AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202501000-00033/figure1/v/2024-05-14T021156Z/r/image-tiff The E3 ubiquitin ligase, carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP), also functions as a co-chaperone and plays a crucial role in the protein quality control system. In this study, we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer's disease. We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain. CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests, reduced amyloid-ß plaques, and decreased the expression of both amyloid-ß and phosphorylated tau. CHIP also alleviated the concentration of microglia and astrocytes around plaques. In APP/PS1 mice of a younger age, CHIP overexpression promoted an increase in ADAM10 expression and inhibited ß-site APP cleaving enzyme 1, insulin degrading enzyme, and neprilysin expression. Levels of HSP70 and HSP40, which have functional relevance to CHIP, were also increased. Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated, which may also reflect a potential mechanism for the neuroprotective effect of CHIP. Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice. Indeed, overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer's disease.

CLCuMuV subverts the processing of hydroxyproline-rich systemin to suppress tobacco defenses against insect vectors.

The interactions of insect vector-virus-plant have important ecological and evolutionary implications. The constant struggle of plants against viruses and insect vectors has driven the evolution of multiple defense strategies in the host as well as counter-defense strategies in the viruses and insect vectors. Cotton leaf curl Multan virus (CLCuMuV) is a major causal agent of cotton leaf curl disease in Asia and is exclusively transmitted by the whitefly Bemisia tabaci. Here, we report that plants infected with CLCuMuV and its betasatellite, cotton leaf curl Multan betasatellite (CLCuMuB) enhance the performance of B. tabaci vector, and ßC1 encoded by CLCuMuB plays an important role in begomovirus-whitefly-tobacco tripartite interactions. We showed that CLCuMuB ßC1 suppresses the jasmonic acid signaling pathway by interacting with the subtilisin-like protease 1.7 (NtSBT1.7) protein, thereby enhancing whitefly performance on tobacco plants. Further studies revealed that in the wild type plants, NtSBT1.7 could process tobacco preprohydroxyproline-rich systemin B (NtpreproHypSysB). After CLCuMuB infection, CLCuMuB ßC1 could interfere with the processing of NtpreproHypSysB by NtSBT1.7, thereby impairing plant defenses against whitefly. These results contribute to our understanding of the tripartite interactions among virus, plant, and whitefly, thus offering ecological insights into the spread of vector insect populations and the prevalence of viral diseases.

Multifunctional lipid droplet probes for observing the polarity change of ferroptosis, inflammation, fatty liver and evaluating the efficacy of drugs.

BACKGROUND: Lipid droplets (LDs) polarity is intricately linked to diverse biological processes and diseases. The visualization of LDs-polarity is of vital importance but challenging due to the lack of high-specificity, high-sensitivity and large-Stokes shift probes for real-time tracking LDs-polarity in biological systems. RESULTS: Four D-π-A based fluorescent probes (TPA-TCF1-TPA-TCF4) have been developed by combining tricyanofuran (an electron acceptor, A) and triphenylamine (an electron donor, D) derivatives with different terminal groups. Among them, TPA-TCF1 and TPA-TCF4 exhibit excellent polar sensitivity, large Stokes shift (≥182 nm in H2O), and efficient LDs targeting ability. In particular, TPA-TCF4 is capable of monitoring the change of LDs-polarity during ferroptosis, inflammation, apoptosis of cancer cell, and fatty liver. SIGNIFICANCE: All these features render TPA-TCF4 a versatile tool for pharmacodynamic evaluation of anti-cancer drugs, in-depth understanding of the biological effect of LDs on ferroptosis, and medical diagnosis of LDs-polarity related diseases.

Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications.

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Expanded ROS Generation and Hypoxia Reversal: Excipient-free Self-assembled Nanotheranostics for Enhanced Cancer Photodynamic Immunotherapy.

