Spatial and Temporal Distribution Characteristics and Cytotoxicity of Atmospheric PM2.5 in the Main Urban Area of Lanzhou City.

PM2.5, as one of the most harmful pollutant in the atmospheric environment and population health, has received much attention. We monitored PM2.5 levels at five sampling sites in the Lanzhou City and collected PM2.5 particles from two representative sites for cytotoxicity experiment. The cytotoxicity of PM2.5 samples on A549 cells and migration ability of the cells were respectively detected by Cell Counting kit-8 (CCK-8) assay and scratch assay. We detected the levels of cellular inflammatory factors and oxidative damage-related biochemical indexes. RT-qPCR was used to detect the mRNA levels of NF-κB and epithelial-mesenchymal transition (EMT)-related genes. We found that the Lanlian Hotel station had the highest PM2.5 annual average concentration. The annual average concentration change curve of PM2.5 showed a roughly "U"-shaped distribution during the whole sampling period. The cytotoxicity experiment showed the viability of A549 cells decreased and the scratch healing rate increased in the 200 and 400 µg/mL PM2.5-treated groups. We also found 400 µg/mL PM2.5 induced changes in the mRNA levels of NF-κB and EMT-related genes, the mRNA levels of IKK-α, NIK, and NF-κB in the 400 µg/mL PM2.5 group were higher than those in the control group. The mRNA levels of E-cadherin decreased and α-SMA increased in the 400 µg/mL PM2.5 groups, and the mRNA levels of Fibronectin increased in the 400 µg/mL PM2.5 groups. Moreover, we found hydroxyl radical scavenging ability and T-AOC levels were lower, and LPO levels were higher in the 200 and 400 µg/mL PM2.5 groups, and the SOD activity of cells in the 400 µg/mL PM2.5 group decreased. And compared with the control group, the levels of TNF-α were higher in the 200 and 400 µg/mL PM2.5 groups and the levels of IL-1 were higher in the 400 µg/mL PM2.5 group. The results indicated that the cytotoxicity of atmospheric PM2.5 was related to oxidative damage, inflammatory response, NF-κB activity and EMT.

The effect of spermatic cord block on reducing the risk of vagal reflex during microsurgical subinguinal varicocelectomy: A randomized trial.

Purpose: This study aimed to compare the risk of vagal reflex during microsurgical subinguinal varicocelectomy (MSV) under general anesthesia (GA) with or without additional local anesthetic (LA) spermatic cord block (SCB). Method: A single-center randomized controlled trial was conducted between January 2022 and June 2023.300 patients with left-sided grade Ⅲ varicocele were randomly divided into two groups: SCB group (n = 153) and control group (n = 147)（computer-generated random numbers list）. During MSV under GA, the SCB group was given of ropivacaine for SCB before pulling the spermatic cord, while the control group was directly lifted. The primary outcome was the reduction in the lowest heart rate in the SCB group as compared with the control group during spermatic cord traction (SCT). Secondary outcomes included the reduction in the lowest blood pressure in the SCB group as compared with the control group; and the reductions in the lowest heart rate and lowest blood pressure as compared with baseline during SCT. The number of times that surgery and medications were suspended because of symptomatic reflex bradycardia was also recorded. Adverse events were also recorded as secondary outcomes. Result: Five patients in the SCB group and 10 patients in the CG were excluded. The lowest heart rate and systolic blood pressure during SCT in the SCB group and the control group were significantly lower than the baseline values (P < 0.05). However, the decrease in the SCB group (70-73bpm VS 108-115 mmHg) was milder than that of the control group（66-72 bpm VS 105-114 mmHg）(P < 0.05). The number of surgeries and medication pauses due to symptomatic reflex bradycardia during surgery was significantly lower in the SCB group (2 VS 1) than in the control group (9 VS 7) (P < 0.05). Conclusion: SCB can effectively reduce the vagal reflex caused by pulling the spermatic cord during MSV, and reduce the risk of anesthesia and surgery.

Comprehensive Multiple Risk Factor Control in Type 2 Diabetes to Mitigate Heart Failure Risk: Insights From a Prospective Cohort Study.

