RABV induces biphasic actin cytoskeletal rearrangement through Rac1 activity modulation.

Rabies virus (RABV) is highly lethal and triggers severe neurological symptoms. The neuropathogenic mechanism remains poorly understood. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho-GTPase that is involved in actin remodeling and has been reported to be closely associated with neuronal dysfunction. In this study, by means of a combination of pharmacological inhibitors, small interfering RNA, and specific dominant-negatives, we characterize the crucial roles of dynamic actin and the regulatory function of Rac1 in RABV infection, dominantly in the viral entry phase. The data show that the RABV phosphoprotein interacts with Rac1. RABV phosphoprotein suppress Rac1 activity and impedes downstream Pak1-Limk1-Cofilin1 signaling, leading to the disruption of F-actin-based structure formation. In early viral infection, the EGFR-Rac1-signaling pathway undergoes a biphasic change, which is first upregulated and subsequently downregulated, corresponding to the RABV entry-induced remodeling pattern of F-actin. Taken together, our findings demonstrate for the first time the role played by the Rac1 signaling pathway in RABV infection and may provide a clue for an explanation for the etiology of rabies neurological pathogenesis.IMPORTANCEThough neuronal dysfunction is predominant in fatal rabies, the detailed mechanism by which rabies virus (RABV) infection causes neurological symptoms remains in question. The actin cytoskeleton is involved in numerous viruses infection and plays a crucial role in maintaining neurological function. The cytoskeletal disruption is closely associated with abnormal nervous symptoms and induces neurogenic diseases. In this study, we show that RABV infection led to the rearrangement of the cytoskeleton as well as the biphasic kinetics of the Rac1 signal transduction. These results help elucidate the mechanism that causes the aberrant neuronal processes by RABV infection and may shed light on therapeutic development aimed at ameliorating neurological disorders.

Transparent cap adjusted the stent placed for stenosis after endoscopic injection of esophageal varices: A case report.

BACKGROUND: The stent embedded in the esophageal mucosa is one of the complications after stenting for esophageal stricture. We present a case of stent adjustment with the aid of a transparent cap after endoscopic injection of an esophageal varices stent. CASE SUMMARY: A 61-year-old male patient came to the hospital with discomfort of the chest after the stent implanted for the stenosis because of endoscopic injection of esophageal varices. The gastroscopy was performed, and the stent embedded into the esophageal mucosa. At first, we pulled the recycling line for shrinking the stent, however, the mucosa could not be removed from the stent. Then a forceps was performed to remove the mucosa in the stent, nevertheless, the bleeding form the mucosa was obvious. And then, we used a transparent cap to scrape the mucosa along the stent, and the mucosa were removed successfully without bleeding. CONCLUSION: A transparent cap helps gastroscopy to remove the mucosa embedded in the stent after endoscopic injection of the esophageal varices stent.

Genome-wide identification of bHLH gene family and its response to cadmium stress in Populus × canescens.

The basic helix-loop-helix (bHLH) gene family is integral to various aspects of plant development and the orchestration of stress response. This study focuses on the bHLH genes within Populus × canescens, a poplar species noted for its significant tolerance to cadmium (Cd) stress. Through our comprehensive genomic analysis, we have identified and characterized 170 bHLH genes within the P. canescens genome. These genes have been systematically classified into 22 distant subfamilies based on their evolutionary relationships. A notable conservation in gene structure and motif compositions were conserved across these subfamilies. Further analysis of the promoter regions of these genes revealed an abundance of essential cis-acting element, which are associated with plant hormonal regulation, development processes, and stress response pathway. Utilizing quantitative PCR (qPCR), we have documented the differential regulation of PcbHLHs in response to elevated Cd concentrations, with distinct expression patterns observed across various tissues. This study is poised to unravel the molecular mechanism underpinning Cd tolerance in P. canescens, offering valuable insights for the development of new cultivars with enhanced Cd accumulation capacity and tolerance. Such advancements are crucial for implementing effective phytoremediation strategies to mitigate soil pollution caused by Cd.

IGFBP1 stabilizes Umod expression through m6A modification to inhibit the occurrence and development of cystitis by blocking NF-κB and ERK signaling pathways.

