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SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

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research 2024年第3期2023卷 369-389页

作者： Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang Lingli Zhang Xingyue Shan Ren Li Yuan Dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang Li Qiang Luo Fei Li Developmental and Behavioral Pediatric Department Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental HealthXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Developmental and Behavioral Pediatric Department Shanghai Xinhua Children's HospitalShanghai 200092China National Clinical research Center for Aging and Medicine at Huashan hospital Institute of Science and Technology for Brain-lnspired IntelligenceMinistry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired IntelligenceFudan UniversityShanghai 200433China State Key Laboratory of Medical Neurobiology and Ministry of education Frontiers Center for Brain Science Institutes of Brain Science and Human Phenom InstituteFudan UniversityShanghai 200032China Shanghai Key Laboratory of Brain Functional Genomics(Ministry of education) School of Life SciencesEast China Normal UniversityShanghai 200062China Department of Rehabilitation Medicine Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Center for Experimental Studies and research The First Affliated Hospital of Kunming Medical UniversityKunming 650032China Shanghai research Center for Brain Science and Brain-lnspired Intelligence Shanghai201210China Institute of Cognitive Neuroscience School of Psychology and Cognitive ScienceEast China Normal UniversityShanghai 200062China.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关键词： metabolism impaired reversed

Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma

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National Science Review 2024年第5期11卷 170-185页

作者： Yong Zhou Shanlan Mo Heyang Cui Ruifang Sun Weimin Zhang Xiaofei Zhuang Enwei Xu Hongyi Li Yikun Cheng Yongsheng Meng Meilin Liu Ting Yan Huijuan Liu Ling Zhang Bin Yang Yanfeng Xi Shubin Wang Xiaolong Cheng Shuai Cheng Li Zhihua Liu Qimin Zhan Zheng Hu Yongping Cui Cancer Institute Department of Pathology Peking University Shenzhen Hospital Shenzhen Peking University-the Hong Kong University of Science and Technology(PKU-HKUST) Medical Center Institute of Cancer ResearchShenzhen Bay Laboratory Key Laboratory of Cellular Physiology of the Ministry of education Department of Pathology Shanxi Medical University City University of Hong Kong Shenzhen research Institute CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of Sciences Department of Surgery Faculty of Medicine The Chinese University of Hong Kong Department of Tumor Biobank Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute research Unit of Molecular Cancer research Chinese Academy of Medical Sciences Department of Thoracic Surgery Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Department of Pathology Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University College of Letters & Science University of California Berkeley State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Esophageal squamous cell carcinoma（ESCC） is a poor-prognostic cancer type with extensive intra-and inter-patient heterogeneity in both genomic variations and tumor microenvironment（TME）. However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2,accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the ***, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted ***, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

关键词： squamous cell carcinoma heterogeneity multi-omics evolution tumor microenvironment

Reducing the global cancer burden with gastrointestinal screening: China's 30 years practice

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Cancer Biology & Medicine 2024年第3期21卷 204-212页

作者： Lei Yang Li Feng Yong Zhu Ning Wang Xinpu Lu Fanghui Gu Xiaotian Zhang Jiafu Ji Peking University Cancer hospital(Inner Mongolia Campus)/Affiliated Cancer hospital of Inner Mongolia Medical University Inner Mongolia Cancer CenterHohhot 010020China Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Bejing) Bejing Office for Cancer Prevention and ControlPeking University Cancer Hospital&InstituteBejing 100142China Key Laboratory of Carcinogenesis and Translational research(Ministry of education) Peking University Cancer Hospital&InstituteBeijing 100142China Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Bejing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Bejing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Gastrointestinal(GI) cancers include esophageal [EC(International Classification of Disease 10^(th) revision: C15)], gastric [GC(C16)], and colorectal [CRC(C18-C21)] cancers. China is a high-incidence country of GI ca... 详细信息

关键词： esophageal colorectal gastrointestinal

Vitamin A deficiency suppresses CEACAM1 to impair colonic epithelial barrier function via downregulating microbial-derived short-chain fatty acids

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Genes & Diseases 2024年第2期11卷 1066-1081页

作者： Junyan Yan Lu Xiao Di Feng Baolin Chen Ting Yang Bei Tong Ruifang Luo Yuting Wang Jie Chen Children Nutrition research Center Children's Hospital of Chongqing Medical UniversityChongqing Key Laboratory of Child Nutrition and HealthMinistry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing 401122China Department of Gastroenterology Children's Hospital of Chongqing Medical UniversityChongqing 401122China

