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A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

Neural Regeneration Research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem Center for Cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia

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A Randomized-Controlled Trial Evaluating the Impact of a Web Tutorial on Perceptions and Usage of Opioids Post-Carpal Tunnel Release Surgery

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Journal of Hand Surgery Global Online 2024年第4期6卷 514-518页

作者： Gilmer, Gabrielle Cluts, Landon Gibbons, John L. Fowler, John Cellular and Molecular Pathology Graduate Program Department of Pathology University of Pittsburgh School of Medicine Pittsburgh PA United States Medical Scientist Training Program University of Pittsburgh School of Medicine Pittsburgh PA United States Department of Orthopaedic Surgery University of Pittsburgh School of Medicine Pittsburgh PA United States

Purpose: The purpose of this study was to evaluate the efficacy of a web tutorial on perceptions of pain management and usage of opioids after carpal tunnel release surgery (post-CTR). Methods: A web tutorial was developed by the authors, and patients were consented and enrolled if they were over the age of 18 years, could speak and understand English, and were having CTR. Patients were randomized to either view or not view the web tutorial before surgery, and all patients took a 19-question online survey approximately 2 weeks after surgery to assess their views on pain management and their self-reported opioid usage. All patients received standard-of-care instructions for postoperative pain management and were prescribed fifteen 5 mg tablets of oxycodone. Independent sample t tests, Wilcoxon rank sum tests, and chi-square tests were used to evaluate variables of interest. Results: Sixty-seven patients were enrolled, with 17 lost to follow-up;therefore, 50 patients were included in the final study cohort and completed the online survey (n = 25/group). There were no statistically significant differences in age, gender (patient reported gender), race, and opioid use history between the groups, but there was a difference in education level with the group that did not watch the video having proportionally more participants whose highest level of education was postgraduate (36% vs 8%) and high school (24% vs 16%). There were no differences between groups in the perceptions of pain post-CTR based on survey statements, in reported opioid consumption on post-op day 1, or in perceived risk of prolonged opioid use. Conversely, on post-op days 2–6 (8% vs 28%) and 7–14 (0% vs 20%), fewer participants from the group that watched the video reported any opioid usage compared with the group that did not watch the video. Conclusions: Our web tutorial did not notably impact the way patients perceived pain management or opioid risks post-CTR. However, a smaller proportion of the group

关键词： Education Hand surgery Postoperative care

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A spatial genome aligner for resolving chromatin architectures from multiplexed DNA FISH (Jan, 10.1038/s41587-022-01568-9, 2023)

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NATURE BIOTECHNOLOGY 2023年第7期41卷 1027-1027页

作者： Jia, Bojing Blair Jussila, Adam Kern, Colin Zhu, Quan Ren, Bing Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla CA USA Medical Scientist Training Program University of California San Diego La Jolla CA USA Department of Cellular and Molecular Medicine Center for Epigenomics University of California San Diego La Jolla CA USA Ludwig Institute for Cancer Research La Jolla CA USA Institute of Genomic Medicine Moores Cancer Center School of Medicine University of California San Diego La Jolla CA USA

Multiplexed fluorescence in situ hybridization (FISH) is a widely used approach for analyzing three-dimensional genome organization, but it is challenging to derive chromosomal conformations from noisy fluorescence signals, and tracing chromatin is not straightforward. Here we report a spatial genome aligner that parses true chromatin signal from noise by aligning signals to a DNA polymer model. Using genomic distances separating imaged loci, our aligner estimates spatial distances expected to separate loci on a polymer in three-dimensional space. Our aligner then evaluates the physical probability observed signals belonging to these loci are connected, thereby tracing chromatin structures. We demonstrate that this spatial genome aligner can efficiently model chromosome architectures from DNA FISH data across multiple scales and be used to predict chromosome ploidies de novo in interphase cells. Reprocessing of previous whole-genome chromosome tracing data with this method indicates the spatial aggregation of sister chromatids in S/G2 phase cells in asynchronous mouse embryonic stem cells and provides evidence for extranumerary chromosomes that remain tightly paired in postmitotic neurons of the adult mouse cortex.

关键词： Gene regulation Image processing

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Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

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Nucleic Acids Research 2024年第11期52卷 6472-6489页

作者： Marie Gaela, Venus Hsia, Hsuan-Yu Joseph, Nithila A. Tzeng, Wan-Yi Ting, Pin-Chao Shen, Yi-Ling Tsai, Chia-Tsen Boudier, Thomas Chen, Liuh-Yow Molecular and Cell Biology Taiwan International Graduate Program Academia Sinica Graduate Institute of Life Sciences National Defense Medical Center Taipei 11529 Taiwan Institute of Molecular Biology Academia Sinica Taipei 11529 Taiwan Insitute of Molecular and Cellular Biology National Taiwan University Taipei 106319 Taiwan Department and Graduate Institute of Microbiology and Immunology National Defense Medical Center Taipei 11490 Taiwan CENTURI multi-engineering platform Aix-Marseille Université Marseille 13288 France

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers. © The Author(s) 2024.

