique (3 patients). The images were presented to every participant for a fixed duration of 5 s each. Eye-tracking device was used to collect and analyze the gaze data of viewers. RESULTS: The nipple-areola complex (NAC) and the periareolar scar captured observers' gaze faster, had longer duration and more count of eye fixation than all other parts of breast scars, regardless of the viewing angle and scar pattern. Moreover, the scar region in the inverted T-scar pattern received greater and faster visual attraction of observer's gaze than the no-vertical-scar pattern. CONCLUSION: The NAC and the periareolar scar seem to be perceived as the most important regions for breast aesthetics. The findings can be helpful to assist plastic surgeons in determining the most appropriate technique for reduction mammoplasty, meanwhile underlining the importance of a fine periareolar scar and symmetric NAC for excellent aesthetic outcomes. This is to our best knowledge the first study using eye-tracking technology in evaluating reduction mammoplasty outcomes. This study explored the influence of different scar patterns after reduction mammoplasty on eye movements and gaze patterns among observers. The study have validated the significance of the NAC and the periareolar scar for breast aesthetics and revealed that the scar region in the inverted T-scar pattern may be judged less visually attractive than the no-vertical-scar pattern. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors  www.springer.com/00266 .

Reconceptualizing Patient Safety Beyond Harm: Insights From a Mixed-Methods Qualitative Inquiry.

BACKGROUND: Although patients' and care partners' perspectives on patient safety can guide health care learning and improvements, this information remains underutilized. Efforts to leverage this valuable data require challenging the narrow focus of safety as the absence of harm. PURPOSE: The purpose of this study was to gain a broader insight into how patients and care partners perceive and experience safety. METHODS: We used a mixed-methods approach that included a literature review and interviews and focus groups with patients, care partners, and health care providers. An emergent coding schema was developed from triangulation of the 2 data sets. RESULTS: Two core themes-feeling unsafe and feeling safe-emerged that collectively represent a broader view of safety. CONCLUSION: Knowledge from patients and care partners about feeling unsafe and safe needs to inform efforts to mitigate harm and promote safety, well-being, and positive outcomes and experiences.

Comprehensive Pan-Cancer Analysis of Connexin 43 as a Potential Biomarker and Therapeutic Target in Human Kidney Renal Clear Cell Carcinoma (KIRC).

Background and Objectives: Connexin 43 (Cx43) is involved in the transfer of small signaling molecules between neighboring cells, thereby exerting a major influence on the initiation and progression of tumorigenesis. However, there is a lack of systematic research on Cx43 expression and its predictive role in clinical diagnosis and prognosis in pan-cancer. Materials and Methods: Several biological databases were used to evaluate the expression levels of GJA1 (encoding Cx43) and its diagnostic and prognostic significance in pan-cancer. We targeted kidney renal clear cell carcinoma (KIRC) and investigated the relationship between GJA1 expression and different clinical features of KIRC patients. Then, we performed cell-based experiments to partially confirm our results and predicted several proteins that were functionally related to Cx43. Results: The expression of GJA1 has a high level of accuracy in predicting KIRC. High GJA1 expression was remarkably correlated with a favorable prognosis, and this expression was reduced in groups with poor clinical features in KIRC. Cell experiments confirmed the inhibitory effects of increased GJA1 expression on the migratory capacity of human renal cancer (RCC) cell lines, and protein-protein interaction (PPI) analysis predicted that CDH1 and CTNNB1 were closely related to Cx43. Conclusions: GJA1 could be a promising independent favorable prognostic factor for KIRC, and upregulation of GJA1 expression could inhibit the migratory capacity of renal cancer cells.

[Stellera chamaejasme against multidrug resistance of triple-negative breast cancer MDA-MB-231 cell through Nrf2].

