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Jia-Yan Ni,1–3 Hong-Liang Sun,1,2 Jiang-Hong Luo,1,2 Xiong-Ying Jiang,1,2 Dong Chen,1,2 Wei-Dong Wang,1,2 Yao-Ting Chen,1,2 Jin-Hua Huang,3 Lin-Feng Xu1,2 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510120, People’s Republic of China; 2Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510120, People’s Republic of China; 3Department of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Cancer for Cancer Medicine, Guangzhou, Guangdong Province 510060, People’s Republic of ChinaCorrespondence: Jin-Hua HuangDepartment of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Cancer for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong Province 510060, People’s Republic of ChinaTel +86-20-87343447Email huangjh_sysucc@163.comLin-Feng XuGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang Road West, Guangzhou, Guangdong Province 510120, People’s Republic of ChinaTel +86-20-34078680Email xu_lin_feng@163.comPurpose: The aim of this study was to investigate the safety and efficacy of transarterial chemoembolization and sorafenib (TACE-S) combined with microwave ablation (TACE-S-MWA) for the treatment of patients with advanced primary hepatocellular carcinoma (HCC).Methods: Between January 2015 and December 2018, 152 consecutive advanced HCC patients, who underwent TACE-S-MWA (MWA group, n=77) or TACE-S (Non-MWA group, n=75), were investigated. Overall survival (OS), time to progression (TTP) and safety were compared between the two groups. Prognostic factors were analyzed using the Cox proportional hazard regression model.Results: Baseline patient characteristics were balanced between the two groups. MWA group was associated with a higher OS (median, 19.0 vs 13.0 months; P

Background: Integrins are the major adhesive molecules in mammalian cells. Each integrin subtype plays a unique role in cell differentiation and embryo development. However, integrin involvement in carcinogenesis has not been well defined.Methods: We identified mutations in integrin alpha7 by sequencing genomic DNAs and cDNAs from 122 specimens, including 62 primary human tumor samples, four cell lines, and 56 matched normal tissues. We evaluated the tumor suppressor activity of integrin alpha7 with colony formation, soft agar colony growth, and cell migration assays by forcing its expression in PC-3 and Du145 prostate cancer cells and SK-UT-1 leiomyosarcoma cells. PC-3 and Du145 xenograft tumors with increased levels of integrin alpha7 in severe combined immune deficient mice were used to assess the effect of integrin alpha7 on tumor growth and metastasis. Immunostaining was used to localize and to measure the level of integrin alpha7 in 701 and 141 specimens of prostate and smooth muscle, respectively. A meta-analysis of integrin alpha7 mRNA microarray data from four studies was performed. Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided.Results: Integrin alpha7 mutations that generate truncations were found in specimens of 16 of 28 prostate cancers (57%, 95% confidence interval [CI] = 37% to 76%), five of 24 hepatocellular carcinomas (21%, 95% CI = 7% to 42%), five of six glioblastomas multiforme (83%, 95% CI = 36% to 99%), and one of four leiomyosarcomas (25%, 95% CI = 0.6% to 81%). Integrin alpha7 mutations were associated with increased recurrence of human prostate cancer (nine recurrences among 13 patients with integrin alpha7 mutations versus one among eight without such mutations; odds ratio [OR] = 14, 95% CI = 1.15 to 782, P = .024) and hepatocellular carcinoma (five recurrences among eight patients with integrin alpha7 mutations versus one among 16 without such mutations, OR = 21, 95% CI = 1.6 to 1245; P = .007). Forced expression of normal integrin alpha7 in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and metastasis both in vitro and in vivo. Focal or no integrin alpha7 expression in human prostate cancer and soft tissue leiomyosarcoma was associated with a reduction of metastasis-free survival (for example, for prostate cancer with focal or no expression, 5-year metastasis-free survival was 32%, 95% CI = 24.4% to 40.3%, and for prostate cancer with at least weak expression, it was 85%, 95% CI = 79% to 91%; P<.001). Microarray analysis indicated that cyclin D kinase inhibitor 3 and GTPase-activating protein may be possible targets for integrin alpha7-mediated tumor suppressor activity and inhibition of cell motility.Conclusion: Integrin alpha7 appears to be a tumor suppressor that operates by suppressing tumor growth and retarding migration. [ABSTRACT FROM AUTHOR]

Adverse Drug Reactions (ADRs) stand out as a pressing challenge in public health and a critical aspect of drug discovery. The dilemma arises from the inherent impossibility of conducting a comprehensive evaluation of a drug before its market release, constrained by the limitations in scale and duration of clinical trials. Therefore, the post-marketing detection of ADRs in a timely and accurate manner becomes imperative. Adding to the complexity, a multitude of tweets harbor concealed information about adverse drug reactions, creating difficulties due to their concise, sporadic, and noisy content. To solve the problem, we regard ADR detection as a question-answer problem and introduces an innovative neural network framework with multiple GRU layers designed for extracting ADR-related information from tweets. The Von Mises-Fisher distribution is applied to derive keyword vectors through tweet sampling. An attention mechanism is employed to enhance the interaction between these keyword vectors and the word sequences within tweets. The credibility of word sequences is systematically evaluated based on the reliability of answer factors. To address concerns related to background information and training speed, we propose a quality assurance mechanism utilizing a GRU network due to its straightforward structure and efficient training capabilities. As a result of the training process, word sequences are mapped to a low-latitude vector space, generating corresponding answers. Experimental results obtained from two Twitter ADR datasets affirm that our Question-Answer Mechanism, leveraging multi-GRU architecture, significantly improves the accuracy of ADR detection in tweets. Our method achieved F1-scores of 81.3% and 73.3% on the two datasets, respectively, while consistently maintaining a higher recall., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Exploring the trend of long time-series ecological quality evolution and spatial differentiation of influencing factors in Guiyang is of great significance for realizing regional ecological protection and high-quality development strategies. Based on the 7-period Landsat remote sensing images from 1991 to 2020, the remote sensing ecological index （RSEI） of Guiyang from 1991 to 2020 was calculated using the GEE remote sensing big data platform, and a geodetector, Hurst index, and coefficient of variation with different random sampling quantities and classification strategies were used to analyze the evolutionary pattern of ecological quality, change trends, and spatial differentiation influencing factors. The results showed that ① The ecological quality of Guiyang in the past 30 years was mainly medium and good, showing a wave-like pattern of change, with the highest and lowest values occurring in 2020 （mean value 0.58） and 2010 （mean value 0.47）, respectively, and the overall trend of the RSEI in the past ten years was good, with a spatial trend of decreasing distribution from the northeast to the southwest. ② The domain of values of the coefficient of variation for the RSEI in Guiyang was in the range of （0-2）, of which 46.61% of the area was in high fluctuation change, and the overall volatility of the RSEI was large； the mean value of the Hurst index was 0.59, and the area greater than 0.5 accounted for 73.98%, most of which showed weak persistence, and the future trend of change was the same as that of the past 30 years. ③ Different classification methods and random samples affect the q -value results of the geodetector, but the trend of the size ordering of the explanatory power of different factors was generally consistent. Land use, nighttime lighting index, slope, and population density indicators had stronger explanatory power for RSEI spatial differentiation； factor interaction detection was two-factor enhancement and nonlinear enhancement； and the interaction between land use and other factors was most favorable for explaining RSEI spatial differentiation.