The efficacy of photodynamic therapy (PDT)-related cancer therapies is significantly restricted by two irreconcilable obstacles, i.e., low reactive oxygen species (ROS) generation capability and hypoxia which constrains the immune response. Herein, this work develops a self-assembled clinical photosensitizer indocyanine green (ICG) and the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) nanoparticles (ISDN) without any excipient. This work discovers that the hydrophobic interaction forces between ICG and 17-DMAG promote the photostability of ICG and its intersystem crossing (ISC) process, thereby improving the ROS quantum yield from 0.112 to 0.46. Augmented ROS generation enhances PDT efficacy and further enhances immunogenic cell death (ICD) effects. 17-DMAG inhibits the HSP90/hypoxia-inducible factor 1α (HIF-1α) axis to dramatically reverse the immunosuppressive tumor microenvironment caused by PDT-aggravated hypoxia. In a mouse model of pancreatic cancer, ISDN markedly improve cytotoxic T lymphocyte infiltration and MHC I and MHC II activation, demonstrating the superior ICD effects in situ tumor and the powerful systematic antitumor immunity generation, eventually achieving vigorous antitumor and recurrence resistance. This study proposes an unsophisticated and versatile strategy to significantly improve PDT efficacy for enhancing systemic antitumor immunity and potentially extending it to multiple cancers.

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

MALAT1 and NEAT1 Are Neuroprotective During Hypoxic Preconditioning in the Mouse Hippocampus Possibly by Regulation of NR2B.

Wang L, Fu G, Han R, Fan P, Yang J, Gong K, Zhao Z, Zhang C, Sun K, Shao GMALAT1 and NEAT1 Are Neuroprotective during Hypoxic Preconditioning in the Mouse Hippocampus Possibly by Regulation of NR2B High Alt Med Biol. 00:000-000, 2024. Background: The regulation of noncoding ribonucleic acid (ncRNA) has been shown to be involved in cellular and molecular responses to hypoxic preconditioning (HPC), a situation created by the induction of sublethal hypoxia in the brain. The ncRNAs metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) are abundantly expressed in the brain, where they regulate the expression of various genes in nerve cells. However, the exact roles of MALAT1 and NEAT1 in HPC are not fully understood. Methods: A mouse model of acute repeated hypoxia was used as a model of HPC, and MALAT1 and NEAT1 levels in the hippocampus were measured using real-time polymerase chain reaction (PCR). The mRNA and protein levels of N-methyl-d-aspartate receptor subunit 2 B (NR2B) in the mouse hippocampus were measured using real-time PCR and western blotting, respectively. HT22 cells knocked-down for MALAT1 and NEAT1 were used for in vitro testing. Expression of NR2B, which is involved in nerve cell injury under ischemic and hypoxic conditions, was also evaluated. The levels of spectrin and cleaved caspase-3 in MALAT1 and NEAT1 knockdown HT22 cells under oxygen glucose deprivation/reperfusion (OGD/R) were determined by western blotting. Results: HPC increased the expression of MALAT1 and NEAT1 and decreased the expression of NR2B mRNA in the mouse hippocampus (p < 0.05). Knockdown of MALAT1 and NEAT1 increased both NR2B mRNA and protein levels nearly twofold and caused damage under OGD/R conditions in HT22 cells (p < 0.05). Conclusion: MALAT1 and NEAT1 exert neuroprotective effects by influencing the expression of NR2B.

The biological response of pH-switch-based gold nanoparticle-composite polyamino acid embolic material.

With continuous advances in medical technology, non-invasive embolization has emerged as a minimally invasive treatment, offering new possibilities in cancer therapy. Fluorescent labeling can achieve visualization of therapeutic agents in vivo, providing technical support for precise treatment. This paper introduces a novel in situ non-invasive embolization composite material, Au NPs@(mPEG-PLGTs), created through the electrostatic combination of L-cysteine-modified gold nanoparticles (Au NPs) and methoxy polyethylene glycol amine-poly[(L-glutamic acid)-(L-tyrosine)] (mPEG-PLGTs). Experiments were undertaken to confirm the biocompatibility, degradability, stability and performance of this tumor therapy. The research results demonstrated a reduction in tumor size as early as the fifth day after the initial injection, with a significant 90% shrinkage in tumor volume observed after a 20-day treatment cycle, successfully inhibiting tumor growth and exhibiting excellent anti-tumor effects. Utilizing near-infrared in vivo imaging, Au NPs@(mPEG-PLGTs) displayed effective fluorescence tracking within the bodies of nude BALB-c mice. This study provides a novel direction for the further development and innovation of in situ non-invasive embolization in the field, highlighting its potential for rapid, significant therapeutic effects with minimal invasiveness and enhanced safety.

