Sperm Concentration Remains Stable Among Fertile American Men: A Systematic Review and Meta-Analysis.

IMPORTANCE: Findings from several high-profile meta-analyses have raised concerns about an ongoing global decline in sperm concentration and male fertility. However, these studies exhibit considerable heterogeneity in key variables including study population, methodology, fertility status, and geographic region. OBJECTIVE: To perform a systematic review and meta-analysis exploring temporal trends in sperm concentration among fertile men and men unselected for fertility status in the United States. DATA SOURCES: A literature search performed in Scopus and PubMed databases for studies published between 1970-2023. Additional studies were included from citations of prior global meta-analyses and reviews evaluating temporal trends in sperm count. Study selection and synthesis: Studies were included if they presented original data on sperm concentration in U.S. men without known infertility from 1970 to 2023. Aggregate data were assessed across all study populations, with additional subgroup analyses stratified by fertility status and U.S. region. MAIN OUTCOMES: Weighted generalized linear models were generated to evaluate the association between mean sperm concentration and sample collection year. RESULTS: A total of 874 articles were screened, with 58 meeting the inclusion criteria. These represented 75 unique study populations totaling 11,787 men in the U.S. Across all study populations, no change in sperm concentration was observed between 1970-2018 in unadjusted models (ß=0.14million/mL/year, p=0.42). When adjusting for U.S. region, no statistically significant decline in sperm concentration was seen. When adjusting for both region and fertility status, a modest annual decline was observed to meet statistical significance (ß=-0.35million/ml/year, p=0.04). Of the 49 study populations reporting adequate data to determine mean total sperm count, there was a significant increase in total sperm count of 2.9 million/year between 1970 and 2018 (p=0.03). Subgroup analysis found no statistically significant change in mean sperm concentration among any U.S. census region or fertility status cohort. CONCLUSION AND RELEVANCE: In contrast to prior global studies, this analysis suggests no clinically significant decline in sperm concentration among confirmed fertile men and the general male U.S. population without known infertility. While these findings provide some reassurance against a widespread rapid decline, further studies are necessary to better understand this important topic.

Platinum-Ruthenium Bimetallic Nanoparticle Catalysts Synthesized Via Direct Joule Heating for Methanol Fuel Cells.

Platinum-Ruthenium (PtRu) bimetallic nanoparticles are promising catalysts for methanol oxidation reaction (MOR) required by direct methanol fuel cells. However, existing catalyst synthesis methods have difficulty controlling their composition and structures. Here, a direct Joule heating method to yield highly active and stable PtRu catalysts for MOR is shown. The optimized Joule heating condition at 1000 °C over 50 microseconds produces uniform PtRu nanoparticles (6.32 wt.% Pt and 2.97 wt% Ru) with an average size of 2.0 ± 0.5 nanometers supported on carbon black substrates. They have a large electrochemically active surface area (ECSA) of 239 m2 g-1 and a high ECSA normalized specific activity of 0.295 mA cm-2. They demonstrate a peak mass activity of 705.9 mA mgPt -1 for MOR, 2.8 times that of commercial 20 wt.% platinum/carbon catalysts, and much superior to PtRu catalysts obtained by standard hydrothermal synthesis. Theoretical calculation results indicate that the superior catalytic activity can be attributed to modified Pt sites in PtRu nanoparticles, enabling strong methanol adsorption and weak carbon monoxide binding. Further, the PtRu catalyst demonstrates excellent stability in two-electrode methanol fuel cell tests with 85.3% current density retention and minimum Pt surface oxidation after 24 h.

Transcription factor DDIT3 is a potential driver in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and aggressive tumor that affects the digestive tract, leading to high mortality and poor survival rates. The purpose of the present study was to evaluate the expression levels of DNA damage-inducible transcript 3 (DDIT3) in pancreatic cancer and to investigate its effects in in vitro and in vivo experiments. Bioinformatics analysis indicated that DDIT3 expression was higher in pancreatic cancer tumor tissues and associated with a poor prognosis. Positive or strong positive DDIT3 expression was observed in PDAC, and no or weak expression was observed in normal pancreatic tissues. It was also highly expressed in PDAC cells, while being expressed at lower levels in normal pancreatic ductal epithelial cells. Transfection of short hairpin RNA targeting the DDIT3 gene reduced the proliferation, migration and invasion of PANC-1 cells. In vivo, in an in situ implantation tumor model with Pan02 cells, the size and weight of the tumors were reduced in the DDIT3 knockdown Pan02 cell-implanted group. These data suggested that DDIT3 represents a novel predictive biomarker for the potential treatment of patients presenting with PDAC.