The husk leaf of maize (Zea mays) encases the ear as a modified leaf and plays pivotal roles in protecting the ear from pathogen infection, translocating nutrition for grains and warranting grain yield. However, the natural genetic basis for variation in husk leaf width remains largely unexplored. Here, we performed a genome-wide association study for maize husk leaf width and identified a 3-bp InDel (insertion/deletion) in the coding region of the nitrate transporter gene ZmNRT2.5. This polymorphism altered the interaction strength of ZmNRT2.5 with another transporter, ZmNPF5, thereby contributing to variation in husk leaf width. We also isolated loss-of-function mutants in ZmNRT2.5, which exhibited a substantial decrease in husk leaf width relative to their controls. We demonstrate that ZmNRT2.5 facilitates the transport of nitrate from husk leaves to maize kernels in plants grown under low-nitrogen conditions, contributing to the accumulation of proteins in maize seeds. Together, our findings uncovered a key gene controlling maize husk leaf width and nitrate transport from husk leaves to kernels. Identification of the ZmNRT2.5 loci offers direct targets for improving the protein content of maize seeds via molecular-assisted maize breeding., (© 2025 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Intestinal ischemia - reperfusion (I/R) injury (II/RI) is a critical condition that results in oxidative stress, inflammation, and damage to multiple organs. Zinc, an essential trace element, offers protective benefits in several tissues during I/R injury, but its effects on intestinal II/RI remain unclear., Aim: To investigate the effects of zinc pretreatment on II/RI and associated multiorgan damage., Methods: C57BL/6 mice were pretreated with zinc sulfate (ZnSO 4 , 10 mg/kg) daily for three days before I/R injury was induced via superior mesenteric artery occlusion (SMAO) and abdominal aortic occlusion (AAO) models. Tissue and serum samples were collected to evaluate intestinal, liver, and kidney damage using Chiu's score, Suzuki score, and histopathological analysis. Caco-2 cells and intestinal organoids were used for in vitro hypoxia - reoxygenation injury models to measure reactive oxygen species (ROS) and superoxide dismutase (SOD) levels., Results: Zinc pretreatment significantly reduced intestinal damage in the SMAO and AAO models ( P < 0.001). The serum levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase) and kidney markers (creatinine and urea) were lower in the zinc-treated mice than in the control mice, indicating reduced hepatic and renal injury. In vitro , zinc decreased ROS levels and increased SOD activity in Caco-2 cells subject to hypoxia - reoxygenation injury. Intestinal organoids pretreated with zinc exhibited enhanced resilience to hypoxic injury compared to controls., Conclusion: Zinc pretreatment mitigates II/RI and reduces associated multiorgan damage. These findings suggest that zinc has potential clinical applications in protecting against I/R injuries., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Organic heterostructures (OHs) with multi-segments exhibit special optoelectronic properties compared with monomeric structures. Nevertheless, the synthesis of multi-block heterostructures remains challenging due to compatibility issues between segment parts, which restricts their application in optical waveguides and integrated optics. Herein, we demonstrate programmable in-situ co-assembly engineering, combining multi-step spontaneous self-assembly processes to promote the synthesis of multi-block heterostructures with a rational arrangement of three or more segments. The rational design of segments enables exciton manipulation and ensures optical waveguides and proper output among the multi-segment OHs. This work enables the controllable growth of segments within multi-block OHs, providing a pathway to construct complex OHs for the rational development of future optical applications., (© 2024 Wiley-VCH GmbH.)