[Effect of Xuming Decoction in Records of Proved Prescriptions, Ancient a nd Modern on cerebral ischemic injury and angiogenesis in rat model of acute cerebral infarction].

This paper aims to explore the effect of Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern on cerebral ischemic injury and angiogenesis in the rat model of acute cerebral infarction. SD rats were randomized into 6 groups: sham group, model group, low-, medium-, and high-dose(5.13, 10.26, and 20.52 g·kg~(-1), respectively) Xuming Decoction groups, and butylphthalide(0.06 g·kg~(-1)) group. After the successful establishment of the rat model by middle cerebral artery occlusion(MCAO), rats in the sham and model groups were administrated with distilled water and those in other groups with corresponding drugs for 7 consecutive days. After the neurological function was scored, all the rats were sacrificed, and the brain tissue samples were collected. The degree of cerebral ischemic injury was assessed by the neurological deficit score and staining with 2,3,5-triphenyltetrazolium chloride. Hematoxylin-eosin staining was performed to observe the pathological changes in the brain. Transmission electron microscopy was employed to observe the ultrastructures of neurons and microvascular endothelial cells(ECs) on the ischemic side of the brain tissue. Immunofluorescence assay was employed to detect the expression of von Willebrand factor(vWF) and hematopoietic progenitor cell antigen CD34(CD34) in the ischemic brain tissue. Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of Runt-related transcription factor 1(RUNX1), vascular endothelial growth factor(VEGF), angiopoietin-1(Ang-1), angiopoietin-2(Ang-2), and VEGF receptor 2(VEGFR2) in the ischemic brain tissue. The results showed that compared with the sham group, the model group showed increased neurological deficit score and cerebral infarction area(P<0.01), pathological changes, and damaged ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Furthermore, the modeling up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.05 or P<0.01). Compared with the model group, high-dose Xuming Decoction and butylphthalide decreased the neurological deficit score and cerebral infarction area(P<0.01) and alleviated the pathological changes and damage of the ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Moreover, they up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01). The results suggest that Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern can promote the angiogenesis and collateral circulation establishment to alleviate neurological dysfunction of the ischemic brain tissue in MCAO rats by regulating the RUNX1/VEGF pathway.

Optimizing lung cancer classification through hyperparameter tuning.

Artificial intelligence is steadily permeating various sectors, including healthcare. This research specifically addresses lung cancer, the world's deadliest disease with the highest mortality rate. Two primary factors contribute to its onset: genetic predisposition and environmental factors, such as smoking and exposure to pollutants. Recognizing the need for more effective diagnosis techniques, our study embarked on devising a machine learning strategy tailored to boost precision in lung cancer detection. Our aim was to devise a diagnostic method that is both less invasive and cost-effective. To this end, we proposed four methods, benchmarking them against prevalent techniques using a universally recognized dataset from Kaggle. Among our methods, one emerged as particularly promising, outperforming the competition in accuracy, precision and sensitivity. This method utilized hyperparameter tuning, focusing on the Gamma and C parameters, which were set at a value of 10. These parameters influence kernel width and regularization strength, respectively. As a result, we achieved an accuracy of 99.16%, a precision of 98% and a sensitivity rate of 100%. In conclusion, our enhanced prediction mechanism has proven to surpass traditional and contemporary strategies in lung cancer detection.

Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders.

Background: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1ß, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1ß (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1ß (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

LAMC2 regulates the proliferation, invasion, and metastasis of gastric cancer via PI3K/Akt signaling pathway.