The impact of an anomalous third segment of the vertebral artery on bypass surgery: a case report and literature review.

The horizontal part of the third segment (V3) of the vertebral artery (VA) is a critical anastomotic site for bypass procedures involving either donor or recipient vessels. It is rare for the V3 segment to deviate from its typical course of passing through the atlanto-transverse foramen. V3 anomaly encountered in occipital artery (OA)-V3 bypass surgery has not been previously reported. Here, we present a case involving a patient undergoing bypass surgery due to recurrent post-stent occlusion at the first segment (V1) of the left VA. During the operation, it was noted that the V3 horizontal segment could not be identified within the left VA groove, leading to initial suspicion of left V3 disuse atrophy attributed to prolonged chronic ischaemia. Consequently, there was a need to modify the operative method and to transition from an OA-V3 bypass to an OA-posterior inferior cerebellar artery bypass. Post-operative computed tomography angiography confirmed that indeed, the left V3 did not traverse through the transverse foramen of the atlas and instead entered the dural membrane between the first cervical vertebra (C1) and the second cervical vertebra (C2).

Efficacy, acceptability and tolerability of second-generation antipsychotics for behavioural and psychological symptoms of dementia: a systematic review and network meta-analysis.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are highly prevalent in people living with dementia. Second-generation antipsychotics (SGAs) are commonly used to treat BPSD, but their comparative efficacy and acceptability are unknown. METHODS: The standard mean difference (SMD) was used to pool the fixed effects of continuous outcomes. We calculated ORs with corresponding 95% credible intervals (CI) for the categorical variable. Efficacy was defined as the scores improved on the standardised scales. Acceptability was defined as the all-cause dropout rate. Tolerability was defined as the discontinuation rate due to adverse effects (AEs). The relative treatment rankings were reported with the surface under the cumulative curve. The AE outcomes included mortality, cerebrovascular adverse events (CVAEs), falls, sedation, extrapyramidal symptoms and urinary symptoms. RESULTS: Twenty randomised controlled trials with a total of 6374 individuals containing 5 types of SGAs (quetiapine, olanzapine, risperidone, brexpiprazole and aripiprazole) with intervention lengths ranging from 6 weeks to 36 weeks were included in this network meta-analysis. For the efficacy outcome, compared with the placebo, brexpiprazole (SMD=-1.77, 95% CI -2.80 to -0.74) was more efficacious, and brexpiprazole was better than quetiapine, olanzapine and aripiprazole. Regarding acceptability, only aripiprazole (OR=0.72, 95% CI 0.54 to 0.96) was better than the placebo, and aripiprazole was also better than brexpiprazole (OR=0.61, 95% CI 0.37 to 0.99). In terms of tolerability, olanzapine was worse than placebo (OR=6.02, 95% CI 2.87 to 12.66), risperidone (OR=3.67, 95% CI 1.66 to 8.11) and quetiapine (OR=3.71, 95% CI 1.46 to 9.42), while aripiprazole was better than olanzapine (OR=0.25, 95% CI 0.08 to 0.78). Quetiapine presented good safety in CVAE. Brexpiprazole has better safety in terms of falls and showed related safety in sedation among included SGAs. CONCLUSION: Brexpiprazole showing great efficacy in the treatment of BPSD, with aripiprazole showing the highest acceptability and olanzapine showing the worst tolerability. The results of this study may be used to guide decision-making.

Environmental DNA assays for Laricobius beetles (Coleoptera: Derodontidae), biocontrol agents of the hemlock woolly adelgid in North America.

The hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae), is an invasive pest causing significant ecological and economic damage to certain hemlock tree (Tsuga (Endlicher) Carrière, Pinales:Pinaceae) species. In response to this invasive threat, biological control strategies have been implemented, introducing natural predators such as Laricobius nigrinus Fender (Coleoptera: Derodontidae) and, more recently, Laricobius osakensis Montgomery and Shiyake (Coleoptera: Derodontidae), as specialist predators against A. tsugae. However, the genetic and morphological similarities between L. osakensis and both L. nigrinus and the native beetle, Laricobius rubidus LeConte (Coleoptera: Derodontidae), pose challenges in their identification. Effective monitoring of released predators is integral to evaluating the success of biological control measures. Environmental DNA (eDNA) holds potential for various detection applications, including species monitoring. In this study, we developed specific primers and probes targeting the mitochondrial cytochrome oxidase 1 gene sequences, achieving high specificity despite their 95% sequence similarity. With an optimal annealing temperature of 60 °C, our tools effectively differentiated L. osakensis from the other 2 beetles and demonstrated eDNA detection sensitivity down to 2 copies/µl. This research underscores the potential of precise molecular tools for advancing biological control and biodiversity assessment against invasive threats like A. tsugae.