Breast cancer (BC) is one of the most common female malignant tumors. BC treatment depends on the use of chemotherapeutic drugs, causing various adverse effects. Increasing evidence has shown that natural polysaccharides (NPs) are potential adjuvants or substitutes for anti-BC drugs. However, the information regarding anti-BC NPs remains scattered. Thus, the recent progress in the structure, bioactivity, mechanism and application of anti-BC NPs is comprehensively summarized in this review. Moreover, the structure-activity relationship is discussed. Additionally, the prospects for future work are proposed. Recent studies have shown that anti-BC NPs have diverse structural features, which are affected by the extraction and purification methods. NPs show anti-BC activities in cell and animal experiments as well as in clinical researches, and enhance anti-BC effects of chemotherapeutic drugs in cell and animal experiments. The anti-BC mechanisms of NPs include anti-proliferation, inducing apoptosis, anti-metastasis and anti-invasion, immunoenhancement, gut microbiota regulation and others. The anti-BC activities of NPs are influenced by molecular weight, monosaccharide composition, functional groups, glycosidic bond types, backbone and side chains. NPs-based nanoparticles, nanocarriers, drug delivery systems, nanocomposites and other materials can also be used in anti-BC. This review provides theoretical bases for future research and functional application of NPs in anti-BC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This prospective randomized controlled trial aimed to compare the effectiveness of functional jejunal interposition (FJI) and simple jejunal interposition (SJI) as reconstruction methods following total gastrectomy for gastric cancer. The study assessed primary endpoints such as nutritional status and quality of life, as well as secondary endpoints including operative time, intraoperative blood loss, perioperative and postoperative complications, and survival rate., Methods: A total of 113 patients were randomly assigned to either the FJI group or the SJI group. Surgical procedures were performed according to the allocated group. Nutritional status was evaluated based on plasma nutritional parameters, weight loss, and the nutritional assessment index (NAI). Quality of life was assessed using Cuschieri scores and Visick scores. Operative time, intraoperative blood loss, perioperative and postoperative complications, and survival rate were also recorded., Results: There were no significant differences observed between the FJI group and the SJI group in terms of primary and secondary endpoints. Both groups showed similar outcomes in terms of nutritional status, quality of life, perioperative and postoperative complications, and survival rate. The operative time was longer in the FJI group compared to the SJI group., Conclusion: This study shows that both FJI and SJI are effective at maintaining nutrition, quality of life, and survival rate after total gastrectomy for gastric cancer. Although FJI is more complex, SJI is preferred due to its shorter duration. Surgeons should choose the most appropriate method based on the patient's characteristics and their own skills., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Evodiae fructus polysaccharide (EFP) has been previously shown to protect against alcohol-induced gastric lesions. However, which and how active fractions in EFP exert gastroprotection remains unclear. This study aimed to characterize the structure of the purified fraction (EFP-2-1) of EFP, and investigate its gastroprotection and underlying mechanisms. EFP-2-1 was obtained through column chromatography, and was characterized using instrumental analytical techniques. Gastroprotective effect of EFP-2-1 was evaluated using alcohol-induced gastric lesions in rats, and its mechanism was explored through proteomics, metabolomics and diversity sequencing. Results showed that EFP-2-1 had a molecular weight of 7.3 kDa, and consisted mainly of rhamnose, galacturonic acid, galactose and arabinose. Its backbone contained HG and RG-I domains, and branched with →5)-α-l-Araf-(1→, α-l-Araf-(1→ and →4)-β-d-Galp-(1→ residues. EFP-2-1 reduced gastric lesions and the levels of MDA, TNF-α and IL-6, activated PPARγ, primarily altered protein digestion and absorption and bile secretion metabolic pathways, regulated gut microbiota like Faecalibaculum and Lachnoclostridium, and increased short-chain fatty acids production. Correlations were observed among the gut microbiota, metabolites and biochemical indexes influenced by EFP-2-1. These findings suggest that EFP-2-1 is an active fraction of EFP for protecting against alcohol-induced gastric lesions, which may be linked to PPARγ activation, gut microbiota and serum metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4 hi PDIA3 hi ACSL4 hi CCL2 hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Edible plant oils are widely used in cooking, cosmetics, health supplement capsules, and other industries, due to their various health-promoting effects. There is increasing evidence that edible plant oils can modulate gut microbiota during their health-promoting effects in animal experiments and cohort or clinical studies. However, the information concerning the gut microbiota modulation of edible plant oils during their health-promoting effects is scattered. In this article, the research progress on gut microbiota modulation of edible plant oils (especially camellia oil, olive oil, and flaxseed oil) is summarized. Meanwhile, a summary on correlations between modulated gut microbiota and changed biochemical indexes is provided. The alterations of edible plant oils on gut microbiota-derived metabolites and the correlations between altered metabolites and modulated gut microbiota as well as changed biochemical indexes are reviewed. Furthermore, the prospects for gut microbiota modulation of edible plant oils during their health-promoting effects are put forward. Existing literature has shown that edible plant oils could modulate gut microbiota during their health-promoting effects, and some differential gut microbiota biomarkers were gained. Some similarities and differences existed while the oils exhibited health-promoting actions. Dosage and treatment time have influences on gut microbiota modulation of edible plant oils. Different edible plant oils exhibited different behaviors in modulating gut microbiota, and edible plant oils were mostly different in modulating gut microbiota compared to edible animal oils. Moreover, the modulated gut microbiota was significantly correlated with the changed biochemical indexes. Furthermore, edible plant oils altered SCFAs and other gut microbiota-derived metabolites. The altered metabolites were obviously correlated with the modulated gut microbiota and changed biochemical indexes. This review is helpful to the future research and application of edible plant oils in health-promoting effects from the perspective of gut microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zou, Chen, Huang, Wang, Luo, Wang and Wang.)

Background: DNA sequencing is a critical tool in modern biology. Over the last two decades, it has been revolutionized by the advent of massively parallel sequencing, leading to significant advances in the genome and transcriptome sequencing of various organisms. Nevertheless, challenges with accuracy, lack of competitive options and prohibitive costs associated with high throughput parallel short-read sequencing persist., Results: Here, we conduct a comparative analysis using matched DNA and RNA short-reads assays between Element Biosciences' AVITI and Illumina's NextSeq 550 chemistries. Similar comparisons were evaluated for synthetic long-read sequencing for RNA and targeted single-cell transcripts between the AVITI and Illumina's NovaSeq 6000. For both DNA and RNA short-read applications, the study found that the AVITI produced significantly higher per sequence quality scores. For PCR-free DNA libraries, we observed an average 89.7% lower experimentally determined error rate when using the AVITI chemistry, compared to the NextSeq 550. For short-read RNA quantification, AVITI platform had an average of 32.5% lower error rate than that for NextSeq 550. With regards to synthetic long-read mRNA and targeted synthetic long read single cell mRNA sequencing, both platforms' respective chemistries performed comparably in quantification of genes and isoforms. The AVITI displayed a marginally lower error rate for long reads, with fewer chemistry-specific errors and a higher mutation detection rate., Conclusion: These results point to the potential of the AVITI platform as a competitive candidate in high-throughput short read sequencing analyses when juxtaposed with the Illumina NextSeq 550., (© 2024. The Author(s).)

