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Better together? Treating traumatic brain injury with minocycline plus n-acetylcysteine

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neural Regeneration Research 2022年第12期17卷 2589-2592页

作者： Siobhán Lawless peter j.Bergold Graduate Program in neural and Behavioral Sciences State University of New York-Downstate Health Sciences UniversityBrooklynNYUSA Department of Physiology and Pharmacology State University of New York-Downstate Health Sciences UniversityBrooklynNYUSA

Traumatic brain injury has a complex pathophysiology that produces both rapid and delayed brain damage. Rapid damage initiates immediately after injury. Treatment of traumatic brain injury is typically delayed many hours, thus only delayed damage can be targeted with drugs. Delayed traumatic brain injury includes neuroinflammation, oxidative damage, apoptosis, and glutamate toxicity. Both the speed and complexity of traumatic brain injury pathophysiology present large obstacles to drug development. Repurposing of Food and Drug Administration-approved drugs may be a highly efficient approach to get therapeutics to the clinic. This review examines the preclinical outcomes of minocycline and n-acetylcysteine as individual drugs and compares them to the minocycline plus n-acetylcysteine combination. Both minocycline and n-acetylcysteine are Food and Drug Administration-approved drugs with pleiotropic therapeutic effects. As individual drugs, minocycline and n-acetylcysteine are well tolerated, with known pharmacokinetics, and enter the brain through an intact blood-brain barrier. At concentrations greater than needed for antimicrobial action, minocycline is a potent anti-inflammatory minocycline, also acts as an antioxidant and inhibits multiple enzymes that promote brain injury including metalloproteases, caspases, and polyADP-ribose-polymerase-1. n-acetylcysteine alone is also an antioxidant. It increases brain glutathione, prevents lipid oxidation, and protects mitochondria. n-acetylcysteine also acts as an anti-inflammatory as well as increases extracellular glutamate by activating the X;cystine-glutamate antitransporter. These multiple actions of minocycline and n-acetylcysteine have made them attractive candidates to treat traumatic brain injury. When first dosed within the one hour after injury, either minocycline or n-acetylcysteine improves a diverse set of therapeutic outcome measures in multiple traumatic brain injury animal models. A small number of clinical

关键词： clinical trial outcome measures preclinical testing rodent models of traumatic brain injury therapeutic time window

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

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Asian journal of Andrology 2012年第5期14卷 676-682页

作者： peter j Stahl Anna n Mielnik Christopher E Barbieri peter n Schlegel Darius A Paduch Department of Urology Weill Cornell Medical CollegeNew York Presbyterian HospitaI-CornellNew YorkNY 10065USA

Maturation arrest （MA） refers to failure of germ cell development leading to clinical nonobstructive azoospermia. Although the azoospermic factor （AZF） region of the human Y chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. We sought to identify single genes on the Y chromosome that may be implicated in the pathogenesis of nonobstructive azoospermia associated with MA in the American population. Genotype-phenotype analysis of 132 men with Y-chromosome microdeletions was performed. Protein-coding genes associated with MA were identified by visual analysis of a genotype-phenotype map. Genes associated with MA were selected as those genes within a segment of the Y chromosome that, when completely or partially deleted, were always associated with MA and absence of retrievable testicular sperm. Expression of each identified gene transcript was then measured with quantitative RT-PCR in testicular tissue from separate cohorts of patients with idiopathic MA and obstructive azoospermia. Ten candidate genes for association with MA were identified within an 8.4-Mb segment of the Y chromosome overlapping the AZFb region. CDY2and HSFYwere the only identified genes for which differences in expression were observed between the MA and obstructive azoospermia cohorts. Men with obstructive azoospermia had 12-fold higher relative expression of CDY2transcript （1.33__.0.40 vs. 0.11＋_0.04; P=O.O003） and 16-fold higher expression of HSFYtranscript （0.78__.0.32 vs. 0.05_0.02; P=O.O005） compared to men with MA. CDY2 and HSFYwere also underexpressed in patients with Sertoli cell only syndrome. These data indicate that CDY2and HSFYare located within a segment of the Y chromosome that is important for sperm maturation, and are underexpressed in testicular tissue derived from men with MA. These observations suggest that impairments in CDY2 or HSFYexpression could be impli

关键词： CDY1 protein CDY2 protein genetics histology HSFY human make infertility nonobstructive azoospermia spermato-genesis sperm maturation

Science Letters:A novel way of liver preservation improves rat liver viability upon reperfusion

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journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2007年第5期8卷 289-295页