A case report of entrapment of PentaRay catheter in the mechanical mitral valve: a known complication experienced anew.

Background: Complex atrial tachycardia (AT) is commonly observed in patients with cardiac surgery. High-density mapping is widely adopted for catheter ablation of complex AT in patients with cardiac surgery. Several case reports have described that PentaRay mapping catheter can be trapped in the mechanical valve and sheared off and successful retrieval of the spline by a snare system. We described a rare case in which PentaRay mapping catheter spline was successfully retrieved from the distal anterior tibial artery by direct syringe suction via the diagnostic catheter following entrapment in the mechanical mitral valve (MV) and rupture of the spline. Case summary: A 70-year-old female with mechanical bileaflet MV underwent catheter ablation for AT. During mapping in left atrium, the catheter was entrapped in mechanical MV and sheared off. We attempted to release the entrapped the spline by advancing the ablation catheter towards the stuck disc and pushing on the hinge portion of the disc with the catheter tip. The stuck and closed disc was opened, and the deeply entrapped spline was released. However, the entrapped PentaRay spline floated through the Valsalva sinus and strayed into the distal left anterior tibial artery. Fortunately, we successfully retrieved the spline from the distal anterior tibial artery by direct syringe suction instead of a snare system. Discussion: The possibility of the entrapment and subsequent rupture of the spline should always be considered during mapping the site close to mechanical valve. A rapid retrieval of embolized material should be carried out. If the spline strays into the distal and small artery in which the snare system is difficult to advance, a direct syringe suction via the diagnostic catheter may be attempted.

DLL1/NOTCH1 signaling pathway maintain angiogenesis in meniscus development and degeneration.

OBJECTIVES: The decline in vascular capacity within the meniscus is a well-documented phenomenon during both development and degeneration. Maintaining vascular integrity has been proposed as a potential therapeutic strategy for osteoarthritis. Therefore, our study aims to investigate the characteristics of endothelial cells and blood vessels in embryonic and degenerated meniscus tissues. METHODS: Human embryonic and mature menisci were used for histological analyses. Single-cell RNA sequencing was used to identify cell clusters and their significant genes in embryo meniscus to uncover characteristic of endothelial cells. Computer analysis and various staining techniques were used to characterize vessels in development and osteoarthritis meniscus. RESULTS: Vessels structure first observed in E12w and increasing in E14w. Vessels were veins majorly and arteries growth in E35w. Endothelial cells located not only perivascular but also in the surface of meniscus. The expression of DLL1 was observed to be significantly altered in endothelial cells within the vascular network that failed to form. Meniscus tissues affected by osteoarthritis, characterized by diminished vascular capacity, displayed reduced levels of DLL1 expression. Experiment in vitro confirmed DLL1/NOTCH1 be vital to angiogenesis. CONCLUSION: Lack of DLL1/NOTCH1 signaling pathway was mechanism of vascular declination in development and degenerated meniscus.

Ruddlesden-Popper Perovskite Nanocrystals as Interface Modification Layer for Efficient Perovskite Solar Cells.

Perovskite nanocrystals are advantageous for interfacial passivation of perovskite solar cells (PSCs), but the insulating long alkyl chain surface ligands impede the charge transfer, while the conventional ligand exchange would possibly introduce surface defects to the nanocrystals. In this work, we reported novel in situ modification of CsPbBr3 nanocrystals using a short chain conjugated molecule 2-methoxyphenylethylammonium iodide (2-MeO-PEAI) for interfacial passivation of PSCs. Transmission electron microscopy studies with atomic resolution unveil the transformation from cubic CsPbBr3 to Ruddlesden-Popper phase (RPP) nanocrystals due to halogen exchange. Synergic passivation by the RPP nanocrystals and 2-MeO-PEA+ has led to suppressed interface defects and enhanced charge carrier transport. Consequently, PSCs with in situ modified RPP nanocrystals achieved a champion power conversion efficiency of 24.39%, along with an improvement in stability. This work brings insights into the microstructural evolution of perovskite nanocrystals, providing a novel and feasible approach for interfacial passivation of PSCs.