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: HCC is one of the most lethal cancers for humans. Mannosidase alpha class 2A member 1 (MAN2A1)-FER is one of the most frequent oncogenic fusion genes in HCC. In this report, we showed that MAN2A1-FER ectopically phosphorylated the extracellular domains of PDGFRA, MET, AXL, and N-cadherin. The ectopic phosphorylation of these transmembrane proteins led to the activation of their kinase activities and initiated the activation cascades of their downstream signaling molecules., Methods: A panel of mouse monoclonal antibodies was developed to recognize the ectopic phosphorylation sites of PDGFRA., Results and Conclusions: The analyses showed that these antibodies bound to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The treatment of MAN2A1-FER-positive cancer HUH7 with one of the antibodies called 2-3B-G8 led to the deactivation of cell growth signaling pathways and cell growth arrest while having minimal impact on HUH7ko cells where MAN2A1-FER expression was disrupted. The treatment of 2-3B-G8 antibody also led to a large number of cell deaths of MAN2A1-FER-positive cancer cells such as HUH7, HEPG2, SNU449, etc., while the same treatment had no impact on HUH7ko cells. When severe combined immunodeficiency mice xenografted with HEPG2 or HUH7 were treated with monomethyl auristatin E-conjugated 2-3B-G8 antibody, it slowed the progression of tumor growth, eliminated the metastasis, and reduced the mortality, in comparison with the controls. Targeting the cancer-specific ectopic phosphorylation sites of PDGFRA induced by MAN2A1-FER may hold promise as an effective treatment for liver cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies. Early diagnosis of HCC is crucial in reducing the risk for mortality. This study analyzed a panel of nine fusion transcripts in serum samples from 61 patients with HCC and 75 patients with non-HCC conditions, using TaqMan real-time quantitative RT-PCR. Seven of the nine fusions frequently detected in patients with HCC included: MAN2A1-FER (100%), SLC45A2-AMACR (62.3%), ZMPSTE24-ZMYM4 (62.3%), PTEN-NOLC1 (57.4%), CCNH-C5orf30 (55.7%), STAMBPL1-FAS (26.2%), and PCMTD1-SNTG1 (16.4%). Machine-learning models were constructed based on serum fusion-gene levels to predict HCC in the training cohort, using the leave-one-out cross-validation approach. One machine-learning model, called the four fusion genes logistic regression model (MAN2A1-FER≤40, CCNH-C5orf30≤38, SLC45A2-AMACR≤41, and PTEN-NOLC1≤40), produced accuracies of 91.5% and 83.3% in the training and testing cohorts, respectively. When serum α-fetal protein level was incorporated into the machine-learning model, a two fusion gene (MAN2A1-FER≤40, CCNH-C5orf30≤38) + α-fetal protein logistic regression model was found to generate an accuracy of 94.8% in the training cohort. The same model resulted in 95% accuracy in both the testing and combined cohorts. Cancer treatment was associated with reduced levels of most of the serum fusion transcripts. Serum fusion-gene machine-learning models may serve as important tools in screening for HCC and in monitoring the impact of HCC treatment., Competing Interests: Disclosure Statement The authors have submitted US patent application 63/603240, "Fusion Genes Associated with Hepatocellular Carcinoma and Related Methods," dated November 28, 2023., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Lymphatic metastasis is the major challenge in the treatment of penile cancer. The prognosis of individuals with lymphatic metastasis is extremely poor. Therefore, early identification of disease progression and lymphatic metastasis is an urgent task for researchers in penile cancer worldwide., Methods: In this study, using single-cell RNA sequencing, an immune landscape was established for the cancer ecosystem based on 46,861 cells from six patients with penile cancer (four with lymphatic metastasis [stage IV] and two without lymphatic metastasis [stage I]). Using bulk RNA sequencing, the discrepancy between the cancers and their respective metastatic lymph nodes was depicted based on seven patients with penile cancer., Results: The interaction between epithelial cells, fibroblasts, and endothelial cells, and the functional cooperation among invasion, epithelial-mesenchymal transition, and angiogenesis were found to be important landscapes in the penile cancer ecosystem, playing important roles in progression of cancer and lymph node metastasis., Conclusions: This study is the first to investigate the altered tumor microenvironment heterogeneity of penile cancer as it evolves from non-lymphatic to lymphatic metastasis and provides insights into the mechanisms underlying malignant progression, the premetastatic niche, and lymphatic metastasis in penile cancer., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated., Methods: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing., Results: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor., Conclusion: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients., (© 2024. The Author(s).)