This study aims to investigate the effect and mechanism of Stellera chamaejasme extract(SCL) on multidrug resistance(MDR) in breast cancer. Human triple-negative breast cancer cell line MDA-MB-231 and its adriamycin-resistant cell line MDA-MB-231/ADR were used in the experiment. Cell viability was detected by methyl thiazolyl tetrazolium(MTT) assay, and cell apoptosis was detected by DAPI staining and Annexin-V/Pi double staining. Western blot(WB) was used to detect the expression levels of Keap1, Nrf2, HO-1, Bcl-2, Bax, caspase-9, and caspase-3. Immunofluorescence staining was used to observe the distribution of Nrf2 in the cell, and flow cytometry was used to detect the level of reactive oxygen species(ROS) in the cell. The results showed that the resis-tance factor of SCL was 0.69, and that of adriamycin and paclitaxel was 8.40 and 16.36, respectively. DAPI staining showed that SCL could cause nuclear shrinkage and fragmentation of breast cancer cells. Annexin-V/Pi double staining showed that the average apoptosis rate of the drug-resistant cells was 32.64% and 50.29%, respectively under medium and high doses of SCL. WB results showed that SCL could significantly reduce the expression levels of anti-apoptotic proteins Bcl-2, caspase-9, and caspase-3 and significantly increase the expression level of pro-apoptotic protein Bax. Further studies showed that SCL could significantly promote the expression of Keap1, significantly inhibit the expression of Nrf2 and HO-1, and significantly reduce the expression level of Nrf2 in the nucleus. Correspondingly, flow cytometry showed that the intracellular ROS level was significantly increased. In conclusion, SCL can significantly inhibit the proliferation of MDA-MB-231 multidrug-resistant cells of triple-negative breast cancer and cause cell apoptosis, and the mechanism is related to inhibiting Keap1/Nrf2 signaling pathway, leading to ROS accumulation in drug-resistant cells and increasing the expression of apoptosis-related proteins.

Precisely Regulating Intermolecular Interactions and Molecular Packing of Nonfused-Ring Electron Acceptors via Halogen Transposition for High-Performance Organic Solar Cells.

The structure of molecular aggregates is crucial for charge transport and photovoltaic performance in organic solar cells (OSCs). Herein, the intermolecular interactions and aggregated structures of nonfused-ring electron acceptors (NFREAs) are precisely regulated through a halogen transposition strategy, resulting in a noteworthy transformation from a 2D-layered structure to a 3D-interconnected packing network. Based on the 3D electron transport pathway, the binary and ternary devices deliver outstanding power conversion efficiencies (PCEs) of 17.46% and 18.24%, respectively, marking the highest value for NFREA-based OSCs.

Multi-system diseases and death trajectory of metabolic dysfunction-associated fatty liver disease: findings from the UK Biobank.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly defined condition encompassing hepatic steatosis and metabolic dysfunction. However, the relationship between MAFLD and multi-system diseases remains unclear, and the time-dependent sequence of these diseases requires further clarification. METHODS: After propensity score matching, 163,303 MAFLD subjects and 163,303 matched subjects were included in the community-based UK Biobank study. The International Classification of Diseases, Tenth Revision (ICD-10), was used to reclassify medical conditions into 490 and 16 specific causes of death. We conducted a disease trajectory analysis to map the key pathways linking MAFLD to various health conditions, providing an overview of their interconnections. RESULTS: Participants aged 59 (51-64) years, predominantly males (62.5%), were included in the study. During the 12.9-year follow-up period, MAFLD participants were found to have a higher risk of 113 medical conditions and eight causes of death, determined through phenome-wide association analysis using Cox regression models. Temporal disease trajectories of MAFLD were established using disease pairing, revealing intermediary diseases such as asthma, diabetes, hypertension, hypothyroid conditions, tobacco abuse, diverticulosis, chronic ischemic heart disease, obesity, benign tumors, and inflammatory arthritis. These trajectories primarily resulted in acute myocardial infarction, disorders of fluid, electrolyte, and acid-base balance, infectious gastroenteritis and colitis, and functional intestinal disorders. Regarding death trajectories of MAFLD, malignant neoplasms, cardiovascular diseases, and respiratory system deaths were the main causes, and organ failure, infective disease, and internal environment disorder were the primary end-stage conditions. Disease trajectory analysis based on the level of genetic susceptibility to MAFLD yielded consistent results. CONCLUSIONS: Individuals with MAFLD have a risk of a number of different medical conditions and causes of death. Notably, these diseases and potential causes of death constitute many pathways that may be promising targets for preventing general health decline in patients with MAFLD.