Dual-functional Separators Regulating Ion Transport Enabled by 3D-Reinforced Polyimide Microspheres Protective Layer for Dendrite-Free and High-Temperature Lithium Metal Batteries.

High-energy-density lithium metal batteries (LMBs) are confronted with crucial concerns of security and a short cycle lifespan caused by the uncontrollable formation of lithium (Li) dendrites. The poor thermal stability and heterogeneous Li deposition of conventional polyolefin separators often cause battery short circuiting and thermal runaway in LMBs. Herein, a novel dual-functional PE composite separator (PI-COOH/PE) coated by carboxyl polyimide (PI) microspheres is fabricated by an etching-acidification method. The three-dimensional (3D) high-temp PI microsphere with rich carboxyl groups on the surface improve the security of LMBs at extremely high temperatures and facilitate the formation of a stable and uniform SEI layer, which contributes to accelerating the Li+ transport and stabilizing the formation of the SEI layer. Consequently, the Li symmetric cell assembled with the (PI-COOH)/PE separator exhibits stable overpotential over 3000 h, and the corresponding Li//NCM811 full cells also show a high-level discharge capacity of 146.6 mAh g-1 at 5 C. Meanwhile, it also demonstrates outstanding cycling stability and thermal safety, which can survive continuously over 160 min at 140 °C (vs 21 min for PE). The above results indicate the (PI-COOH)/PE separator constructed by a low-cost and industrial-friendly strategy simultaneously addresses high-temperature stability and dendrite resistance.

New implications for prion diseases therapy and prophylaxis.

Prion diseases are rare, fatal, progressive neurodegenerative disorders that affect both animal and human. Human prion diseases mainly present as Creutzfeldt-Jakob disease (CJD). However, there are no curable therapies, and animal prion diseases may negatively affect the ecosystem and human society. Over the past five decades, scientists are devoting to finding available therapeutic or prophylactic agents for prion diseases. Numerous chemical compounds have been shown to be effective in experimental research on prion diseases, but with the limitations of toxicity, poor efficacy, and low pharmacokinetics. The earliest clinical treatments of CJD were almost carried out with anti-infectious agents that had little amelioration of the course. With the discovery of pathogenic misfolding prion protein (PrPSc) and increasing insights into prion biology, amounts of novel technologies have attempted to eliminate PrPSc. This review presents new perspectives on clinical and experimental prion diseases, including immunotherapy, gene therapy, small-molecule drug, and stem cell therapy. It further explores the prospects and challenge associated with these emerging therapeutic approaches for prion diseases.

Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance.

Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.

Revolutionizing Airborne Virus Defense: Electromagnetic MXene-Coated Air Filtration for Superior Aerosol Viral Removal.

The COVID-19 pandemic sparked public health concerns about the transmission of airborne viruses. Current methods mainly capture pathogens without inactivation, leading to potential secondary pollution. Herein, we evaluated the inactivation performance of a model viral species (MS2) in simulated bioaerosol by an electromagnetically enhanced air filtration system under a 300 kHz electromagnetic induction field. A nonwoven fabric filter was coated with a 2D catalyst, MXene (Ti3C2Tx), at a coating density of 4.56 mg·cm-2 to absorb electromagnetic irradiation and produce local heating and electromagnetic field for microbial inactivation. The results showed that the MXene-coated air filter significantly enhanced the viral removal efficiency by achieving a log removal of 3.4 ± 0.15 under an electromagnetic power density of 369 W·cm-2. By contrast, the pristine filter without catalyst coating only garnered a log removal of 0.3 ± 0.04. Though the primary antimicrobial mechanism is the local heating as indicated by the elevated surface temperature of 72.2 ± 4 °C under the electromagnetic field, additional nonthermal effects (e.g., dielectrophoresis) on enhanced viral capture during electromagnetically enhanced filtration were investigated by COMSOL simulation to delineate the potential transmission trajectories of bioaerosol. The results provide unique insights into the mechanisms of pathogen control and thus promote alternative solutions for preventing the transmission of airborne pathogens.