Advancements in long-read transcriptome sequencing (long-RNA-seq) technology have revolutionized the study of isoform diversity. These full-length transcripts enhance the detection of various transcriptome structural variations, including novel isoforms, alternative splicing events, and fusion transcripts. By shifting the open reading frame or altering gene expressions, studies have proved that these transcript alterations can serve as crucial biomarkers for disease diagnosis and therapeutic targets. In this project, we proposed IFDlong, a bioinformatics and biostatistics tool to detect isoform and fusion transcripts using bulk or single-cell long-RNA-seq data. Specifically, the software performed gene and isoform annotation for each long-read, defined novel isoforms, quantified isoform expression by a novel expectation-maximization algorithm, and profiled the fusion transcripts. For evaluation, IFDlong pipeline achieved overall the best performance when compared with several existing tools in large-scale simulation studies. In both isoform and fusion transcript quantification, IFDlong is able to reach more than 0.8 Spearman's correlation with the truth, and more than 0.9 cosine similarity when distinguishing multiple alternative splicing events. In novel isoform simulation, IFDlong can successfully balance the sensitivity (higher than 90%) and specificity (higher than 90%). Furthermore, IFDlong has proved its accuracy and robustness in diverse in-house and public datasets on healthy tissues, cell lines and multiple types of diseases. Besides bulk long-RNA-seq, IFDlong pipeline has proved its compatibility to single-cell long-RNA-seq data. This new software may hold promise for significant impact on long-read transcriptome analysis. The IFDlong software is available at https://github.com/wenjiaking/IFDlong.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

N6-methyladenosine (m6A) in mRNA and 5-methylcytosine (5mC) in DNA have critical functions for regulating gene expression and modulating plant growth and development. However, the interplay between m6A and 5mC is an elusive territory and remains unclear mechanistically in plants. We reported an occurrence of crosstalk between m6A and 5mC in maize (Zea mays) via the interaction between mRNA adenosine methylase (ZmMTA), the core component of the m6A methyltransferase complex, and decrease in DNA methylation 1 (ZmDDM1), a key chromatin-remodeling factor that regulates DNA methylation. Genes with m6A modification were coordinated with a much higher level of DNA methylation than genes without m6A modification. Dysfunction of ZmMTA caused severe arrest during maize embryogenesis and endosperm development, leading to a significant decrease in CHH methylation in the 5' region of m6A-modified genes. Instead, loss of function of ZmDDM1 had no noteworthy effects on ZmMTA-related activity. This study establishes a direct link between m6A and 5mC during maize kernel development and provides insights into the interplay between RNA modification and DNA methylation., Competing Interests: Conflict of interest statement. The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Liver cancer is one of the most lethal malignancies for humans. The treatment options for advanced-stage liver cancer remain limited. A new treatment is urgently needed to reduce the mortality of the disease., Methods: In this report, we developed a technology for mutation site insertion of a suicide gene (herpes simplex virus type 1- thymidine kinase) based on type II CRISPR RNA-guided endonuclease Cas9-mediated genome editing to treat liver cancers., Results: We applied the strategy to 3 different mutations: S45P mutation of catenin beta 1, chromosome breakpoint of solute carrier family 45 member 2-alpha-methylacyl-CoA racemase gene fusion, and V235G mutation of SAFB-like transcription modulator. The results showed that the herpes simplex virus type 1-thymidine kinase insertion rate at the S45P mutation site of catenin beta 1 reached 77.8%, while the insertion rates at the breakpoint of solute carrier family 45 member 2 - alpha-methylacyl-CoA racemase gene fusion were 95.1%-98.7%, and the insertion at V235G of SAFB-like transcription modulator was 51.4%. When these targeting reagents were applied to treat mouse spontaneous liver cancer induced by catenin beta 1S45P or solute carrier family 45 member 2-alpha-methylacyl-CoA racemase, the mice experienced reduced tumor burden and increased survival rate. Similar results were also obtained for the xenografted liver cancer model: Significant reduction of tumor volume, reduction of metastasis rate, and improved survival were found in mice treated with the targeting reagent, in comparison with the control-treated groups., Conclusions: Our studies suggested that mutation targeting may hold promise as a versatile and effective approach to treating liver cancers., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Genetic mutation is essential in species evolution and cancer development. Accurate long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPSeq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPSeq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome., Competing Interests: SL, YY, BR, WW, AO, AS, JL No competing interests declared, TB He is an employee of Element Biosciences, Inc, CO She is an employee of Element Biosciences, Inc, MS MS is an employee of Element Biosciences, Inc, (© 2023, Liu et al.)

Objective: To evaluate the participation rate and detection of colorectal neoplasms based on annual fecal immunochemical testing (FIT) for three consecutive years in a population-based colorectal cancer screening program in China. Methods: Based on a population-based colorectal cancer screening program conducted from May 2018 to May 2021 in 6 centers in China, 7 793 eligible participants aged 50-74 were included and offered free FIT and colonoscopy (for those who were FIT-positive on initial screening). At baseline, all participants were invited to receive FIT. In subsequent screening rounds, only FIT-positive participants who did not undergo colonoscopy or FIT-negative participants were invited to have repeated FIT screening. FIT-positive participants were recommended to undertake colonoscopy and pathological examination (if abnormalities were found during colonoscopy). An overall of three rounds of annual FIT screening were conducted. The primary outcomes of the study were the participation rate of FIT screening, the compliance rate of colonoscopy for FIT-positive participants, and the detection rate of colorectal neoplasms. Results: Among the 7 793 participants included in this study, 3 310 (42.5%) were male, with age of (60.50±6.49) years. The overall participation rates for the first, second and third round of FIT screening were 94.0%(7 327/7 793), 86.8% (6 048/6 968) and 91.3% (6 113/6 693), respectively. Overall, 7 742 out of 7 793 participants (99.3%) attended at least one round of screening, and 5 163 out of 7 793 participants (66.3%) attended all three rounds of screening. The positivity rate was significantly higher in the first (14.6%, 1 071/7 327) round compared with the second (5.6%, 3 41/6 048) and third (5.5%, 3 39/6 113) screening rounds ( P <0.001). The overall compliance rates of colonoscopy examination among FIT-positive subjects were over 70% in three rounds, which were 76.3% (817/1 071), 75.7% (258/341) and 71.7% (243/339), respectively. In a multivariate logistic regression model considering factors including sex, education background, smoking, alcohol drinking, previous colonoscopy examination, colonic polyp history and family history of colorectal cancer among first-degree relatives, gender and smoking status were related factors affecting the participation rate of FIT screening, with higher rate in males and non-smokers. In addition, logistic regression analysis also found that age was negatively correlated with the compliance rate of colonoscopy in FIT positive patients. The detection rate of advanced tumors (colorectal cancer + advanced adenoma) declined from the first round to subsequent rounds [1st round: 1.15% (90/7 793); 2nd round: 0.57% (40/6 968); and 3rd round: 0.58% (39/6 693)], however, the positive predictive value for advanced neoplasms increased round by round, and was 11.02% in the first screening round, 15.50% in the second screening round, and 16.05 % in the third screening round. In each screening round, the detection rate for advanced neoplasms was higher in men than that in women, and increased with age. Conclusions: Annual repeated FIT screening has high acceptance and satisfying detection rates in the Chinese population. To optimize and improve the effectiveness of colorectal cancer screening, multi-round repeated FIT screening should be implemented while ensuring high participation rates.