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Cooperative Gsx2-DNA binding requires DNA bending and a novel Gsx2 homeodomain interface (Jun, gkae522, 2024)

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NUCLEIC ACIDS RESEARCH 2024年第13期52卷 8037-8037页

作者： Webb, Jordan A. Farrow, Edward Cain, Brittany Yuan, Zhenyu Yarawsky, Alexander E. Schoch, Emma Gagliani, Ellen K. Herr, Andrew B. Gebelein, Brian Kovall, Rhett A. Department of Molecular and Cellular Biosciences University of Cincinnati College of Medicine Cincinnati OH 45267 USA. Graduate Program in Molecular and Developmental Biology Cincinnati Children's Hospital Research Foundation Cincinnati OH 45229 USA. Medical-Scientist Training Program University of Cincinnati College of Medicine Cincinnati OH 45229 USA. Division of Developmental Biology Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue MLC 7007 Cincinnati OH 45229 USA. Division of Immunobiology Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229 USA. Department of Medical Education University of Cincinnati College of Medicine Cincinnati OH 45229 USA. Department of Chemistry Xavier University Cincinnati OH 45207 USA. Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH 45229 USA.

The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely 7 bp apart. However, the mechanistic basis for Gsx-DNA binding and cooperativity is poorly understood. Here, we used biochemical, biophysical, structural and modeling approaches to (i) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation, (ii) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions, (iii) solve a high-resolution monomer/DNA structure that reveals that Gsx2 induces a 20° bend in DNA, (iv) identify a Gsx2 protein-protein interface required for cooperative DNA binding and (v) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors.

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Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses

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Small GTPases 2022年第1期13卷 14-47页

作者： Duman, Joseph G. Blanco, Francisco A. Cronkite, Christopher A. Ru, Qin Erikson, Kelly C. Mulherkar, Shalaka Saifullah, Ali Bin Firozi, Karen Tolias, Kimberley F. Department of Neuroscience Baylor College of Medicine Houston TX United States Integrative Molecular and Biomedical Science Graduate Program Baylor College of Medicine Houston TX United States Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX United States Medical Scientist Training Program Baylor College of Medicine Houston TX United States

Synaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system. Among the mechanisms that control Rho-GTPase activity and signalling are cell surface receptors, GEF/GAP complexes that tightly regulate single Rho-GTPase dynamics, GEF/GAP and GEF/GEF functional complexes that coordinate multiple Rho-family GTPase activities, effector positive feedback loops, and mutual antagonism of opposing Rho-GTPase pathways. These complex regulatory mechanisms are employed by the cells of the nervous system in almost every step of development, and prominently figure into the processes of synaptic plasticity that underlie learning and memory. Finally, misregulation of Rho-GTPases plays critical roles in responses to neuronal injury, such as traumatic brain injury and neuropathic pain, and in neurodevelopmental and neurodegenerative disorders, including intellectual disability, autism spectrum disorder, schizophrenia, and Alzheimer’s Disease. Thus, decoding the mechanisms of Rho-GTPase regulation and function at excitatory synapses has great potential for combatting many of the biggest current challenges in mental health. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

关键词： AMPA receptor Cdc42 dendritic spine LTD LTP NMDA receptor Rac1 RhoA

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An innate drive to save a life

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Science (New York, N.Y.) 2025年第6736期387卷 827-828页

作者： William M Sheeran Zoe R Donaldson Department of Molecular Cellular and Developmental Biology University of Colorado Boulder Boulder CO USA. Medical Scientist Training Program University of Colorado School of Medicine Aurora CO USA. Department of Psychology and Neuroscience University of Colorado Boulder Boulder CO USA.

In mice, two brain regions drive the impulse to revive an unconscious companion.

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Invasion and metastasis in cancer:molecular insights and therapeutic targets

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Signal Transduction and Targeted Therapy 2025年第3期10卷 1503-1540页

作者： Yongxing Li Fengshuo Liu Qingjin Cai Lijun Deng Qin Ouyang Xiang H.-F.Zhang Ji Zheng Department of Urology Urologic Surgery CenterXinqiao HospitalThird Military Medical University(Army Medical University)ChongqingChina State Key Laboratory of Trauma and Chemical Poisoning Third Military Medical University(Army Medical University)ChongqingChina Lester and Sue Smith Breast Center Baylor College of MedicineHoustonTXUSA Dan L.Duncan Cancer Center Baylor College of MedicineHoustonTXUSA Department of Molecular and Cellular Biology Baylor College of MedicineHoustonTXUSA McNair Medical Institute Baylor College of MedicineHoustonTXUSA Graduate School of Biomedical Science Cancer and Cell Biology ProgramBaylor College of MedicineHoustonTXUSA Department of Medicinal Chemistry Third Military Medical University(Army Medical University)ChongqingChina

The progression of malignant tumors leads to the development of secondary tumors in various organs,including bones,the brain,liver,and *** metastatic process severely impacts the prognosis of patients,significantly affecting their quality of life and survival *** efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management ***,a comprehensive understanding of the biological foundations of tumor metastasis,identification of pivotal signaling pathways,and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic ***,current research is primarily focused on metastasis within specific cancer types,leaving significant gaps in our understanding of the complex metastatic cascade,organ-specific tropism mechanisms,and the development of targeted *** this study,we examine the sequential processes of tumor metastasis,elucidate the underlying mechanisms driving organ-tropic metastasis,and systematically analyze therapeutic strategies for metastatic tumors,including those tailored to specific organ ***,we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone *** objective is to offer insights that can inform future research and clinical practice in this crucial field.

