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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Sex differences in aging and injured brain

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Neural Regeneration Research 2025年第10期20卷 2901-2902页

作者： Jordan N.Williamson Yuan Yang University of illinois Urbana-Champaign Grainger College of EngineeringDepartment of BioengineeringUrbanaILUSA Carle Foundation Hospital Stephenson Family Clinical Research InstituteClinical Imaging Research CenterUrbanaILUSA University of illinois Urbana-Champaign Beckman Institute for Advanced Science and TechnologyUrbanaILUSA Northwestern University Department of Physical Therapy and Human Movement SciencesChicagoILUSA

Background:The prevalence,age of onset,and symptomatology of traumatic brain injury,stroke,and neurodegenerative diseases(such as Alzheimer’s disease(AD),Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease)differ substantially between males and *** higher prevalence of these brain disorders has been attributed to females having a greater longevity compared with *** one of the greatest risk factors of acquired brain injury(such as stroke,traumatic brain injury caused by fall)and neurodegenerative disease is age.

关键词： Huntington prevalence traumatic

Nano-enabled cellular engineering for bioelectric studies

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Nano Research 2020年第5期13卷 1214-1227页

作者： Jiuyun Shi Clementene Clayton Bozhi Tian Department of Chemistry University of ChicagoChicagoIL 60637USA The James Franck Institute University of ChicagoChicagoIL 60637USA The Institute for Biophysical Dynamics University of ChicagoChicagoIL 60637USA

Engineered cells have opened up a new avenue for scientists and engineers to achieve specialized biological ***,such as silicon nanowires and quantum dots,can establish tight interfaces with cells either extra-or intracellularly,and they have already been widely used to control cellular *** future exploration of nanomaterials in cellular engineering may reveal numerous opportunities in both fundamental bioelectric studies and clinic *** this review,we highlight several nanomaterials-enabled non-genetic approaches to fabricating engineered ***,we briefly review the latest progress in engineered or synthetic cells,such as protocells that create cell-like behaviors from nonliving building blocks,and cells made by genetic or chemical ***,we illustrate the need for non-genetic cellular engineering with semiconductors and present some examples where chemical synthesis yields complex morphology or functions needed for *** then provide discussions in detail about the semiconductor nanostructure-enabled neural,cardiac,and microbial *** also suggest the need to integrate tissue engineering with semiconductor devices to carry out more complex *** end this review by providing our perspectives for future development in non-genetic cellular engineering.

关键词： cellular engineering nano-bio interface biological modulation tissue engineering

The pursuit of transplantation tolerance:new mechanistic insights

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Cellular & Molecular Immunology 2019年第4期16卷 324-333页

作者： Pawan K.Gupta Christine M.McIntosh Anita S.Chong Maria-Luisa Alegre Department of Medicine The University of ChicagoChicagoIL 60637USA Department of Surgery The University of ChicagoChicagoIL 60637USA

Donor-specific transplantation tolerance that enables weaning from immunosuppressive drugs but retains immune competence to non-graft antigens has been a lasting pursuit since the discovery of neonatal *** recently,efforts have been devoted not only to understanding how transplantation tolerance can be induced but also the mechanisms necessary to maintain it as well as how inflammatory exposure challenges its *** review focuses on recent advances regarding key peripheral mechanisms of T cell tolerance,with the underlying hypothesis that a combination of several of these mechanisms may afford a more robust and durable tolerance and that a better understanding of these individual pathways may permit longitudinal tracking of tolerance following clinical transplantation to serve as *** review may enable a personalized assessment of the degree of tolerance in individual patients and the opportunity to strengthen the robustness of peripheral tolerance.

关键词： tolerance TCR avidity Treg T cell dysfunction

The Promise of Pharmacogenomics in ReducingToxicity During Acute Lymphoblastic LeukemiaMaintenance Treatment

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Genomics, Proteomics & Bioinformatics 2017年第2期15卷 82-93页

作者： Shoshana Rudin Marcus Marable R. Stephanie Huang Biological Sciences Division University of Chicago Chicago IL 60637 USA Department of Medicine University of Chicago Chicago IL 60637 USA

Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

关键词： Acute lymphoblastic leukemia 6-Mercaptopurine Methotrexate Pharmacogenomics Maintenance therapy

Solar Activity and Classical Physics

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Chinese Journal of Astronomy and Astrophysics 2001年第2期1卷 99-124页

作者： E. N. Parker (Department of Physics, University of Chicago, Chicago, il 60637) Department of Physics University of Chicago Chicago IL 60637

This review of solar physics emphasizes several of the more conspicuous scientific puzzles posed by contemporary observational knowledge of the magnetic activity of the Sun. The puzzles emphasize how much classical physics we have yet to learn from the Sun. The physics of solar activity is based on the principles of Newton, Maxwell, Lorentz, Boltzmann, et. al., along with the principles of radiative transfer. In the large, these principles are expressed by magnetohydro dynamics. A brief derivation of the magnetohydrodynamic induction and moment um equations is provided, with a discussion of popular misconceptions.