Three new cadinene sesquiterpenoids 1 - 3 , were isolated from the aerial sections of Ageratina adenophora using various chromatographic techniques. Their structures were characterised by comprehensive spectroscopic investigations (including 1D, 2D-NMR and HRMS), and single crystal X-ray diffraction. The cytotoxic activity of new compounds 1 - 3 were evaluated by testing in vitro tumour growth inhibitory rate against five human tumour cell lines, HL-60, A-549, SMMC-7721, MDA-MB-231, and SW480.

Diabetes mellitus (DM) poses a significant global health burden, with hyperglycemia being a primary contributor to complications and high morbidity associated with this disorder. Existing glucose management strategies have shown suboptimal effectiveness, necessitating alternative approaches. In this study, we explored the role of high mobility group box 1 (HMGB1) in hyperglycemia, a protein implicated in initiating inflammation and strongly correlated with DM onset and progression. We hypothesized that HMGB1 knockdown will mitigate hyperglycemia severity and enhance glucose tolerance. To test this hypothesis, we utilized a novel inducible HMGB1 knockout (iHMGB1 KO) mouse model exhibiting systemic HMGB1 knockdown. Hyperglycemic phenotype was induced using low dose streptozotocin (STZ) injections, followed by longitudinal glucose measurements and oral glucose tolerance tests to evaluate the effect of HMGB1 knockdown on glucose metabolism. Our findings showed a substantial reduction in glucose levels and enhanced glucose tolerance in HMGB1 knockdown mice. Additionally, we performed RNA sequencing analyses, which identified potential alternations in genes and molecular pathways within the liver and skeletal muscle tissue that may account for the in vivo phenotypic changes observed in hyperglycemic mice following HMGB1 knockdown. In conclusion, our present study delivers the first direct evidence of a causal relationship between systemic HMGB1 knockdown and hyperglycemia in vivo, an association that had remained unexamined prior to this research. This discovery positions HMGB1 knockdown as a potentially efficacious therapeutic target for addressing hyperglycemia and, by extension, the DM epidemic. Furthermore, we have revealed potential underlying mechanisms, establishing the essential groundwork for subsequent in-depth mechanistic investigations focused on further elucidating and harnessing the promising therapeutic potential of HMGB1 in DM management., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential., (© 2023 The Authors.)

Screening and early diagnosis and treatment have been proven effective in reducing the incidence and mortality of colorectal cancer. Colonoscopy combined with pathological examination is the gold standard for colorectal cancer screening. However, due to the invasiveness, high cost and the need for professional endoscopists of colonoscopy, it is not feasible to directly use this method for mass population screening. Fecal immunochemical test (FIT) is one of the screening techniques recommended by authoritative international guidelines for colorectal cancer screening, and has been widely used in population-based colorectal cancer screening programs in countries around the world. This paper elaborates on the value of FIT in colorectal cancer screening from different aspects, such as the technical principles, the screening efficiency, the screening strategies, and the population effects and benefits. Additionally, it describes the current situation of colorectal cancer screening in China and summarizes the challenges faced in colorectal cancer screening in order to optimize the FIT-based colorectal cancer screening strategies in the population and provide theoretical reference for effective colorectal cancer screening.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing., (© 2023. The Author(s).)

This study focused on screening novel markers associated with cellular senescence for predicting the prognosis of breast cancer. The RNA-seq expression profile of BRCA and clinical data were obtained from TCGA. The pam algorithm was used to cluster patients based on senescence-related genes. The weighted gene co-expression network analysis was used to identify co-expressed genes, and LASSO-Cox analysis was performed to build a risk prognosis model. The performance of the model was also evaluated. We additionally explored the role of senescence in cancer development and possible regulatory mechanism. The patients were clustered into 2 subtypes. A total of 5259 genes significantly related to senescence were identified by weighted gene co-expression network analysis. LASSO-Cox finally established a 6-signature risk model (ADAMTS8, DCAF12L2, PCDHA10, PGK1, SLC16A2, and TMEM233) that exhibited favorable and stable performance in our training, validation, and whole BRCA datasets. Furthermore, the superiority of our model was also observed after comparing it to other published models. The 6-signature was proved to be an independent risk factor for prognosis. In addition, mechanism prediction implied the activation of glycometabolism processes such as glycolysis and TCA cycle under the condition of senescence. Glycometabolism pathways were further found to negatively correlate with the infiltration level of CD8 T-cells and natural killer cells but positively correlate with M2 macrophage infiltration and expressions of tissue degeneration biomarkers, which suggested the deficit immune surveillance and risk of tumor migration. The constructed 6-gene model based on cellular senescence could be an effective indicator for predicting the prognosis of BRCA., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: To study the efficacy and safety of Xiyanping injection through intramuscular injection for the treatment of acute bronchitis in children., Methods: A prospective study was conducted from December 2021 to October 2022, including 78 children with acute bronchitis from three hospitals using a multicenter, randomized, parallel-controlled design. The participants were divided into a test group (conventional treatment plus Xiyanping injection; n =36) and a control group (conventional treatment alone; n =37) in a 1:1 ratio. Xiyanping injection was administered at a dose of 0.3 mL/(kg·d) (total daily dose ≤8 mL), twice daily via intramuscular injection, with a treatment duration of ≤4 days and a follow-up period of 7 days. The treatment efficacy and safety were compared between the two groups., Results: The total effective rate on the 3rd day after treatment in the test group was significantly higher than that in the control group ( P <0.05), while there was no significant difference in the total effective rate on the 5th day between the two groups ( P >0.05). The rates of fever relief, cough relief, and lung rale relief in the test group on the 3rd day after treatment were higher than those in the control group ( P <0.05). The cough relief rate on the 5th day after treatment in the test group was higher than that in the control group ( P <0.05), while there was no significant difference in the fever relief rate and lung rale relief rate between the two groups ( P >0.05). The cough relief time, daily cough relief time, and nocturnal cough relief time in the test group were significantly shorter than those in the control group ( P <0.05), while there were no significant differences in the fever duration and lung rale relief time between the two groups ( P >0.05). There was no significant difference in the incidence of adverse events between the two groups ( P >0.05)., Conclusions: The overall efficacy of combined routine treatment with intramuscular injection of Xiyanping injection in the treatment of acute bronchitis in children is superior to that of routine treatment alone, without an increase in the incidence of adverse reactions.