Evaluation of commercial nanofiltration and reverse osmosis membrane filtration to remove per-and polyfluoroalkyl substances (PFAS): Effects of transmembrane pressures and water matrices.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are now widely found in aquatic ecosystems, including sources of drinking water and portable water, due to their increasing prevalence. Among different PFAS treatment or separation technologies, nanofiltration (NF) and reverse osmosis (RO) both yield high rejection efficiencies (>95%) of diverse PFAS in water; however, both technologies are affected by many intrinsic and extrinsic factors. This study evaluated the rejection of PFAS of different carbon chain length (e.g., PFOA and PFBA) by two commercial RO and NF membranes under different operational conditions (e.g., applied pressure and initial PFAS concentration) and feed solution matrixes, such as pH (4-10), salinity (0- to 1000-mM NaCl), and organic matters (0-10 mM). We further performed principal component analysis (PCA) to demonstrate the interrelationships of molecular weight (213-499 g·mol-1 ), membrane characteristics (RO or NF), feed water matrices, and operational conditions on PFAS rejection. Our results confirmed that size exclusion is a primary mechanism of PFAS rejection by RO and NF, as well as the fact that electrostatic interactions are important when PFAS molecules have sizes less than the NF membrane pores. PRACTITIONER POINTS: Two commercial RO and NF membranes were both evaluated to remove 10 different PFAS. High transmembrane pressures facilitated permeate recovery and PFAS rejection by RO. Electrostatic repulsion and pore size exclusion are dominant rejection mechanisms for PFAS removal. pH, ionic strength, and organic matters affected PFAS rejection. Mechanisms of PFAS rejection with RO/NF membranes were explained by PCA analysis.

Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging.

BACKGROUND: With the growing aging population and longer life expectancy, periodontitis and tooth loss have become major health concerns. The gut microbiota, as a key regulator in bone homeostasis, has gathered immense interest. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis Georgi, has shown antioxidant and anti-inflammatory activities. PURPOSE: This study investigated, for the first time, the protective mechanism of baicalin against alveolar bone inflammatory resorption in aging mice by regulating intestinal flora and metabolites, as well as intestinal barrier function. METHODS: A ligature-induced periodontitis model was established in d-galactose (D-gal)-induced aging mice, and baicalin was administered at different dosages for 13 weeks. Body weight was measured weekly. The antioxidant and anti-inflammatory activity of baicalin were evaluated using serum superoxide dismutase (SOD), malonaldehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. The immune capability was assessed by thymus and spleen indices. Histopathological changes were observed in the heart, liver, ileum, and periodontal tissues. Alveolar bone absorption of maxillary second molars was examined, and osteoclasts were counted by tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, fecal samples were analyzed using 16S rRNA sequencing and non-targeted metabolomics to identify differences in intestinal bacterial composition and metabolites. RESULTS: Baicalin exhibited anti-aging properties, as evidenced by increased SOD activity and decreased levels of MDA, IL-6, and TNF-α in serum compared to the control group. Baicalin also ameliorated alveolar bone loss in the d-gal-induced aging-periodontitis group (p < 0.05). Furthermore, baicalin restored ileal permeability by up-regulating the expression of ZO-1 and occludin in aging-periodontitis groups (p < 0.05). Alpha diversity analysis indicated that baicalin-treated mice harbored a higher diversity of gut microbe. PCoA and ANOSIM results revealed significant dissimilarity between groups. The Firmicutes/Bacteroidetes (F/B) ratio, which decreased in periodontitis mice, was restored by baicalin treatment. Additionally, medium-dosage baicalin promoted the production of beneficial flavonoids, and enriched short-chain fatty acids (SCFAs)-producing bacteria. CONCLUSION: Intestinal homeostasis is a potential avenue for treating age-related alveolar bone loss. Baicalin exerts anti-inflammatory, antioxidant, and osteo-protective properties by regulating the gut microbiota and metabolites.

Unraveling the pH-Dependent Oxygen Reduction Performance on Single-Atom Catalysts: From Single- to Dual-Sabatier Optima.

Metal-nitrogen-carbon (M-N-C) single-atom catalysts (SACs) have emerged as a potential substitute for the costly platinum-group catalysts in oxygen reduction reaction (ORR). However, several critical aspects of M-N-C SACs in ORR remain poorly understood, including their pH-dependent activity, selectivity for 2- or 4-electron transfer pathways, and the identification of the rate-determining steps. Herein, by analyzing >100 M-N-C structures and >2000 sets of energetics, we unveil a pH-dependent evolution in ORR activity volcanos─from a single peak in alkaline media to a double peak in acids. We found that this pH-dependent behavior in M-N-C catalysts fundamentally stems from their moderate dipole moments and polarizability for O* and HOO* adsorbates, as well as unique scaling relations among ORR adsorbates. To validate our theoretical discovery, we synthesized a series of molecular M-N-C catalysts, each characterized by well-defined atomic coordination environments. Impressively, the experiments matched our theoretical predictions on kinetic current, Tafel slope, and turnover frequency in both acidic and alkaline environments. These new insights also refine the famous Sabatier principle by emphasizing the need to avoid an "acid trap" while designing M-N-C catalysts for ORR or any other pH-dependent electrochemical applications.