OBJECTIVE: The impact of comprehensive risk factor control on heart failure (HF) risk and HF-free survival time in individuals with type 2 diabetes (T2D) was evaluated in this study. RESEARCH DESIGN AND METHODS: This prospective study included 11,949 individuals diagnosed with T2D, matched with 47,796 non-T2D control study participants from the UK Biobank cohort. The degree of comprehensive risk factor control was assessed on the basis of the major cardiovascular risk factors, including blood pressure, BMI, LDL cholesterol, hemoglobin A1c, renal function, smoking, diet, and physical activity. Cox proportional hazards models were used to measure the associations between the degree of risk factor control and HF risk. Irwin's restricted mean was used to evaluate HF-free survival time. RESULTS: During a median follow-up of 12.3 years, 702 individuals (5.87%) with T2D and 1,402 matched control participants (2.93%) developed HF. Each additional risk factor controlled was associated with an average 19% lower risk of HF. Optimal control of at least six risk factors was associated with a 67% lower HF risk (hazard ratio [HR] 0.33; 95% CI 0.20, 0.54). BMI was the primary attributable risk factor for HF. Notably, the excess risk of HF associated with T2D could be attenuated to levels comparable to those of non-T2D control participants when individuals had a high degree of risk factor control (HR 0.66; 95% CI 0.40, 1.07), and they exhibited a longer HF-free survival time. CONCLUSIONS: Comprehensive management of risk factors is inversely associated with HF risk, and optimal risk factor control may prolong HF-free survival time among individuals with T2D.

Distributed Privacy-Preserving Optimization With Accumulated Noise in ADMM.

Privacy preservation for distributed optimization in multiagent systems has been widely concerned in recent years. In this article, the accumulated noise privacy-preserving alternating direction method of multipliers (ANPPM) algorithm is proposed to preserve the private information of each agent. The masked states of each agent are sent to its neighbors with a designed noise-adding mechanism, and an accumulated term is introduced to confuse the gradients at each iteration. With ANPPM, all the agents can achieve privacy preservation for the information of real states and subgradients. Moreover, the states of all the agents can be guaranteed to converge to the optimal solution. The convergence rate of O(1/k) is consistent with standard ADMM, hence no adverse effect is induced by the privacy-preserving mechanism. Numerical results are provided to validate the effectiveness of the proposed ANPPM algorithm.

Modulating Visible-Light Driven NIR Lanthanide Polymer Photocatalysis for Amplification Detection of Exosomal Proteins and Cancer Diagnosis.

Near-infrared (NIR) luminescent lanthanide materials hold great promise for bioanalysis, as they have anti-interference properties. The approach of efficient luminescence is sensitization through a reasonable chromophore to overcome the obstacle of the aqueous phase. The involvement of the surfactant motif is an innovative strategy to arrange the amphiphilic groups to be regularly distributed near the polymer to form a closed sensitized space. Herein, a lanthanide polymer (TCPP-PEI70K-FITC@Yb/SDBS) is designed in which the meso-tetra(4-carboxyphenyl)porphine (TCPP) ligand serves as both a sensitizer and photocatalytic switch. The surfactant sodium dodecyl benzenesulfonate (SDBS) wraps the photosensitive polymers to form a hydrophobic layer, which augments the light-harvesting ability and expedites its photocatalysis. TCPP-PEI70K-FITC@Yb/SDBS is subsequently applied as an amplified photocatalysis toolbox for universally regulating the generation of reactive oxygen species (ROS). Boosting 3,3',5,5'-tetramethylbenzidine (TMB) oxidation to produce blue products, a dual-mode biosensor is fabricated for improving the diagnosis of programmed death ligand-1-positive (PDL1) cancer exosomes. Exosomes were captured by Fe3O4 modified by the PDL1 aptamer, enabling replacement of alkaline phosphatase (ALP)-labeled multiple hybridized chains; then, the isolated ALP triggered a hydrolysis reaction to block the generation of oxTMB. Detection sensitivity improves by 1 order of magnitude through SDBS modulation, down to 104 particles/mL. The sensor performed well clinically in distinguishing cancer patients from healthy individuals, expanding physiological applications of near-infrared lanthanide luminescence.