Pharmaceutically active compounds(PhACs) have become a class of new pollutants in the environment after extensive production and use of PhACs in China. To investigate the pollution characteristics of PhACs in Guangdong Province, raw sewage was collected from 186 sewage treatment plants in 21 cities, including 178 townships and administrative districts in Guangdong Province. The pollution levels of ten typical PhACs in influent water of sewage treatment plants were analyzed using automatic solid phase extraction and high performance liquid chromatography-triple quadrupole mass spectrometry. The spatial distribution characteristics of PhACs in Guangdong Province were fully revealed, and the potential ecological risks of PhACs were evaluated. The results showed that PhACs were detected in all wastewater plants, and the mass concentration of PhACs ranged from 21.00 to 9558.25 ng·L -1 . Metoprolo, acetaminophen, bezafibrate, and caffeine were the main pollutants. In terms of spatial distribution, the average mass concentration of ΣPhACs in various regions of Guangdong Province was in the following order:Pearl River Delta>North Guangdong>East Guangdong≈West Guangdong. When the mass concentration of ΣPhACs was over 2500 ng·L -1 in the influent water of sewage treatment plants, the concentration of PhACs in effluent was estimated according to the sewage disposal technology. The ecological risk of PhACs was carried out based on the effluent. The results revealed that the ecological risk of PhACs was low in Guangdong Province, and the risk of bezafibrate was moderate in the cities of Shaoguan, Jiangmen, and Shenzhen. The highest ecological risk of ΣPhACs was located in Shaoguan.

Background: The association between muscle defects and hypertension is well-established. However, the absence of pertinent and uncomplicated clinical indicators presents a challenge. Relative muscle strength (RMS) may offer a viable indicator. This study aimed to explore the association between RMS and hypertension., Methods: A total of 12,720 individuals aged ≥ 45 years from the 2011 wave of the China Health and Retirement Longitudinal Study (CHARLS) were included. Grip strength was recorded and appendicular skeletal muscle mass (ASM) was estimated using a validated mathematical formula. The RMS was calculated as the ratio of grip strength to ASM. Hypertension was determined based on previous diagnosis, history of hypertension medication use, and current blood pressure. Logistic regression models were employed to investigate the relationship between RMS and hypertension., Results: The prevalence of hypertension was 41.7% (5,307/12,720 patients). RMS was negatively correlated with hypertension with an OR (95% CI) of 0.68 (0.59-0.79) for males, 0.81 (0.73-0.90) for females, and 0.78 (0.72-0.85) for the entire population after adjusting for related covariates including age, education, marital history, smoking history, drinking history, diabetes, hyperlipidemia, and obesity. The trend test showed a linear association among males, females, or the entire population. Stratified analysis showed a consistent negative correlation between RMS and hypertension., Conclusions: Higher RMS is an independent protective factor against hypertension and efforts to promote RMS may be beneficial for the prevention and management of hypertension., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The number of pollen grains is a critical determinant of reproductive success in seed plants and varies among species and individuals. However, in contrast with many mutant-screening studies relevant to anther and pollen development, the natural genetic basis for variations in pollen number remains largely unexplored. To address this issue, we carried out a genome-wide association study in maize, ultimately revealing that a large presence/absence variation in the promoter region of ZmRPN1 alters its expression level and thereby contributes to pollen number variation. Molecular analyses showed that ZmRPN1 interacts with ZmMSP1, which is known as a germline cell number regulator, and facilitates ZmMSP1 localization to the plasma membrane. Importantly, ZmRPN1 dysfunction resulted in a substantial increase in pollen number, consequently boosting seed production by increasing female-male planting ratio. Together, our findings uncover a key gene controlling pollen number, and therefore, modulation of ZmRPN1 expression could be efficiently used to develop elite pollinators for modern hybrid maize breeding., (© 2023 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

The chemical analysis on the aerial sections of Eupatorium adenophorum Spreng. resulted in the identification of four unprecedented 5/5 fused bicyclosesquiterpenoids, eupatorid A (1), and its analogues named eupatorester A-C (2-4) using various chromatographic techniques. Their structures were unambiguously confirmed by detailed spectroscopic investigations (including 1D, 2D-NMR and HRMS), and single crystal X-ray diffraction. The anti-inflammatory activities, in vitro tumor growth inhibitory activities and antibacterial activities of these compounds were evaluated., Competing Interests: Declaration of Competing Interest This article did not contain a conflict of interest statement upon online publication. All authors had completed a disclosure form stating that they did not have any potential conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8 + T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8 + T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca 2+ -ATPase SERCA2, facilitating the mitochondrial Ca 2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca 2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca 2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8 + T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8 + T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.