作者： KEBIS Anton KUKAn Marián GRAnI peter jAKUBOVSK■ ján Laboratory of Perfused Organs Slovak Center for Organ TransplantationSlovak Medical UniversityLimbová 1283303 BratislavaSlovakia Department of Pathology School of MedicineComenius University81372 BratislavaSlovakia

Background/aim： Currently, the liver is cold-preserved at 0-4 ℃ for experimental and clinical purposes. Here, we investigated whether milder hypothermia during the initial phase of the preservation period was beneficial for liver viability upon reperfusion. Methods： In the first set of experiments, rat livers were preserved either conventionally in clinically used histidine-trypthopan-ketoglutarate （HTK） solution （Group A： 45 min and Group B： 24 h） or by slow cooling HTK solution （from 13 ℃ to 3 ℃） during the initial 45 min of preservation （Group C： 24 h）. In the second set of experiments, additional groups of livers were evaluated： Group BB-preservation according to Group B and Group CC-preservation according to Group C. Further, some livers were preserved at 13 ℃ for 24 h. Livers were then reperfused using a blood-free perfusion model. Results： Bile production was approximately 2-fold greater in Group C compared to Group B. Alanine transaminase （ALT） and aspartate transaminase （AST） release into perfusate were 2-3-fold higher in Group B compared to Group C. no significant differences were found in ALT and AST release between Group C and Group A. Livers in Group CC compared to Group BB exhibited significantly lower portal resistance, greater oxygen consumption and bromosulfophthalein excretion into bile and lower lactate dehydrogenase （LDH） release into perfusate. Histological evaluation of tissue sections in Group BB showed parenchymal dystrophy of hepatocytes, while dystrophy ofhepatocytes was absent in Group CC. Livers preserved at 13 ℃ for 24 h exhibited severe ischemic injury Conclusion： These results suggest that the conventional way of liver preservation is not suitable at least for rat livers and that slow cooling of HTK solution during the initial phase of cold storage can improve liver viability during reperfusion.

关键词： Rat Hepatic graft Cold ischemia Liver protection Histidine-trypthopan-ketoglutarate solution (HTK)

Microdissection testicular sperm extraction： an update

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Asian journal of Andrology 2013年第1期15卷 35-39页

作者： Ali A Dabaja peter n Schlegel Department of Urology Male Reproductive Medicine Weill Cornell Medical College New York NY 10065 USA

Patients with non-obstructive azoospermia （nOA） were once considered to be infertile with few treatment options due to the absence of sperm in the ejaculate. In the last two decades, the advent of intracytoplasmic sperm injection （ICSI）, and the application of various testicular sperm retrieval techniques, including fine needle aspiration （FnA）, conventional testicular sperm extraction （TESE） and microdissection testicular sperm extraction （micro-TESE） have revolutionized treatment in this group of men. Because most men with nOA will have isolated regions of spermatogenesis within the testis, studies have illustrated that sperm can be retrieved in most men with nOA, including Klinefelter＇s syndrome （KS）, prior history of chemotherapy and cryptorchidism. Micro-TESE, when compared with conventional TESE has a higher sperm retrieval rate （SRR） with fewer postoperative complications and negative effects on testicular function. In this article, we will compare the efficacy of the different procedures of sperm extraction, discuss the medical treatment and the role of testosterone optimization in men with nOA and describe the micro-TESE surgical technique. Furthermore, we will update our overall experience to allow counseling on the prognosis of sperm retrieval for the specific subsets of nOA.

关键词： azoospermia genetics male infertility microsurgery non-obstructive azoospermia sperm retrieval testicular sperm extraction

From first fibers to mode-division multiplexing(Invited Paper)

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Chinese Optics Letters 2016年第12期14卷 2-6页

作者： peter j.Winzer nokia Bell Labs Holmdel NJ 07733 USA

This Review focuses on optical transmission fibers and the high-capacity systems operating thereon. It attempts to combine key lessons learned from the 50-year history of low-loss optical fibers with views on future fiber and systems requirements, discussing likely evolution paths and potential pitfalls in resolving the optical network capacity crunch.