Cystitis is a common disease closely associated with urinary tract infections, and the specific mechanisms underlying its occurrence and development remain largely unknown. In this study, we discovered that IGFBP1 suppresses the occurrence and development of cystitis by stabilizing the expression of Umod through m6A modification, inhibiting the NF-κB and ERK signaling pathways. Initially, we obtained a bladder cystitis-related transcriptome dataset from the GEO database and identified the characteristic genes Umod and IGFBP1. Further exploration revealed that IGFBP1 in primary cells of cystitis can stabilize the expression of Umod through m6A modification. Overexpression of both IGFBP1 and Umod significantly inhibited cell apoptosis and the NF-κB and ERK signaling pathways, ultimately suppressing the production of pro-inflammatory factors. Finally, using a rat model of cystitis, we demonstrated that overexpression of IGFBP1 stabilizes the expression of Umod, inhibits the NF-κB and ERK signaling pathways, reduces the production of pro-inflammatory factors, and thus prevents the occurrence and development of cystitis. Our study elucidates the crucial role of IGFBP1 and Umod in cystitis and reveals the molecular mechanisms that inhibit the occurrence and development of cystitis. This research holds promise for offering new insights into the treatment of cystitis in the future.

Knockdown of YTHDF2 initiates ERS-induced apoptosis and cancer stemness suppression by sustaining GLI2 stability in cervical cancer.

Cervical cancer ranks fourth in women in terms of incidence and mortality. The RNA-binding protein YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) contributes to cancer progression by incompletely understood mechanisms. We show how YTHDF2 controls the fate of cervical cancer cells and whether YTHDF2 could be a valid target for the therapy of cervical cancer. Sphere formation and alkaline phosphatase staining assays were performed to evaluate tumor stemness of cervical cancer cells following YTHDF2 knockdown. Apoptosis was detected by flow cytometry and TUNEL assay. The compounds 4PBA and SP600125 were used to investigate the correlation between JNK, endoplasmic reticulum stress, tumor stemness, and apoptosis. Data from The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) revealed that GLI family zinc finger 2 (GLI2) might be the target of YTHDF2. The transcription inhibitor actinomycin D and dual-luciferase reporter gene assays were employed to investigate the association between the GLI2 mRNA and YTHDF2. Nude mouse xenografts were generated to assess the effects of YTHDF2 knockdown on cervical cancer growth in vivo. Knockdown of YTHDF2 up-regulated the expression of GLI2, leading to JNK phosphorylation and endoplasmic reticulum stress. These processes inhibited the proliferation of cervical cancer cells and their tumor cell stemness and promotion of apoptosis. In conclusion, the knockdown of YTHDF2 significantly affects the progression of cervical cancer cells, making it a potential target for treating cervical cancer.

Downregulation of HHATL promotes cardiac hypertrophy via activation of SHH/DRP1.

HHATL, previously implicated in cardiac hypertrophy in the zebrafish model, has emerged as a prioritized HCM risk gene. We identified six rare mutations in HHATL, present in 6.94 % of nonsarcomeric HCM patients (5/72). Moreover, a decrease of HHATL in the heart tissue from HCM patients and cardiac hypertrophy mouse model using transverse aortic constriction was observed. Despite this, the precise pathogenic mechanisms underlying HHATL-associated cardiac hypertrophy remain elusive. In this study, we observed that HHATL downregulation in H9C2 cells resulted in elevated expression of hypertrophic markers and reactive oxygen species (ROS), culminating in cardiac hypertrophy and mitochondrial dysfunction. Notably, the bioactive form of SHH, SHHN, exhibited a significant increase, while the mitochondrial fission protein dynamin-like GTPase (DRP1) decreased upon HHATL depletion. Intervention with the SHH inhibitor RU-SKI 43 or DRP1 overexpression effectively prevented Hhatl-depletion-induced cardiac hypertrophy, mitigating disruptions in mitochondrial morphology and membrane potential through the SHH/DRP1 axis. In summary, our findings suggest that HHATL depletion activates SHH signaling, reducing DRP1 levels and thereby promoting the expression of hypertrophic markers, ROS generation, and mitochondrial dysfunction, ultimately leading to cardiac hypertrophy. This study provides additional compelling evidence supporting the association of HHATL with cardiac hypertrophy.