关键词： Sun: activety - Magnetohydro dynamics - radiative transfer

Separation and Determination of Methylnaltrexone in Human Plasma Samples After Oral Administration by HPLC Coupled with Electrochemical Detection

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Chemical Research in Chinese Universities 2005年第3期21卷 268-273页

作者： WANGAn-bao JosephF.Foss YUANChun-su JoachimOsinski DepartmentofAnesthesiaandCriticalCare TheUniversityofChicagoChicagoIL60637USA DepartmentofAnesthesiaandCriticalCare TheUniversityofChicagoChicagoIL60637USA／／ShanghaiInstituteofCeramicsChineseAcademyofSciencesShanghai200050P.R.China

A high performance liquid chromatography(HPLC) method coupled with electrochemical detection and solid phase extraction is described for the separation and determination of methylnaltrexone(MNTX), a quaternary opioid antagonist, in human clinical plasma samples after oral administration. Linearity of the standard curve for MNTX was found in the range of 4.0_150 ng/mL and was statistically conformed. The correlation coefficient(r2) and calibration equation obtained from linear regression analysis are 0.9999 and Y=54.27X-0.22, where Y and X represent the peak area and concentration of MNTX, respectively. The detection limit of MNTX under the present experimental conditions is 2.0 ng/mL by estimating at a ratio of 3 of signal to noise. The mean recovery of MNTX in human plasma is higher than 97%. The analytical method was applied to the pharmacokinetic determination of MNTX after single dose oral administration. These data demonstrate that the change of MNTX plasma concentration versus time is obvious. MNTX level of plasma reaches to a plateau between 45 to 120 minutes and then falls slowly. The content of MNTX in plasma sample maintains at an obviously detectable level after twelve hours of oral administration. The pharmacokinetic parameters for a single dose of 19.2 mg/kg in plasma are c_~max =206.42(±16.53) ng/mL and t_~max =60 min.

关键词： Liquid chromatography Electrochemical detection Methylnaltrexone Pharmaceutical Serum Biological analysis

TNF-α Induces Transient Resistance to Fas-Induced Apoptosis in Eosinophilic Acute Myeloid Leukemia Cells

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Cellular & Molecular Immunology 2007年第1期4卷 43-52页

作者： Yimin Qin Sogyong Auh Lyubov Blokh Catherine Long Isabelle Gagnon Kimm J. Hamann Pulmonary ＆ Critical care medicine Department of Medicine Universityof Chicago Chicago IL 60637 USA Department of Pathology University of Chicago Chicago IL 60637 USA

Tumor necrosis factor α （TNF-α） has been recognized as an activator of nuclear factor kB （NF-kB）, a factor implicated in the protection of many cell types from apoptosis. We and others have presented evidence to suggest that Fas-induced apoptosis may be an important aspect of the resolution of inflammation, and that delayed resolution of inflammation may be directly associated with NF-kB-dependent resistance to Fas. Because TNF-α activates NF-kB in many cell types including inflammatory cells such as eosinophils, we examined effects of TNF-α signaling on the Fas-mediated killing of an eosinophilic cell line AML14. While agonist anti-Fas （CHII） treatment induced apoptosis in AML14 cells, no significant cell death occurred in response to TNF-α alone. Electrophoretic mobility shift assay （EMSA） revealed that TNF-α induced NF-kB transactivation in AMLI4 cells in a time- and dose-dependent fashion, and subsequent supershift assays indicated that the translocated NF-kB was the heterodimer p65 （RelA）/p50. Pre-treatment of cells with TNF-α dramatically decreased the CHll-induced cell death in a transient fashion, accompanied by suppression of activation of caspase-8 and caspase-3 activation. Inhibition of NF-kB transactivation by inhibitors, BAY 11-7085 and parthenolide, reversed the suppression of Fas-mediated apoptosis by TNF-α. Furthermore, TNF-α up-regulated X-linked inhibitor of apoptosis protein （XIAP） transiently and XIAP levels were correlated with the temporal pattern of TNF-α protection against Fas-mediated apoptosis. This finding suggested that TNF-α may contribute to the prolonged survival of inflammatory cells by suppression of Fas-mediated apoptosis, the process involved with NF-kB transactivation, anti-apoptotic XIAP up-regulation and caspase suppression. Cellular ＆ Molecular Immunology. 2007;4（1）：43-52.

关键词： TNF-α NF-kB transactivation apoptosis XIAP inflammatory cell resolution

Vibrationally resolved optical excitations of the nitrogen-vacancy center in diamond

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npj Computational Materials 2022年第1期8卷 2258-2266页

作者： Yu Jin Marco Govoni Giulia Galli Department of Chemistry University of ChicagoChicagoIL60637USA Pritzker School of Molecular Engineering University of ChicagoChicagoIL60637USA Materials Science Division and Center for Molecular Engineering Argonne National LaboratoryLemontIL60439USA

A comprehensive description of the optical cycle of spin defects in solids requires the understanding of the electronic and atomistic structure of states with different spin multiplicity,including singlet states which are particularly challenging from a theoretical *** present a general framework,based on spin-flip time-dependent density function theory,to determine the excited state potential energy surfaces of the many-body singlet states of spin defects;we then predict the vibrationally resolved absorption spectrum between singlet shelving states of a prototypical defect,the nitrogen-vacancy center in *** results,which are in very good agreement with experiments,provide an interpretation of the measured spectra and reveal the key role of specific phonons in determining absorption processes,and the notable influence of non-adiabatic *** insights gained from our calculations may be useful in defining strategies to improve infrared-absorption-based magnetometry and optical pumping *** theoretical framework developed here is general and applicable to a variety of other spin defects and materials.

关键词： vacancy resolved singlet