Role of ideal cardiovascular health metrics in reducing risk of incident arrhythmias.

AIMS: Cardiovascular health (CVH) has been proven to reduce cardiovascular disease burden and mortality, but data are lacking regarding cardiac arrhythmias. The aim of this study was to assess the association between CVH metrics and atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS AND RESULTS: This study analysed data from the Atherosclerosis Risk in Communities (ARIC) cohort, with participants recruited from four different communities across the United States. Cardiovascular health metrics were scored at baseline (1987-89) following the American Heart Association's recommendations and categorized as poor, intermediate, or ideal. Arrhythmia episodes were diagnosed by International Classification of Diseases (ICD)-9 code. Adjusted associations were estimated using Cox models and event rates and population attributable fractions were calculated by CVH metrics category. The study population consisted of 13 078 participants, with 2548 AF, 1363 ventricular arrhythmias, and 706 bradyarrhythmias occurred. The adjusted hazard ratios (HRs) for ideal (vs. poor) CVH metrics were 0.59 [95% confidence interval (CI): 0.50-0.69] for AF, 0.38 (95% CI: 0.28-0.51) for ventricular arrhythmias, and 0.70 (95% CI: 0.51-0.97) for bradyarrhythmia. The risk of incident arrhythmias decreased steadily as the CVH metrics improved from 0 to 14 scores. The adjusted population attributable fractions were calculated to be 29.9% for AF, 54.4% for ventricular arrhythmias, and 21.9% for bradyarrhythmia, respectively. The association between CVH metrics and incident arrhythmias was also seen in people who remained free of coronary heart disease over the follow-up. CONCLUSION: Achieving ideal CVH metrics recommendations by AHA in midlife was associated with a lower risk of incident arrhythmias later in life.

Intermediate and ideal levels of cardiovascular health (CVH) metrics are associated with a markedly reduced risk of developing incident arrhythmias, including atrial fibrillation/flutter, ventricular arrhythmias, and bradyarrhythmia, independent of coronary heart disease. A majority of incident arrhythmias could be prevented if the risk profile of the entire population was optimized. These findings emphasize the significance of public health policies that improve CVH to reduce the social and economic burden of arrhythmias.

LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation.

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA (lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer (TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1 (PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.

Single-cell RNA-seq reveals MIF-(CD74 + CXCR4) dependent inhibition of macrophages in metastatic papillary thyroid carcinoma.

BACKGROUND: The mechanism promoting papillary thyroid carcinoma (PTC) metastasis remains unclear. We aimed to investigate the potential metastatic mechanisms at a single-cell resolution. METHODS: We performed single-cell RNA-seq (scRNA-seq) profiling of thyroid tumour (TT), adjacent normal thyroid (NT) and lymph node metastasized tumour (LN) from a young female with PTC. Validation of our results was conducted in 31 tumours with metastasis and 30 without metastasis. RESULTS: ScRNA-seq analysis generated data on 38,215 genes and 0.14 billion transcripts from 28,839 cells, classified into 18 clusters, each annotated to represent 10 cell types. PTC cells were found to originate from epithelial cells. Epithelial cells and macrophages emerged as the strongest signal emitters and receivers, respectively. After reclustering epithelial cells and macrophages, our analysis, incorporating gene set variation analysis (GSVA), SCENIC analysis, and pseudotime trajectory analysis, indicated that subcluster 0 of epithelial cells (EP_0) showed a more malignant phenotype, and subclusters 3 and 4 of macrophages (M_3 and M_4) demonstrated heightened activity. Further analysis suggested that EP_0 may suppress the activity of M_3 and M_4 via MIF - (CD74 + CXCR4) in the MIF pathway. After analysing the expression of the 4 genes in the MIF pathway in both the TCGA cohort and our cohort (n = 61), CD74 was identified as significantly overexpressed in PTC tumours particularly those with lymph node metastasis. CONCLUSION: Our study revealed that PTC may facilitate lymph node metastasis by inhibiting macrophages via MIF signalling. It is suggested that malignant PTC cells may suppress the immune activity of macrophages by consistently releasing signals to them via MIF-(CD74 + CXCR4).