OBJECTIVES: Gastric cancer (GC) is a prevalent malignant tumor widely distributed globally, exhibiting elevated incidence and fatality rates. The gene LAMC2 encodes the laminin subunit gamma-2 chain and is found specifically in the basement membrane of epithelial cells. Its expression is aberrant in multiple types of malignant tumors. This research elucidated a link between LAMC2 and the clinical characteristics of GC and investigated the potential involvement of LAMC2 in GC proliferation and advancement. MATERIALS AND METHODS: LAMC2 expressions were detected in GC cell lines and normal gastric epithelial cell lines via qRT-PCR. Silencing and overexpression of the LAMC2 were conducted by lentiviral transfection. A xenograft mouse model was also developed for in vivo analysis. Cell functional assays were conducted to elucidate the involvement of LAMC2 in cell growth, migration, and penetration. Further, immunoblotting was conducted to investigate the impact of LAMC2 on the activation of signal pathways after lentiviral transfection. RESULTS: In the findings, LAMC2 expression was markedly upregulated in GC cell lines as opposed to normal gastric epithelial cells. In vitro analysis showed that sh-LAMC2 substantially inhibited GC cell growth, migration, and invasion, while oe-LAMC2 displayed a contrasting effect. Xenograft tumor models demonstrated that oe-LAMC2 accelerated tumor growth via high expression of Ki-67. Immunoblotting analysis revealed a substantial decrease in various signaling pathway proteins, PI3K, p-Akt, and Vimentin levels upon LAMC2 knockdown, followed by increased E-cadherin expression. Conversely, its overexpression exhibited contrasting effects. Besides, epithelial-mesenchymal transition (EMT) was accelerated by LAMC2. CONCLUSION: This study provides evidence indicating that LAMC2, by stimulating signaling pathways, facilitated EMT and stimulated the progression of GC cells in laboratory settings and mouse models. Research also explored that the abnormal LAMC2 expression acts as a biomarker for GC.

Colon and lung cancer classification from multi-modal images using resilient and efficient neural network architectures.

Automatic classification of colon and lung cancer images is crucial for early detection and accurate diagnostics. However, there is room for improvement to enhance accuracy, ensuring better diagnostic precision. This study introduces two novel dense architectures (D1 and D2) and emphasizes their effectiveness in classifying colon and lung cancer from diverse images. It also highlights their resilience, efficiency, and superior performance across multiple datasets. These architectures were tested on various types of datasets, including NCT-CRC-HE-100K (set of 100,000 non-overlapping image patches from hematoxylin and eosin (H&E) stained histological images of human colorectal cancer (CRC) and normal tissue), CRC-VAL-HE-7K (set of 7180 image patches from N = 50 patients with colorectal adenocarcinoma, no overlap with patients in NCT-CRC-HE-100K), LC25000 (Lung and Colon Cancer Histopathological Image), and IQ-OTHNCCD (Iraq-Oncology Teaching Hospital/National Center for Cancer Diseases), showcasing their effectiveness in classifying colon and lung cancers from histopathological and Computed Tomography (CT) scan images. This underscores the multi-modal image classification capability of the proposed models. Moreover, the study addresses imbalanced datasets, particularly in CRC-VAL-HE-7K and IQ-OTHNCCD, with a specific focus on model resilience and robustness. To assess overall performance, the study conducted experiments in different scenarios. The D1 model achieved an impressive 99.80 % accuracy on the NCT-CRC-HE-100K dataset, with a Jaccard Index (J) of 0.8371, a Matthew's Correlation Coefficient (MCC) of 0.9073, a Cohen's Kappa (Kp) of 0.9057, and a Critical Success Index (CSI) of 0.8213. When subjected to 10-fold cross-validation on LC25000, the D1 model averaged (avg) 99.96 % accuracy (avg J, MCC, Kp, and CSI of 0.9993, 0.9987, 0.9853, and 0.9990), surpassing recent reported performances. Furthermore, the ensemble of D1 and D2 reached 93 % accuracy (J, MCC, Kp, and CSI of 0.7556, 0.8839, 0.8796, and 0.7140) on the IQ-OTHNCCD dataset, exceeding recent benchmarks and aligning with other reported results. Efficiency evaluations were conducted in various scenarios. For instance, training on only 10 % of LC25000 resulted in high accuracy rates of 99.19 % (J, MCC, Kp, and CSI of 0.9840, 0.9898, 0.9898, and 0.9837) (D1) and 99.30 % (J, MCC, Kp, and CSI of 0.9863, 0.9913, 0.9913, and 0.9861) (D2). In NCT-CRC-HE-100K, D2 achieved an impressive 99.53 % accuracy (J, MCC, Kp, and CSI of 0.9906, 0.9946, 0.9946, and 0.9906) with training on only 30 % of the dataset and testing on the remaining 70 %. When tested on CRC-VAL-HE-7K, D1 and D2 achieved 95 % accuracy (J, MCC, Kp, and CSI of 0.8845, 0.9455, 0.9452, and 0.8745) and 96 % accuracy (J, MCC, Kp, and CSI of 0.8926, 0.9504, 0.9503, and 0.8798), respectively, outperforming previously reported results and aligning closely with others. Lastly, training D2 on just 10 % of NCT-CRC-HE-100K and testing on CRC-VAL-HE-7K resulted in significant outperformance of InceptionV3, Xception, and DenseNet201 benchmarks, achieving an accuracy rate of 82.98 % (J, MCC, Kp, and CSI of 0.7227, 0.8095, 0.8081, and 0.6671). Finally, using explainable AI algorithms such as Grad-CAM, Grad-CAM++, Score-CAM, and Faster Score-CAM, along with their emphasized versions, we visualized the features from the last layer of DenseNet201 for histopathological as well as CT-scan image samples. The proposed dense models, with their multi-modality, robustness, and efficiency in cancer image classification, hold the promise of significant advancements in medical diagnostics. They have the potential to revolutionize early cancer detection and improve healthcare accessibility worldwide.

