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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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ADAM10 facilitates rapid neural stem cell cycling and proper positioning within the subventricular zone niche via JAMC/RAP1Gap signaling

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Neural Regeneration Research 2022年第11期17卷 2472-2483页

作者： Nadia McMillan Gregory W.Kirschen Sanket Desai Emma Xia Stella E.Tsirka Adan Aguirre Program in Neuroscience and Medical Scientist Training Program Renaissance School of Medicine at Stony Brook UniversityStony BrookNYUSA Department of Pharmacological Sciences Renaissance School of Medicine at Stony Brook UniversityStony BrookNYUSA Department of Neurology Beth Israel Deaconess Medical Center/Harvard Medical SchoolBostonMAUSA Department of Gynecology and Obstetrics Johns Hopkins HospitalBaltimoreMDUSA

The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well *** NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular ***,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell *** of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP *** molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage *** the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.

关键词： ADAM10 adhesion junctional adhesion molecule C neural stem cells neurogenesis olfactory bulb Rap1Gap sub-ventricular zone

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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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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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Visualizing drug actions on dendrites: psilocybin and other classic psychedelics

Visualizing drug actions on dendrites: psilocybin and other ...

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Optics and the Brain, BRAIN 2023 - Part of Optica Biophotonics Congress: Optics in the Life Sciences 2023

作者： Shao, Ling-Xiao Liao, Clara Gregg, Ian Davoudian, Pasha A. Savalia, Neil K. Delagarza, Kristina Kwan, Alex C. Department of Psychiatry Yale University School of Medicine New HavenCT06511 United States Interdepartmental Neuroscience Program Yale University School of Medicine New HavenCT06511 United States Medical Scientist Training Program Yale University School of Medicine New HavenCT06511 United States Department of Neuroscience Yale University School of Medicine New HavenCT06511 United States Meinig School of Biomedical Engineering Cornell University IthacaNY14853 United States

To determine effects of psychedelics on neuronal architecture, we used two-photon microscopy to image dendritic spines in mouse frontal cortex after administering psilocybin (Neuron, 109, 2535, 2021) and compared with... 详细信息

ISBN: (纸本)9781957171210

关键词： Green fluorescent protein High speed photography Multiphoton microscopy Strain

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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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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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Targeted tumor coating with antigenic, CTL-recognizable peptides via Annexin A5 chimeric constructs following chemotherapy redirects adaptive CD8+ T cell immunity for tumor clearance

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Cellular & Molecular Immunology 2021年第6期18卷 1578-1580页

作者： Tae Heung Kang Andrew Yang Yachea Tsai Louise Ferrall Chien-Fu Hung Institute of Biomedical Science and Technology Konkuk UniversitySeoulSouth Korea Genetics and Genomics Graduate Program Baylor College of MedicineHoustonTXUSA Medical Scientist Training Program Baylor College of MedicineHoustonTXUSA Department of Pathology Johns Hopkins UniversityBaltimoreMDUSA Department of Oncology Johns Hopkins UniversityBaltimoreMDUSA

A common drawback of many cancer immunotherapies,including immune checkpoint blockade,is their reliance on the expression of immunogenic tumor antigens by cancer cells for immune recognition and clearance,which limits their efficacy against cancers with weak antigenicity.1 To overcome this obstacle,we and others have explored strategies to harness the immune responses against nontumor antigens and redirect those immune responses to target tumor cells.2,3,4,5 In particular,we have pioneered a therapeutic strategy fusing tumor-targeting proteins with known antigenic peptide epitopes not naturally expressed by tumor cells,which are flanked by peptide sequences that can be recognized and cleaved by proteases overexpressed in most cancers.2,3 This strategy facilitates the targeted delivery of immunogenic peptides into tumor foci,the release of immunogenic peptides into the tumor microenvironment(TME)via tumor protease cleavage,and subsequent loading of these peptides onto major histocompatibility complex class 1(MHC-I)on the tumor cell surface,allowing the recognition of coated tumor cells by the respective peptide-specific cytotoxic CD8+T lymphocytes(CTLs)for elimination.

关键词： immunity overcome coating

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Epigenetic Control of an Auxiliary Subunit of Voltage-Gated Sodium Channels Regulates the Strength of Drug-Cue Associations and Relapse-Like Cocaine Seeking

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Biological Psychiatry 2025年

作者： Wood, Daniel J. Tsvetkov, Evgeny Comte-Walters, Susana Welsh, Colin L. Bloyd, Michelle Wood, Timothy G. Akiki, Rose Marie Anderson, Ethan M. Penrod, Rachel D. Madan, Lalima K. Ball, Lauren E. Taniguchi, Makoto Cowan, Christopher W. Department of Neuroscience Medical University of South Carolina Charleston South Carolina United States Medical Scientist Training Program Medical University of South Carolina Charleston South Carolina United States Department of Pharmacology and Immunology Medical University of South Carolina Charleston South Carolina United States

Background: Repeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear. Methods: We used a combination of molecular biology, cultured cells, tandem mass spectrometry, deacetylase activity measurements, co-immunoprecipitation, and molecular dynamics simulations to assess HDAC5 structure-activity relationships. In male and female Long Evans rats, we used viral-mediated expression of HDAC5 mutants in the nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative reverse transcriptase–polymerase chain reaction, viral-mediated expression of Scn4b short hairpin RNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking. Results: We discovered that 2 conserved cysteines located near HDAC5’s catalytic domain were required for its intrinsic deacetylase activity and that HDAC5’s deacetylase activity was required in NAc medium spiny neurons (MSNs) to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine-seeking, but not sucrose-seeking, behavior by reducing NAc MSN intrinsic excitability through the deacetylase-dependent repression of Scn4b, which codes for an auxiliary subunit of voltage-gated sodium channels. Conclusions: Our findings suggest that HDAC5’s control of NAc Scn4b expression governs the formation of cocaine-cue, but not sucrose-cue, associations through modulation of NAc MSN intrinsic excitability and drug-induced NAc plasticity mechanisms. © 2025 Society of Biological Psychiatry

关键词： Epigenetics Neuronal excitability Nucleus accumbens Reinstatement behavior Substance use disorder

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