Life's essential 8, genetic susceptibility, and incident cardiac arrhythmias: a population-based prospective cohort study.

BACKGROUND: Ideal cardiovascular health (CVH) has been associated with reduced cardiovascular disease risk and mortality, but its association with cardiac arrhythmias were still unsettled. In this prospective cohort study, we investigated the relationship between CVH and subsequent arrhythmias risk, including atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS: Data from 287,264 participants initially free of arrhythmias in the UK Biobank were included in the analysis. Cox regression models were used to examine the relationship between CVH levels calculated by the American Heart Association's Life's Essential 8 (LE8) metrics, with cardiac arrhythmias risk. RESULTS: During a median follow-up period of 12.8 years, 16,802 incident AF, 2186 incident ventricular arrhythmias, and 4128 incident bradyarrhythmias were identified. After adjustment for confounding factors, participants with high initial CVH levels had a significantly lower risk for AF (HR 0.63, 95% CI 0.59-0.68), ventricular arrhythmias (HR 0.48, 95% CI 0.40-0.59), and bradyarrhythmias (HR 0.64, 95% CI 0.55-0.74) compared to those with low CVH levels. Furthermore, each SD increase in LE8 scores was associated with a 15% lower risk of AF, 21% for ventricular arrhythmias, and 13% for bradyarrhythmias, respectively. Additionally, a significant interaction was observed between CVH levels and the genetic risk of AF (P for interaction, 0.021). The reverse correlation seemed to be more noticeable in individuals with a lower genetic susceptibility to AF. CONCLUSIONS: We concluded that higher levels of CVH, estimated by the LE8 metrics, were associated with significantly reduced risks of AF, ventricular arrhythmias, and bradyarrhythmias.

TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Mechanism and complex roles of HSC70/HSPA8 in viral entry.

The process of viruses entering host cells is complex, involving multiple aspects of the molecular organization of the cell membrane, viral proteins, the interaction of receptor molecules, and cellular signaling. Most viruses depend on endocytosis for uptake, when viruses reach the appropriate location, they are released from the vesicles, undergo uncoating, and release their genomes. Heat shock cognate protein 70(HSC70): also known as HSPA8, a protein involved in mediating clathrin-mediated endocytosis (CME), is involved in various viral entry processes. In this mini-review, our goal is to provide a summary of the function of HSC70 in viral entry. Understanding the interaction networks of HSC70 with viral proteins helps to provide new directions for targeted therapeutic strategies against viral infections.

The first-principles study of interfacial bonding strength and segregation behavior of alloyed elements at the η(MgZn2)/Al interface.

For precipitation-strengthened Al alloys, the interfacial segregation behavior of alloying elements plays an important role in controlling the effectiveness of precipitation strengthening. In this work, the adhesion work (Wad) and interfacial energy (γ) of the η(0001)/Al(111) interface were studied to gain an insight into the interface properties between the precipitate η and the Al matrix. Additionally, we examined the impact of the segregation behavior of alloyed elements on the bonding strength of the interface. The computed values for Wad and interfacial energies indicated that the T6S3 terminated configuration represents the interfacial structure with the highest stability across all models analyzed. Focusing on the T6S3 interface, the assessed segregated energies (Eseg) disclose that the segregation ability of elements from strong to weak exhibits the order of Ti > Sc > Zr > Y > Ta > Nb > Lu > Hf > Mo > V > W, while Cr and Mn elements are not easy to segregate at the interface. Sc, Ti, V, Cr, Mn, Zr, Nb, Mo, Hf, and Ta preferentially occupy Al atoms, whereas Y and Lu predominantly inhabit Mg atoms. Relative to the clean interface, the electron cloud enrichment at the interface after alloying element X (Zr, Sc, Ti, W, Hf, Mn, Y, Lu and V) doping is weakened, and the ion interaction among interface atoms is enhanced. After doping alloying element X (Nb, Mo, Ta, and Cr), the degree of electron cloud enrichment at the interface is obviously enhanced, and the covalent interaction among interface atoms is enhanced. This suggests that the introduction of alloyed elements through doping can augment the bond strength at the interface between the precipitated phase and matrix, thereby reinforcing the strength and toughness of 7xxx series alloys.