Vitamin A (VA) plays an essential role in modulating both the gut microbiota and gut barrier ***-chain fatty acids (SCFAs),as metabolites of the gut microbiota,protect the physiological intestinal barrier;however,they are compromised when VA is ***,there is an urgent need to understand how and which SCFAs modulate colonic epithelial barrier integrity in VA deficiency (VAD).Herein,compared with normal VA rats (VAN),at the beginning of pregnancy,we confirmed that the colonic desmosome junction was impaired in the VAD group,and the amounts of acetate,propionate,and butyrate declined because of the decreased abundance of SCFA-producing bacteria (Romboutsia ,Collinsella ,and Allobaculum ).The differentially expressed genes correlated with the gut barrier and the histone deacetylase complex between the VAD and VAN groups were enriched by RNA *** the VAD group,the expression levels of colonic CEA cell adhesion molecule 1 (CEACAM1) were down-regulated,and the levels of histone deacetylase 1 (HDAC1) and HDAC3 were ***,the above changes in the VAD groups were rescued by VA supplementation in the early postnatal *** study indicated that in Caco-2 cells,butyrate treatment significantly repressed the enrichment of HDAC3 on the promoter of the CEACAM1 gene to induce its *** findings support that butyrate intervention can alleviate the impairment of colonic barrier function caused by VAD,and timely postnatal VA intervention may reverse the damage caused by VAD on gut barrier integrity during pregnancy.

关键词： CEACAM1 Colonic epithelial barrier HDAC3 Short-chain fatty acids Vitamin A deficiency

Investigation of risk factors in the development of recurrent urethral stricture after internal urethrotomy

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World Journal of Clinical Cases 2024年第14期12卷 2324-2331页

作者： Abdullah Gul Ozgur Ekici Salim Zengin Deniz Barali Tarik Keskin Department of Urology University of Health SciencesBursa Yüksekİhtisas Education and Research HospitalBursa 16100Türkiye Department of Urology University of Health SciencesBursa City HospitalBursa 16000Türkiye

BACKGROUND Urethral stricture is a condition that often develops with trauma and results in narrowing of the urethral *** endoscopic methods are mostly used in its treatment,it has high recurrence ***,open urethroplasty is recommended after unsuccessful endoscopic *** To investigate the risk factors associated with urethral stricture *** The data of male patients who underwent internal urethrotomy for urethral stricture between January 2017 and January 2023 were retrospectively *** data,comorbidities,preoperative haemogram,and biochemical values obtained from peripheral blood and operative data were *** were divided into two groups in terms of recurrence development;recurrence and *** recorded data were compared between the two *** A total of 303 patients were included in the *** mean age of the patients was 66.6±13.6 *** mean duration of recurrence development was 9.63±9.84(min-max:1-39)months in the recurrence *** did not occur in non-recurrence group throughout the follow-up period with an average time of 44.15±24.07(min-max:12-84)*** the comparison of both groups,the presence of diabetes mellitus(DM),hypertension(HT),and multiple comorbidi-ties were significantly higher in the recurrence(+)group(P=0.038,P=0.012,P=0.013).Blood group,postoperative use of non-steroidal anti-inflammatory drugs,preoperative cystostomy,cause of stricture,iatrogenic cause of stricture,location and length of stricture,indwelling urinary cathater size and day of catheter removal did not differ between the two *** statistically significant difference was observed between the two groups in terms of age,uroflowmetric maximum flow rate value,hemo-gram parameters,aspartate aminotransferase(AST),alanine aminotransferase(ALT),fasting blood sugar,creati-nine,glomerular filtration rate,neutrophil-lymphocyte ratio,platelet-lymphocyte ratio,lymphocyte-

关键词： Inflammation Internal urethrotomy Recurrence Urethral stricture Urethra

Can we predict the incidence of high-grade Clavien-Dindo complications in patients with forgotten encrusted stents undergoing endourologic management?

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Asian Journal of Urology 2024年第1期11卷 99-104页

作者： Praanjal Gupta Ramanitharan Manikandan Lalgudi Narayanan Dorairajan Kodakattil Sreenivasan Sreerag Sidhartha Kalra Swapnil Singh Kushwaha Department of Urology Jawaharlal Institute of Postgraduate Medical Education and ResearchPondicherryIndia