EMP1 correlated with cancer progression and immune characteristics in pan-cancer and ovarian cancer.

This study examines the prognostic role and immunological relevance of EMP1 (epithelial membrane protein-1) in a pan-cancer analysis, with a focus on ovarian cancer. Utilizing data from TCGA, CCLE, and GTEx databases, we assessed EMP1 mRNA expression and its correlation with tumor progression, prognosis, and immune microenvironment across various cancers. Our results indicate that EMP1 expression is significantly associated with poor prognosis in multiple cancer types, including ovarian, bladder, testicular, pancreatic, breast, brain, and uveal melanoma. Immune-related analyses reveal a positive correlation between EMP1 and immune cell infiltration, particularly neutrophils, macrophages, and dendritic cells, as well as high expression of immune checkpoint such as CD274, HAVCR2, IL10, PDCD1LG2, and TGFB1 in most tumors. In vivo experiments confirm that EMP1 promotes ovarian cancer cell proliferation, metastasis, and invasion. In conclusion, EMP1 emerges as a potential prognostic biomarker and therapeutic target in various cancers, particularly ovarian cancer, due to its influence on tumor progression and immune cell dynamics. Further research is warranted to elucidate the precise mechanisms of EMP1 in cancer biology and to translate these findings into clinical applications.

Less Acetabular Coverage Predicts the Failure of Core Decompression for Osteonecrosis of the Femoral Head: A Retrospective Cohort Study.

OBJECTIVE: It is unclear whether less acetabular coverage is associated with the failure of core decompression (CD) for osteonecrosis of the femoral head (ONFH). This study aimed to investigate the clinical outcomes of CD for ONFH with small- or medium-sized pre-collapse lesions, and determine what factors, especially acetabular anatomical parameters, predict the failure of CD. METHODS: Between January 2010 and December 2022, we retrospectively reviewed 269 consecutive CDs in 188 patients diagnosed with ONFH with small- or medium-sized pre-collapse lesions. The Kaplan-Meier method was used to evaluate the survival rate of CD for ONFH with progression of collapse or conversion to total hip arthroplasty (THA) as the endpoint. Univariate and multivariate logistic regression analyses were conducted to identify the potential risk factors for the failure of CD. Receiver operating characteristic (ROC) curve analysis was further performed with conversion to THA as the endpoint to determine the predictive value of these factors. RESULTS: The overall 5-year survival rate of CD for ONFH with small- or medium-sized pre-collapse lesions was 74.3% (95% confidence interval (CI) 69.0%-81.1%) with progression of collapse as the endpoint and 83.9% (95% CI 79.3%-88.7%) with conversion to THA as the endpoint. Univariate logistic regression analysis showed that bilateral affected hips was significantly associated with progression of collapse, and center-edge angle (CEA), sharp angle, acetabular head index (AHI), as well as acetabular depth ratio (ADR) were significantly associated with both progression of collapse and conversion to THA. Multivariate logistic regression analysis further indicated that CEA and AHI were independent risk factors for both progression of collapse and conversion to THA. ROC curve analysis with conversion to THA as the endpoint revealed that the cutoff values for CEA and AHI were 26.8° (sensitivity = 74.4%, specificity = 78.6%, area under the curve (AUC) = 0.809) and 79.8 (sensitivity = 78.4%, specificity = 73.8%, AUC = 0.818), respectively. CONCLUSIONS: CD showed satisfactory clinical outcomes for ONFH with small- or medium-sized pre-collapse lesions where less acetabular coverage with a CEA < 26.8° or AHI < 79.8 was identified as an independent risk factor for the failure of CD.