Extended Left Hemihapatectomy with Right Hepatic Artery Reconstruction for Primary Hepatic Neuroendocrine Neoplasm: A Brief Report.

BACKGROUND rimary hepatic neuroendocrine neoplasms (PHNEN) are exceedingly rare tumors with atypical clinical manifestations, accounting for less than 0.5% of all neuroendocrine tumors. Currently, there is a lack of consensus on their management, and guidelines do not recommend postoperative chemotherapy for patients with stage G1/G2 disease after curative resection. We present a case report of PHNEN, outlining its diagnostic challenges, treatment strategy, and clinical outcomes. CASE REPORT A 31-year-old man presented with jaundice and was initially diagnosed with suspected IgG4-related disease, which initially appeared to respond to steroid therapy, but manifested worsening jaundice 4 months after initial treatment. Subsequent evaluation revealed a PHNEN NET G2 with lymph node metastasis and invasion of the right hepatic artery; and involvement of the hepatic duct at the hepatic hilum, primarily the left hepatic duct. The patient underwent extended left hemi-hepatectomy with caudate lobe resection, bile duct resection, and lymphadenectomy, followed by reconstruction of the right hepatic artery. Postoperatively, the patient received adjuvant chemotherapy consisting of capecitabine (1000 mg bid D1-14) and temozolomide (200 mg qn D10-14) for 6 cycles. Currently, the patient remains disease free 43 months after treatment. CONCLUSIONS PHNEN presents diagnostic challenges due to its rarity and lack of specific markers. Surgical resection remains the cornerstone of treatment, with chemotherapy being considered in select cases with high-risk features. Further research is needed to refine treatment approaches and improve outcomes for patients with PHNEN.

Organic Passivation-Enhanced Ferroelectricity in Perovskite Oxide Films.

Perovskite oxides and organic-inorganic halide perovskite materials, with numerous fascinating features, have been subjected to extensive studies. Most of the properties of perovskite materials are dependence on their ferroelectricity that denoted by remanent polarization (Pr). Thus, the increase of Pr in perovskite films is mainly an effort in material physics. At present, commonplace improvement schemes, i.e., controlling material crystallinity, and post-annealing by using a high-temperature process, are normally used. However, a simpler and temporal strategy for Pr improvement is always unavailable to perovskite material researchers. In this study, an organic coating layer, low-temperature, and vacuum-free strategy is proposed to improve the Pr, directly increasing the Pr from 36 to 56 µC cm-2. Further study finds that the increased Pr originates from the suppression of the oxygen defects and Ti defects. This organic coating layer strategy for passivating the defects may open a new way for the preparation of higher-performance and cost-effective perovskite products, further improving its prospective for application in the electron devices field.

Individualized Structural Perturbations on Normative Brain Connectome Restrict Deep Brain Stimulation Outcomes in Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) respond to deep brain stimulation (DBS) variably. However, how brain substrates restrict DBS outcomes remains unclear. OBJECTIVE: In this article, we aim to identify prognostic brain signatures for explaining the response variability. METHODS: We retrospectively investigated a cohort of patients with PD (n = 141) between 2017 and 2022, and defined DBS outcomes as the improvement ratio of clinical motor scores. We used a deviation index to quantify individual perturbations on a reference structural covariance network acquired with preoperative T1-weighted magnetic resonance imaging. The neurobiological perturbations of patients were represented as z scored indices based on the chronological perturbations measured on a group of normal aging adults. RESULTS: After applying stringent statistical tests (z > 2.5) and correcting for false discoveries (P < 0.01), we found that accelerated deviations mainly affected the prefrontal cortex, motor strip, limbic system, and cerebellum in PD. Particularly, a negative network within the accelerated deviations, expressed as "more preoperative deviations, less postoperative improvements," could predict DBS outcomes (mean absolute error = 0.09, R2 = 0.15). Moreover, a fusion of personal brain predictors and medical responses significantly improved traditional evaluations of DBS outcomes. Notably, the most important brain predictor, a pathway connecting the cognitive unit (prefrontal cortex) and motor control unit (cerebellum and motor strip), partially mediates DBS outcomes with the age at surgery. CONCLUSIONS: Our findings suggest that individual structural perturbations on the cognitive motor control circuit are critical for modulating DBS outcomes. Interventions toward the circuit have the potential for additional clinical improvements. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases.