As a global phenomenon, mobile phone addiction has become an increasingly common issue among Chinese university students. Although previous research explored the link between mobile phone addiction and mental health, the possible mechanism underlying the above association is unclear. We administered a cross-sectional survey to 585 participants from two universities in Kunming, southwest China, from October 2021 to January 2022. Our results suggested that mobile phone addiction was negatively associated with mental health, and sleep quality partially mediated the relationship between mobile phone addiction and mental health. Furthermore, perceived social support positively moderated the direct effect of sleep quality on mental health, as well as the indirect effect of mobile phone addiction on mental health. These findings provide a new insight into the underlying mechanism by which mobile phone addiction affects university students' mental health. The results emphasize a necessary task for administrators, health workers, and family members to attach importance to the overuse of mobile phones among university students., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Guo, Li, Gan and Luo.)

Clear cell Renal Cell Carcinoma (ccRCC) is a highly heterogeneous disease, making it challenging to predict prognosis and therapy efficacy. In this study, we aimed to explore the role of 5-methylcytosine (m5C) RNA modification in ccRCC and its potential as a predictor for therapy response and overall survival (OS). We established a novel 5-methylcytosine RNA modification-related gene index (M5CRMRGI) and studied its effect on the tumor microenvironment (TME) using single-cell sequencing data for in-depth analysis, and verified it using spatial sequencing data. Our results showed that M5CRMRGI is an independent predictor of OS in multiple datasets and exhibited outstanding performance in predicting the OS of ccRCC. Distinct mutation profiles, hallmark pathways, and infiltration of immune cells in TME were observed between high- and low-M5CRMRGI groups. Single-cell/spatial transcriptomics revealed that M5CRMRGI could reprogram the distribution of tumor-infiltrating immune cells. Moreover, significant differences in tumor immunogenicity and tumor immune dysfunction and exclusion (TIDE) were observed between the two risk groups, suggesting a better response to immune checkpoint blockade therapy of the high-risk group. We also predicted six potential drugs binding to the core target of the M5CRMRGI signature via molecular docking. Real-world treatment cohort data proved once again that high-risk patients were appropriate for immune checkpoint blockade therapy, while low-risk patients were appropriate for Everolimus. Our study shows that the m5C modification landscape plays a role in TME distribution. The proposed M5CRMRGI-guided strategy for predicting survival and immunotherapy efficacy, we reported here, might also be applied to more cancers other than ccRCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory β cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy., (© 2023. Society of Chinese Bioscientists in America (SCBA).)

The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Genetic mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPseq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection (UMAP) analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen (HLA) molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPseq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome., Competing Interests: Statement of conflict of interest: Tuval Ben-Yehezkel, Caroline Obert, and Mat Smith are employees of Element Biosciences, Inc. Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, and Jian-Hua Luo declare no conflict of interest.

Background: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence., Methods: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI)., Findings: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001)., Interpretation: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy., Funding: National Natural Science Foundation of China, and National Key Research and Development Program of China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive., Methods: We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval., Results: We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors., Conclusions: Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effectiveness of a risk-adapted colorectal cancer screening strategy constructed utilizing genetic and environmental risk score (ERS). Methods: A polygenic risk score (PRS) was constructed based on 20 previously published single nucleotide polymorphisms for colorectal cancer in East Asian populations, using 2 160 samples with MassARRAY test results from a multicenter randomized controlled trial of colorectal cancer screening in China. The ERS was calculated using the Asia-Pacific Colorectal Screening Score system. Logistic regression was used to analyze the association between PRS alone and PRS combined with ERS and colorectal neoplasms risk, respectively. We also designed a risk-adapted screening strategy based on PRS and ERS (high-risk participants undergo a single colonoscopy, low-risk participants undergo an annual fecal immunochemical test, and those with positive results undergo further diagnostic colonoscopy) and compared its effectiveness with the all-acceptance colonoscopy strategy. Results: The high PRS group had a 26% increased risk of colorectal neoplasms compared with the low PRS group ( OR =1.26, 95% CI : 1.03-1.54, P =0.026). Participants with the highest PRS and ERS were 3.03 times more likely to develop advanced colorectal neoplasms than those with the lowest score (95% CI : 1.87-4.90, P <0.001). As the risk-adapted screening simulation reached the third round, the detection rate of the PRS combined with ERS strategy was not statistically different from the all-acceptance colonoscopy strategy (8.79% vs. 10.46%, P =0.075) and had a higher positive predictive value (14.11% vs. 10.46%, P <0.001) and lower number of colonoscopies per advanced neoplasms detected (7.1 vs. 9.6, P <0.001). Conclusion: The risk-adapted screening strategy combining PRS and ERS helps achieve population risk stratification and better effectiveness than the traditional colonoscopy-based screening strategy.

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC., (© 2023. The Author(s).)

Prostate cancer remains one of the most fatal malignancies in men in the United States. Predicting the course of prostate cancer is challenging given that only a fraction of prostate cancer patients experience cancer recurrence after radical prostatectomy or radiation therapy. This study examined the expressions of 14 fusion genes in 607 prostate cancer samples from the University of Pittsburgh, Stanford University, and the University of Wisconsin-Madison. The profiling of 14 fusion genes was integrated with Gleason score of the primary prostate cancer and serum prostate-specific antigen level to develop machine-learning models to predict the recurrence of prostate cancer after radical prostatectomy. Machine-learning algorithms were developed by analysis of the data from the University of Pittsburgh cohort as a training set using the leave-one-out cross-validation method. These algorithms were then applied to the data set from the combined Stanford/Wisconsin cohort (testing set). The results showed that the addition of fusion gene profiling consistently improved the prediction accuracy rate of prostate cancer recurrence by Gleason score, serum prostate-specific antigen level, or a combination of both. These improvements occurred in both the training and testing cohorts and were corroborated by multiple models., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)