Utility of real-time 3D visualization system in the early stage of phacoemulsification training.

AIM: To determine the teaching effects of a real-time three dimensional (3D) visualization system in the operating room for early-stage phacoemulsification training. METHODS: A total of 10 ophthalmology residents of the first-year postgraduate were included. All the residents were novices to cataract surgery. Real-time cataract surgical observations were performed using a custom-built 3D visualization system. The training lasted 4wk (32h) in all. A modified International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric (ICO-OSCAR) containing 4 specific steps of cataract surgery was applied. The self-assessment (self) and expert-assessment (expert) were performed through the microsurgical attempts in the wet lab for each participant. RESULTS: Compared with pre-training assessments (self 3.2±0.8, expert 2.5±0.6), the overall mean scores of post-training (self 5.2±0.4, expert 4.7±0.6) were significantly improved after real-time observation training of 3D visualization system (P<0.05). Scores of 4 surgical items were significantly improved both self and expert assessment after training (P<0.05). CONCLUSION: The 3D observation training provides novice ophthalmic residents with a better understanding of intraocular microsurgical techniques. It is a useful tool to improve teaching efficiency of surgical education.

Views of health care professionals on the implementation of preoperative advance care planning in older patients with head and neck cancer: Q methodology.

Objective: To investigate the views of health care professionals in a head and neck surgical department toward the implementation of advance care planning prior to surgery for older patients with head and neck cancer. Method: Q methodology was used to explore and analyze participants' views by combining quantitative and qualitative methods. Participants were asked to rank 35 Q statements generated via semi-structured interviews and a literature review and to explain the reasons for their ranking in subsequent interviews. The data was then analyzed and used to develop a factor series to illustrate participants' views. Results: This study surveyed 15 health care professionals, including eight doctors and seven nurses. The views of health care professionals toward preoperative implementation of advance care planning discussions were varied and could be categorized into three types: defending the autonomy of patients, patients' knowledge and the Chinese traditional cultural context hinder the implementation of preoperative advance care planning, and lack of confidence in performing preoperative advance care planning. Conclusions: Although the health care professionals in the head and neck surgical department in this study recognized the benefits of preoperative discussions regarding advance care planning, patients' knowledge level, traditional Chinese values, inadequate capacity among health care professionals, and unsound legal policies have caused these professionals to have misgivings about preoperative counseling and discussing advance care planning with patients. Further studies should be conducted, and strategies to overcome barriers to discussions of preoperative advance care planning should be developed.

Prognostic Assessment of Histopathologic Lesions in Patients with Community-Acquired Acute Kidney Injury with Biopsy-Proven Acute Tubular Necrosis.

BACKGROUND: Community-acquired acute kidney injury (CA-AKI) was more likely to be comorbid with underlying kidney histopathological lesions in addition to acute tubular necrosis (ATN). Thus, we tried to clarify the histological determinants that could influence the prognosis and recovery of CA-AKI patients with biopsy-proven ATN. METHODS: Adult patients with CA-AKI with biopsy-proven ATN who underwent renal biopsy at Shanghai Changzheng Hospital from January 1, 2010, to December 31, 2018, were included and followed up for 5 years. The impacts of histopathological lesions on short-term and long-term renal dysfunction were also analysed. RESULTS: Multivariate analysis revealed that ATNs, crescents, and decrease of arteriole lumens increased short-term dialysis requirements. The severity of ATN was closely associated with renal survival. According to the Kaplan-Meier analysis, the severity of ATN was significantly associated with short-term dialysis needs and long-term development of end-stage kidney disease (ESKD) during follow-up. Crescent and decrease of arteriole lumens are significantly associated with progression to ESKD and exert synergistic effects with ATN. For patients who did not progress to dialysis, tubular atrophic/interstitial fibrosis and endocapillary lesions were more relevant to partial recovery of renal function after CA-AKI at the three-month follow-up and increased the risk of chronic kidney disease (CKD) stage 3-5 at the five-year follow-up. According to our correlation analysis, endocapillary lesions and crescents were positively correlated with ATN. CONCLUSIONS: Histopathologic lesions, apart from tubular necrosis, contributed to the detrimental short-term and long-term renal prognosis of CA-AKI patients with ATN; concomitant histopathologic lesions exerted a combined impact on renal survival together with ATN in CA-AKI patients.