The DNA-dependent protein kinase (DNA-PK), catalytic subunit, also known as DNA-PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA-PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA-PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA-PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS-STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA-PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA-PKcs and diseases for better targeting DNA-PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA-PKcs in human diseases, meanwhile, we discuss the progresses of DNA-PKcs inhibitors and their potential in clinical trials. The most updated review about DNA-PKcs will hopefully provide insights and ideas to understand DNA-PKcs associated diseases.

Recent advances in circularly polarized luminescence of planar chiral organic compounds.

Circularly polarized luminescence (CPL), as an important chiroptical phenomenon, can not only directly characterize excited-state structural information about chiroptical materials but also has great application prospects in 3D optical displays, information storage, biological probes, CPL lasers and so forth. Recently, chiral organic small molecules with CPL have attracted a lot of research interest because of their excellent luminescence efficiency, clear molecular structures, unique flexibility and easy functionalization. Planar chiral organic compounds make up an important class of chiral organic small molecular materials and often have rigid macrocyclic skeletons, which have important research value in the field of chiral supramolecular chemistry (e.g., chiral self-assembly and chiral host-guest chemistry). Therefore, research into planar chiral organic compounds has become a hotspot for CPL. It is time to summarize the recent developments in CPL-active compounds based on planar chirality. In this feature article, we summarize various types of CPL-active compounds based on planar chirality. Meanwhile, we overview recent research in the field of planar chiral CPL-active compounds in terms of optoelectronic devices, asymmetric catalysis, and chiroptical sensing. Finally, we discuss their future research prospects in the field of CPL-active materials. We hope that this review will be helpful to research work related to planar chiral luminescent materials and promote the development of chiral macrocyclic chemistry.

Effects of melatonin on sperm quality, enzyme activity, antioxidant gene expression and fertility of cryopreserved bovine semen.

Melatonin (MLT) has strong antioxidant capacity and can reduce the damage caused by oxidative stress in sperm, but there is still little content in the field we have studied. In this study, we are committed to scientific research on adding melatonin to Belgian blue bull semen diluent for cryopreservation. Different concentrations (0, 0.1, 0.3, 0.5 or 0.7 mg/mL) of MLT were added diluent. Sperm kinetic parameters, enzyme activity, antioxidant gene expression and fertility were analyzed after thawing. The results showed that MLT concentration of 0.3 mg/mL exerted positive effects on post-thaw kinetic parameters. Compared with other groups, 0.3 mg/mL MLT treated sperm acrosome and plasma membrane integrity, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels significantly increased. Meanwhile, the mRNA expression of antioxidant genes SOD2, CAT and GPx increased in the 0.3 mg/mL MLT treatment group, and the mRNA expression of apoptosis genes Caspase-3 and Bax were significantly reduced. In addition, in vitro fertilization (IVF) embryo cleavage, blastocyst rate and artificial insemination (AI) pregnancy rate were higher in 0.3 mg/mL MLT. Therefore, MLT showed cryoprotective capacity to the freezing diluent used for Belgian blue bull sperm during the process of freezing-thawing, and the optimal concentration of MLT for the frozen diluent was 0.3 mg/mL.

Dynamic causal modeling analysis reveals the modulation of motor cortex and integration in superior temporal gyrus during multisensory speech perception.