Characterization of extrachromosomal circular DNAs in plasma of patients with clear cell renal cell carcinoma.

BACKGROUND AND PURPOSE: Extrachromosomal circular DNAs (eccDNAs) have been recognized for their significant involvement in numerous biological processes. Nonetheless, the existence and molecular characteristics of eccDNA in the peripheral blood of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have not yet been reported. Our aim was to identify potentially marked plasma eccDNAs in ccRCC patients. METHODS AND MATERIALS: The detection of plasma eccDNA in ccRCC patients and healthy controls was performed using the Tn5-tagmentation and next-generation sequencing (NGS) method. Comparisons were made between ccRCC patients and healthy controls regarding the distribution of length, gene annotation, pattern of junctional nucleotide motif, and expression pattern of plasma eccDNA. RESULTS: We found 8,568 and 8,150 plasma eccDNAs in ccRCC patients and healthy controls, respectively. There were no statistical differences in the length distribution, gene annotation, and motif signature of plasma eccDNAs between the two groups. A total of 701 differentially expressed plasma eccDNAs were identified, and 25 plasma eccDNAs with potential diagnostic value for ccRCC have been successfully screened. These up-regulated plasma eccDNAs also be indicated to originate from the genomic region of the tumor-associated genes. CONCLUSION: This work demonstrates the characterization of plasma eccDNAs in ccRCC and suggests that the up-regulated plasma eccDNAs could be considered as a promising non-invasive biomarker in ccRCC.

SMS2, a Novel Allele of OsINV3, Regulates Grain Size in Rice.

Grain size has an important effect on rice yield. Although several key genes that regulate seed size have been reported in rice, their molecular mechanisms remain unclear. In this study, a rice small grain size 2 (sms2) mutant was identified, and MutMap resequencing analysis results showed that a 2 bp insertion in the second exon of the LOC_Os02g01590 gene resulted in a grain length and width lower than those of the wild-type Teqing (TQ). We found that SMS2 encoded vacuolar acid invertase, a novel allele of OsINV3, which regulates grain size. GO and KEGG enrichment analyses showed that SMS2 was involved in endoplasmic reticulum protein synthesis, cysteine and methionine metabolism, and propionic acid metabolism, thereby regulating grain size. An analysis of sugar content in young panicles showed that SMS2 reduced sucrose, fructose, and starch contents, thus regulating grain size. A haplotype analysis showed that Hap2 of SMS2 had a longer grain and was widely present in indica rice varieties. Our results provide a new theoretical basis for the molecular and physiological mechanisms by which SMS2 regulates grain size.

The association between education and premature mortality in the Chinese population: a 10-year cohort study.

Background: Recent studies have shown significant associations between education and premature mortality. However, the relationship differs across countries. We aimed to present the latest evidence on the educational inequalities in premature mortality in the Chinese population. Methods: We linked two databases, to establish a population-based, ten-year cohort spanning 2010 to 2020. Cox proportional hazard regression analyses adjusting for age, sex and urbanicity were conducted for all-cause mortality, and competing risk models were fitted for cause-specific mortality. We calculated population attributable fraction (PAF) using the hazard ratios (HRs) obtained by regression analyses. Additionally, we fitted models adjusting for risk factors and investigated the mediating effect of income, smoking, alcohol consumption and diets. Findings: Compared with individuals with upper secondary and above education, the HR for premature all-cause mortality for those with less than primary education was 1.93 (95% CI: 1.72-2.19). The HRs were the highest for deaths from respiratory diseases (HR = 3.09, 95% CI 1.82-5.27). The excess risk of premature mortality associated with low education was higher among women and urban population. The association of education remained significant after accounting for risk factors, and income was the main mediator, which accounted for 23.0% of mediation in men and 11.1% in women. Interpretation: The study's findings support the increased risk of premature mortality associated with low education, particularly in women and urban populations. The considerable number of deaths attributed to educational inequality underscores the necessity for more effective and targeted public health interventions. Funding: Chinese Central Government.

Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease.

Background: Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD. Objective: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies. Methods: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy. Results: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity. Conclusion: P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.