DSFE: Decoding EEG-based finger motor imagery using feature-dependent frequency, feature fusion and ensemble learning.

Accurate decoding finger motor imagery is essential for fine motor control using EEG signals. However, decoding finger motor imagery is particularly challenging compared with ordinary motor imagery. This paper proposed a novel EEG decoding method of featuredependent frequency band selection, feature fusion, and ensemble learning (DSFE) for finger motor imagery. First, a feature-dependent frequency band selection method based on correlation coefficient (FDCC) was proposed to select feature-specific effective bands. Second, a feature fusion method was proposed to fuse different types of candidate features to produce multiple refined sets of decoding features. Finally, an ensemble model using the weighted voting strategy was proposed to make full use of these diverse sets of final features. The results on a public EEG dataset of five fingers motor imagery showed that the DSFE method is effective and achieves the highest decoding accuracy of 50.64%, which is 7.64% higher than existing studies using exactly the same data. The experiments further revealed that both the effective frequency bands of different subjects and the effective frequency bands of different types of features are different in finger motor imagery. Furthermore, compared with two-hand motor imagery, the effective decoding information of finger motor imagery is transferred to the lower frequency. The idea and findings in this paper provide a valuable perspective for understanding fine motor imagery in-depth.

Hypomethylation-enhanced CRTC2 expression drives malignant phenotypes and primary resistance to immunotherapy in hepatocellular carcinoma.

The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher CRTC2 expression in HCC. Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/ß-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, Crtc2 facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.

Electrochemical Restructuring Driven Catalytic Cycle of Bi-Based Heterojunctions for High-Performance Lithium-Sulfur Batteries.

Restructuring is an important phenomenon in catalytic reactions. Conversion-type materials with suitable redox potential may undergo in situ electrochemically driven restructurings and induce highly active catalytic sites in a working lithium-sulfur battery. Herein, driven by the electrochemical conversion reaction of BiVO4, a reversible catalytic cycle of Bi/amorphous Li3VO4 (a-Li3VO4) and Bi2S3/a-Li3VO4 heterojunctions is constructed, which targets the oxidation of Li2S and the conversion of polysulfide, respectively. The heterostructures and electrochemically driven size confinement provide abundant sites for shuttle restraining and sulfur conversion. Especially, the p-block Bi and Bi2S3 could dramatically reduce the conversion energy barriers of Li2S and polysulfide by virtue of the p-p orbital hybridization, promoting bidirectional reactions of the sulfur cathode. As a result, the corresponding sulfur cathode possesses a high reversible capacity of 7.5 mAh cm-2 after 120 cycles under a high sulfur loading of 10.3 mg cm-2 with a current density of 0.38 mA cm-2. This study furnishes a feasible scheme to obtain highly effective catalysts for bidirectional sulfur redox by utilizing the electrochemically induced restructuring.

A Chinese version of the infertility self-efficacy scale: Reliability and validity assessment.

Objective: To translate, cross-culturally adapt and test the reliability and validity of a Chinese version of the Infertility Self-Efficacy scale. Methods: The Infertility Self-Efficacy (ISE) scale was translated into Chinese using forward and backward translations, expert consultation, cognitive interviews and a pilot study. To test the scale's reliability and validity, 515 infertile women in two hospitals were recruited to evaluate the Chinese version of the scale. Content validity was assessed by means of expert consultation. Exploratory factor and confirmatory factor analyses were performed using SPSS 26.0 and Amos 24.0. Reliability tests of the scale included Cronbach's alpha coefficient, split-half reliability and test-retest reliability. Results: The Chinese version of the ISE scale contains 16 items and one dimension. Content validity of the scale was 0.96. Results of exploratory factor analysis suggested that the one factor model was suitable for the scale, and factor loading of all items was greater than 0.4. Model fitting parameters of confirmatory factor analysis of the ISE scale were χ2/df = 2.710, Root Mean Square Error Approximation (RMSEA) = 0.079, Standardized Root Mean Square Residual (SRMR) = 0.042, Comparative Fit Index (CFI) = 0.953, and Tucker-Lewis Index (TLI) = 0.939. Cronbach's alpha coefficient of the Chinese ISE was 0.980; split-half coefficient was 0.972 and retest reliability was 0.848 (P < 0.01). Conclusion: The Chinese ISE scale is a reliable and valid instrument to evaluate the self-efficacy of infertile Chinese women.