关键词： secondary tumors invasion metastatic process therapeutic targets molecular insights malignant tumors tumor metastasis metastasis

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A Murine Model with JAK2V617F Expression in Both Hematopoietic Cells and Vascular Endothelial Cells Recapitulates the Key Features of Human Myeloproliferative Neoplasm

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BLOOD 2021年第Sup1期138卷 1467-1467页

作者： Zhang, Haotian Yeware, Amar Lee, Sandy Zhan, Huichun Graduate Program in Molecular & Cellular Biology Stony Brook University Stony Brook NY Stony Brook University Stonybrook NY Graduate Program in Molecular & Cellular Pharmacology Stony Brook University Stony Brook NY Northport VA Medical Center Northport Department of Medicine Stony Brook School of Medicine Stony Brook

Introduction Although murine models have provided unequivocal evidence that the JAK2V617F mutation is able to cause myeloproliferative neoplasms (MPNs), there is significant heterogeneity in disease phenotypes between different murine models and none has been able to recapitulate both the myeloproliferative phenotype and cardiovascular pathology seen in patients with MPNs. In addition, these murine models were mostly followed for less than 3-9 months and how aging affects MPN disease progression has not been studied. Endothelial cells (ECs) are an essential component of the hematopoietic niche, and they have been shown to express the JAK2V617F mutation in patients with MPNs. In this study, we investigated how MPN progresses in the JAK2V617F-bearing vascular niche during aging. Methods JAK2V617F Flip-Flop (FF1) mice (which carry a Cre-inducible human JAK2V617F gene driven by the human JAK2 promoter) were crossed with Tie2-cre mice to express JAK2V617F specifically in all hematopoietic cells (including HSPCs) and vascular ECs (Tie2FF1). Results The Tie2FF1 mice developed essential thrombocythemia to primary myelofibrosisdisease transformation with extramedullary splenic hematopoiesis during 18-month follow up. No evidence of leukemia transformation was observed in the Tie2FF1 mice. (Figure 1) Hematopoietic colony formation assays, flow cytometry analysis, and in vitro culture experiments revealed that there was a loss of both HSPC number and HSPC function in the marrow of old Tie2FF1 mice during aging, mimicking the advanced phases of myelofibrosis. In contrast, the spleen of old Tie2FF1 mice was able to maintain the expansion of JAK2V617F mutant hematopoiesis during aging and MPN disease progression. (Figure 2) These differences between marrow and spleen hematopoiesis in the old Tie2FF1 mice prompted us to investigate how aging affects the JAK2V617F mutant hematopoiesis differently in the marrow and spleen. We found that, although the JAK2V617F mutant HSCs (Lin - cKi

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Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II

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Kaohsiung Journal of medical Sciences 2023年第7期39卷 718-731页

作者： Chin, Hsien-Kuo Lu, Mei-Chin Hsu, Kai-Cheng El-Shazly, Mohamed Tsai, Tsen-Ni Lin, Tzu-Yung Shih, Shou-Ping Lin, Tony Eight Wen, Zhi-Hong Yang, Yu-Chen S. H. Liu, Yi-Chang Department of Marine Biotechnology and Resources National Sun Yat-Sen University Kaohsiung Taiwan Division of Cardiovascular Surgery Department of Surgery Kaohsiung Armed Forces General Hospital Kaohsiung Taiwan Graduate Institute of Marine Biology National Dong Hwa University Hualien Taiwan National Museum of Marine Biology and Aquarium Pingtung Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Master Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan TMU Research Center of Drug Discovery Taipei Medical University Taipei Taiwan Department of Pharmacognosy Faculty of Pharmacy Ain-Shams University Cairo Egypt Division of Hematology-Oncology Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Taiwan Department and Graduate Institute of Aquaculture National Kaohsiung University of Science and Technology Kaohsiung Taiwan Doctoral Degree Program in Marine Biotechnology National Sun Yat-Sen University Kaohsiung Taiwan Doctoral Degree Program in Marine Biotechnology Academia Sinica Taipei Taiwan Joint Biobank Office of Human Research Taipei Medical University Taipei Taiwan Department of Internal Medicine Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Cellular Therapy and Research Center Kaohsiung Medical University Hospital Kaohsiung Taiwan

13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation. © 2023 The Authors. The Kaohsiung Journal of medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung medical University.

关键词： 13-Acetoxysarcocrassolide heat shock protein 90 leukemia oxidative stress topoisomerase II

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