Objective:Ureteral stents are customarily inserted to facilitate urinary drainage,but they come with their own glitches of being forgotten and/or encrusted leading to serious *** present study aimed to report the complications in patients with forgotten and encrusted stents according to the Clavien-Dindo system specific to urological procedures and identify the factors leading to high-grade(Clavien-Dindo Grade 4A or above)***:The hospital records of patients with forgotten encrusted double-J stents over a period of 8 years were *** parameters recorded included patient demographics,indwelling time,need for percutaneous nephrostomy,hemodialysis,urine culture,blood culture,total blood counts,serum creatinine,radiologic findings,management techniques,number of surgical interventions,modified Clavien-Dindo complications,follow-up,and mortality,if ***:Forty patients were included in the *** median age was 52(range 6-85)*** the total,25(62.5%)patients had a“significant”stent load;31(77.5%)had renal failure or acute kidney injury on presentation;19(47.5%)patients had sepsis at *** the patients presented with sepsis,11(57.9%)patients demonstrated a positive urine culture;and 7/11(63.6%)patients exhibited pan-resistant *** out of 40(30.0%)patients in our series developed high-grade Clavien-Dindo *** univariate analysis,sepsis at presentation(p=0.007),stent load(p=0.031),diabetes(p=0.023),positive urine culture(p=0.007),and stent indwelling time of more than 1 year(p=0.031)were found to be *** multivariate logistic regression analysis,sepsis at presentation(p=0.017)and positive urine culture(p=0.016)were significant predictors for high-grade ***:It is prudent to identify specific risk factors,namely sepsis at presentation and positive urine culture to triage and optimize these patients before surgical management.

关键词： Forgotten Encrusted stent Outcome Predictor Clavien-Dindo complication

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas

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Chinese Journal of Cancer research 2024年第1期36卷 90-102页

作者： Jianwei Zhang Hanxiao Chen Junli Zhang Sha Wang Yanfang Guan Wenguang Gu Jie Li Xiaotian Zhang Jian Li Xicheng Wang Zhihao Lu Jun Zhou Zhi Peng Yu Sun Yang Shao Lin Shen Minglei Zhuo Ming Lu Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Department of Radiation Therapy National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen 518172China Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Beijing) Department I of Thoracic OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Medical Department Nanjing Geneseeq Technology Inc.Nanjing 210061China Geneplus-Beijing Beijing 102200China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Key Laboratory of Carcinogenesis and Translational research(Ministry of education/Beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its ***: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable ***: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive *** the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

关键词： Neuroendocrine carcinoma gastroenteropancreatic lung genetic alterations molecular markers

Overcoming the Challenges Encountered in the Performance Appraisal of Faculty Members

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Journal of Forensic Science and Medicine 2024年第2期10卷 152-154页

作者： Saurabh RamBihariLal Shrivastava Ulfa Zora Yulia Putri Ayunigdyah Abhishek Joshi Deputy Director(research and Development) Datta Meghe Institute of Higher Education and Research NagpurOff CampusDepartment of Community MedicineDatta Meghe Medical CollegeOff-campus Centre of Datta Meghe Institute of Higher Education and ResearchHingna RoadWanadongriNagpurMaharashtraIndia Department of Medical education Faculty of MedicinePublic Health and NursingUniversitas Gadjah MadaYogyakartaIndonesia Department of research and education Dr.Yap Eye HospitalYogyakartaIndonesia Department of Community Medicine Jawaharlal Nehru Medical CollegeDatta Meghe Institute of Higher Education and ResearchSawangiWardhaMaharashtraIndia

Performance appraisal of teaching faculty who are involved in the act of delivery of medical education to prepare future doctors plays a pivotal role in measuring their competency level to train students,assessing the effectiveness in discharging their other roles,and acts as a motivating factor to continuously improvise and augment their knowledge and ***,the ground reality is that in most settings,this task is not acknowledged as an action for motivating a faculty member,but rather just an act of *** the identification of these challenges,we must look for remedial measures to overcome them to streamline and enhance the effectiveness of the performance appraisal *** conclusion,the performance appraisal of teaching faculty is an essential and indispensable ***,the success of performance appraisal,in terms of promoting professional development and organizational success,will depend a lot on the effective redressal of the existing challenges.

关键词： Faculty medical education performance appraisal

Roles of THEM4 in the Akt pathway:a double-edged sword

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 541-556页

作者： Wen XIE Weidong LIU Lei WANG Bin ZHU Cong ZHAO Ziling LIAO Yihan LI Xingjun JIANG Jie LIU Caiping REN NHC Key Laboratory of Carcinogenesis Department of NeurosurgeryXiangya HospitalCentral South UniversityChangsha 410008China National Clinical research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China The Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of education Cancer Research InstituteSchool of Basic Medical ScienceCentral South UniversityChangsha 410078China Department of Critical Care Medicine Hainan Hospital of Chinese PLA General HospitalHainan Province Clinical Medical CenterSanya 572013China

The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of *** superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding *** studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its ***,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous *** these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially *** work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.

关键词： Protein kinase B(Akt) Thioesterase superfamily member 4(THEM4) Tumor proliferation Tumor metastasis