The processing of speech information from various sensory modalities is crucial for human communication. Both left posterior superior temporal gyrus (pSTG) and motor cortex importantly involve in the multisensory speech perception. However, the dynamic integration of primary sensory regions to pSTG and the motor cortex remain unclear. Here, we implemented a behavioral experiment of classical McGurk effect paradigm and acquired the task functional magnetic resonance imaging (fMRI) data during synchronized audiovisual syllabic perception from 63 normal adults. We conducted dynamic causal modeling (DCM) analysis to explore the cross-modal interactions among the left pSTG, left precentral gyrus (PrG), left middle superior temporal gyrus (mSTG), and left fusiform gyrus (FuG). Bayesian model selection favored a winning model that included modulations of connections to PrG (mSTG → PrG, FuG → PrG), from PrG (PrG → mSTG, PrG → FuG), and to pSTG (mSTG → pSTG, FuG → pSTG). Moreover, the coupling strength of the above connections correlated with behavioral McGurk susceptibility. In addition, significant differences were found in the coupling strength of these connections between strong and weak McGurk perceivers. Strong perceivers modulated less inhibitory visual influence, allowed less excitatory auditory information flowing into PrG, but integrated more audiovisual information in pSTG. Taken together, our findings show that the PrG and pSTG interact dynamically with primary cortices during audiovisual speech, and support the motor cortex plays a specifically functional role in modulating the gain and salience between auditory and visual modalities. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09945-z.

Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

Low remnant cholesterol and the subsequent risk of new-onset atrial fibrillation: A prospective cohort study.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia with high morbidity and mortality implications. Several studies have described a paradoxical inverse relationship between serum cholesterol and the risk of AF, but it remains unknown whether remnant cholesterol (RC) is associated with AF incidence. OBJECTIVE: This study aims to prospectively investigate the association between RC and AF. METHODS: A total of 392,783 participants free of AF at baseline from the UK Biobank were included for the analysis. Cox proportional hazards model, subgroup analysis, and sensitivity analyses were used to evaluate the independent association between RC levels and the risk of new-onset AF. Furthermore, we performed a discordance analysis by using the median cutoff points of low-density lipoprotein cholesterol (LDL-C) and RC. RESULTS: After a median follow-up of 12.8 years (interquartile range 12.0-13.6 years), a total of 23,558 participants experienced incident AF. Compared with the highest RC level, the lower RC level was associated with an increased risk of AF incidence (quartile 1 vs quartile 4: hazard ratio 1.396; 95% confidence interval [CI] 1.343-1.452). The results remained robust across a series of sensitivity analyses. In the discordance analyses, a significantly higher risk of AF was observed in participants with discordant low RC/high LDL-C levels than in those with concordant high RC/LDL-C levels. In the low LDL-C group, RC reduction even contributed to an additional 15.8% increased rate of incident AF (low RC/low LDL-C: hazard ratio 1.303; 95% CI 1.260-1.348 vs high RC/low LDL-C: hazard ratio 1.125; 95% CI 1.079-1.172). CONCLUSION: Low RC levels were associated with an increased risk of incident AF independent of traditional cardiovascular risk factors.

Altered regional brain activity and functional connectivity in primary intravaginal anejaculation patients revealed by resting-state fMRI.

ABSTRACT: Ejaculation is regulated by the central nervous system. However, the central pathophysiology of primary intravaginal anejaculation (PIAJ) is unclear. The present study aimed to examine the changes in regional brain activity and functional connectivity underlying PIAJ. A total of 20 PIAJ patients and 16 healthy controls (HCs) were enrolled from September 2020 to September 2022 in the Department of Andrology, Nanjing Drum Tower Hospital (Nanjing, China). Magnetic resonance imaging data were acquired from all participants and then were preprocessed. The measures of fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) were calculated and compared between the groups. PIAJ patients showed increased fALFF values in the left precuneus compared with HCs. Additionally, PIAJ patients showed increased ReHo values in the left precuneus, left postcentral gyrus, left superior occipital gyrus, left calcarine fissure, right precuneus, and right middle temporal gyrus, and decreased ReHo values in the left inferior parietal gyrus, compared with HCs. Finally, brain regions with altered fALFF and ReHo values in PIAJ patients showed increased FC with widespread cortical regions, which included the frontal, parietal, temporal, and occipital regions, compared with HCs. In conclusion, increased regional brain activity in the parietal, temporal, and occipital regions, and increased FC between these brain regions, may be associated with PIAJ occurrence.