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence.

Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8+ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)+ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2+ tumor cells are induced to produce transforming growth factor ß to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8+ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2+ tumor cells driving CD8+ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8+ T cell senescence for chemoradiotherapy recurrence.

Controlled In Situ Self-Assembly of Biotinylated Trans-Cyclooctene Nanoparticles for Orthogonal Dual-Pretargeted Near-Infrared Fluorescence and Magnetic Resonance Imaging.

A pretargeted strategy that decouples targeting vectors from radionuclides has shown promise for nuclear imaging and/or therapy in vivo. However, the current pretargeted approach relies on the use of antibodies or nanoparticles as the targeting vectors, which may be compromised by poor tissue penetration and limited accumulation of targeting vectors in the tumor tissues. Herein, we present an orthogonal dual-pretargeted approach by combining stimuli-triggered in situ self-assembly strategy with fast inverse electron demand Diels-Alder (IEDDA) reaction and strong biotin-streptavidin (SA) interaction for near-infrared fluorescence (NIR FL) and magnetic resonance (MR) imaging of tumors. This approach uses a small-molecule probe (P-Cy-TCO&Bio) containing both biotin and trans-cyclooctene (TCO) as a tumor-targeting vector. P-Cy-TCO&Bio can efficiently penetrate subcutaneous HeLa tumors through biotin-assisted targeted delivery and undergo in situ self-assembly to form biotinylated TCO-bearing nanoparticles (Cy-TCO&Bio NPs) on tumor cell membranes. Cy-TCO&Bio NPs exhibited an "off-on" NIR FL and retained in the tumors, offering a high density of TCO and biotin groups for the concurrent capture of Gd-chelate-labeled tetrazine (Tz-Gd) and IR780-labeled SA (SA-780) via the orthogonal IEDDA reaction and SA-biotin interaction. Moreover, Cy-TCO&Bio NPs offered multiple-valent binding modes toward SA, which additionally regulated the cross-linking of Cy-Gd&Bio NPs into microparticles (Cy-Gd&Bio/SA MPs). This process could significantly (1) increase r1 relaxivity and (2) enhance the accumulation of Tz-Gd and SA-780 in the tumors, resulting in strong NIR FL, bright MR contrast, and an extended time window for the clear and precise imaging of HeLa tumors.

Enhancement of Upconversion Luminescence through Three-Dimensional Design of Plasma Ti3O5-Coupled Structural Domain-Limiting Effects.

Upconversion luminescence plays a crucial role in various technological applications, and among the various valence states of lanthanide elements, Ln3+ has the highest stability. The 4f orbitals of these elements are in a fully empty, semifull, or full state. This special 4f electron configuration allows them to exhibit rich discrete energy levels. However, the 4f-4f transition of Ln3+ rare earth ions itself is prohibited, resulting in a lower luminescence efficiency. This limitation greatly hinders the practical application of upconversion luminescence. In this study, we report nanostructured luminescence-enhanced substrate platforms with both semiconductive local surface plasmons and spatially confined domain effects on a single defect semiconductor substrate. By coupling NaYF4:Yb-Er nanoparticle emitters to the surface of Ti3O5 NC-arrays plasmonic nanostructures, an ultrabright luminescence with a 32-fold increase in green emission and a 40-fold increase in red emission was achieved. Furthermore, the fluorescence resonance energy transfer characteristics observed in the R6G/NaYF4/Ti3O5 NC-array composite film enable accurate detection of fluorescent molecules. The results provide an innovative and intelligent approach to enhance the upconversion luminescence intensity of rare-doped nanoparticles and develop highly sensitive molecular detection systems based on the above luminescence enhancement.