关键词： multiplexing crosstalk likely resolving combine installed learned today coherent deployment

The n-formyl peptide receptors: contemporary roles in neuronal function and dysfunction

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neural Regeneration Research 2020年第7期15卷 1191-1198页

作者： peter j.G. Cussell Margarita Gomez Escalada nathaniel G.n. Milton Andrew W.j. Paterson Centre for Biomedical Science Research School of Clinical and Applied Sciences Leeds Beckett University

n-formyl peptide receptors(FPRs)were first identified upon phagocytic leukocytes,but more than four decades of research has unearthed a plethora of non-myeloid roles for this receptor *** are expressed within neuronal tissues and markedly in the central nervous system,where FPR interactions with endogenous ligands have been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease,as well as neurological cancers such as *** the homeostatic function of FPRs in the nervous system is currently undefined,a variety of novel physiological roles for this receptor family in the neuronal context have been posited in both human and animal *** developments in recent years have implicated FPRs in the process of neurogenesis and neuronal differentiation which,upon greater characterisation,could represent a novel pharmacological target for neuronal regeneration therapies that may be used in the treatment of brain/spinal cord injury,stroke and *** review aims to summarize the recent progress made to determine the physiological role of FPRs in a neuronal setting,and to put forward a case for FPRs as a novel pharmacological target for conditions of the nervous system,and for their potential to open the door to novel neuronal regeneration therapies.

关键词： Alzheimer's disease formyl peptide receptor neural regeneration neuroblastoma neurodegeneration neuroinflammation neuronal differentiation stroke

Small extrachromosomal circular DnA in amyotrophic lateral sclerosis matter

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neural Regeneration Research 2025年第5期20卷 1411-1413页

作者： Marcos j.Arauzo-Bravo Daniela Gerovska Matthias Schwab Alexandra Kretz Computational Biology and Systems Biomedicine Biodonostia Health Research InstituteSan SebastianSpain Basque Foundation for Science IKERBASQUEBilbaoSpainMax Planck Institute for Molecular BiomedicineComputational Biology and Bioinformatics GroupMünsterNorth Rhine-WestphaliaGermany Department of Cell Biology and Histology Faculty of Medicine and NursingUniversity of Basque Country(UPV/EHU)LeioaSpain Department of neurology Jena University HospitalJenaThuringiaGermany

Comprehensive studies identify motor neuron spectrum disorders including amyotrophic lateral sclerosis(ALS)as globally rising fatal disorders with the highest prevalence in aging populations,influenced by ethnicity and ancestry(GBD 2016 Motor neuron Disease Colla borators,2018).While~10% of diagnoses involve a family history(fALS),most cases are considered sporadic(sALS).However,population-based studies suggest that even cases without a common index mutation impart heritability(Ryan et al.,2019),indicating a crucial role of rare and as yet unknown genetic denominators.

关键词： amyotrophic sclerosis

Mass Transport in nanowire Synthesis:An Overview of Scalable nanomanufacturing

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journal of Materials Science & Technology 2015年第6期31卷 523-532页

作者： Matthew j.Crane peter j.Pauzauskie Department of Chemical Engineering University of WashingtonSeattleWA 98195-1750.USA Department of Materials Science & Engineering Seattle.WA 98195-2120USA Fundamental Computational Science Directorate Pacific Northwest National LaboratoryRichland.WAUSA

The ability to rationally engineer the growth and nanomanufacturing of one-dimensional nanowires in high volumes has the potential to enable applications of nanoscale materials in a diverse range of fields including energy conversion and storage,catalysis,sensing,medicine,and information *** review provides a roadmap for the development of large-scale nanowire *** myriad techniques exist for bench-scale nanowire synthesis,these growth strategies typically fall within two major categories:1) anisotropically-catalyzed growth and 2) confined,template-based ***,comparisons between growth methods with different mass transport pathways have led to confusion in interpreting observations,in particular Gibbs-Thomson *** review mass transport in nanowire synthesis techniques to unify growth models and to allow for direct comparison of observations across different *** addition,we discuss the applicability of nanoscale,Gibbs-Thomson effects on mass transport and provide guidelines for the development of new growth *** explore the scalability of these complex processes with dimensionless numbers and consider the effects of pressure,temperature,and precursor material on nanowire growth.

关键词： nanowire Mass transport Modeling Scalable growth

Duality for cochain DG algebras

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Science China Mathematics 2013年第1期56卷 79-89页

作者： jφRGEnSEn peter School of Mathematics and Statistics Newcastle University

This paper develops a duality theory for connected cochain DG algebras,with particular emphasis on the non-commutative *** of the main items is a dualizing DG module which induces a duality between the derived categories of DG left-modules and DG right-modules with finitely generated *** an application,it is proved that if the canonical module k=A/A≥1 has a semi-free resolution where the cohomological degree of the generators is bounded above,then the same is true for each DG module with finitely generated cohomology.

关键词： balanced dualizing complex Castelnuovo-Mumford regularity Cech DG module derived comple-tion derived torsion DG left-module DG right-module dualizing DG module endomorphism DG algebra Extregularity non-commutative DG algebra