Identification and expression profiling of GAPDH family genes involved in response to Sclerotinia sclerotiorum infection and phytohormones in Brassica napus.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a crucial enzyme in glycolysis, an essential metabolic pathway for carbohydrate metabolism across all living organisms. Recent research indicates that phosphorylating GAPDH exhibits various moonlighting functions, contributing to plant growth and development, autophagy, drought tolerance, salt tolerance, and bacterial/viral diseases resistance. However, in rapeseed (Brassica napus), the role of GAPDHs in plant immune responses to fungal pathogens remains unexplored. In this study, 28 genes encoding GAPDH proteins were revealed in B. napus and classified into three distinct subclasses based on their protein structural and phylogenetic relationships. Whole-genome duplication plays a major role in the evolution of BnaGAPDHs. Synteny analyses revealed orthologous relationships, identifying 23, 26, and 26 BnaGAPDH genes with counterparts in Arabidopsis, Brassica rapa, and Brassica oleracea, respectively. The promoter regions of 12 BnaGAPDHs uncovered a spectrum of responsive elements to biotic and abiotic stresses, indicating their crucial role in plant stress resistance. Transcriptome analysis characterized the expression profiles of different BnaGAPDH genes during Sclerotinia sclerotiorum infection and hormonal treatment. Notably, BnaGAPDH17, BnaGAPDH20, BnaGAPDH21, and BnaGAPDH22 exhibited sensitivity to S. sclerotiorum infection, oxalic acid, hormone signals. Intriguingly, under standard physiological conditions, BnaGAPDH17, BnaGAPDH20, and BnaGAPDH22 are primarily localized in the cytoplasm and plasma membrane, with BnaGAPDH21 also detectable in the nucleus. Furthermore, the nuclear translocation of BnaGAPDH20 was observed under H2O2 treatment and S. sclerotiorum infection. These findings might provide a theoretical foundation for elucidating the functions of phosphorylating GAPDH.

Associations Between Neuroinflammation-Related Conditions and Alzheimer's Disease: A Study of US Insurance Claims Data.

Background: Early detection of Alzheimer's disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Objective: Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). Methods: We used Optum's de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N = 67,825 matched pairs); 2) patients with hemorrhage stroke and controls (N = 81,510 matched pairs); 3) patients with MS and controls (N = 9,853 matched pairs); and 4) patients TBI and controls (N = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. Results: We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Conclusions: Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions.

Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

CRISPR/Cas9 screen reveals that targeting TRIM34 enhances ferroptosis sensitivity and augments immunotherapy efficacy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by complex heterogeneity and drug resistance. Resistance to ferroptosis is closely related to the progression of HCC. While HCC tumors vary in their sensitivity to ferroptosis, the precise factors underlying this heterogeneity remain unclear. In this study, we sought to elucidate the mechanisms that contribute to ferroptosis resistance in HCC. Whole-genome CRISPR/Cas9 screen using a subtoxic concentration (IC20) of ferroptosis inducer erastin in the HCC cell line Huh7 revealed TRIM34 as a critical driver of ferroptosis resistance in HCC. Further investigation revealed that TRIM34 suppresses ferroptosis in HCC cells, promoting their proliferation, migration, and invasion both in vitro and in vivo. Furthermore, TRIM34 expression is elevated in HCC tumor tissues, correlating with a poor prognosis. Mechanistically, TRIM34 directly interacts with Up-frameshift 1 (UPF1), a core component of the nonsense-mediated mRNA decay (NMD) pathway, to promote its ubiquitination and degradation. This interaction suppresses GPX4 transcript degradation, thus promoting the protein levels of this critical ferroptosis suppressor in HCC. In light of the close crosstalk between ferroptosis and the adaptive immune response in cancer, HCC cells with targeting knockdown of TRIM34 exhibited an improved response to anti-PD-1 treatment. Taken together, the TRIM34/UPF1/GPX4 axis mediates ferroptosis resistance in HCC, thereby promoting malignant phenotypes. Targeting TRIM34 may thus represent a promising new strategy for HCC treatment.