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Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer＇s disease

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Neural Regeneration Research 2018年第6期13卷 1066-1080页

作者： Sara H.Mokhtar Min Joung Kim Kylie A.Magee Pei Mun Aui Speros Thomas Maha M.Bakhuraysah Amani A.Alrehaili Jae Young lee david l.steer Rachel Kenny Catriona Mc lean Michael F.Azari Antonis Birpanagos Ewlina lipiec Philip Heraud Bayden Wood Steven Petratos Department of Neuroscience Central Clinical School Monash University Prahran Victoria Australia Department of Biochemistry and Molecular Biology Monash Universityl Clayton Victoria Australia Department of Anatomy & Developmental Biology Monash University Clayton Victoria Australia Department of Anatomical Pathology Alfred Hospital Prahran Victoria Australia School of Health and Biomedical Sciences RMIT University Bundoora Victoria Australia Division of Animal and Human Physiology Department of Biology National and Kapodistrian University of Athens Ilisia Athens Greece The Henryk Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences Department of Applied Spectroscopy RadzikowskiegoKrakow Poland Centre for Biospectroscopy and Department of Microbiology Monash University Clayton Victoria Australia

Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary *** to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is ***,the key proteins that initiate these intracellular impairments remain *** collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases ***,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in *** found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 ***,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic *** SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with *** overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon *** data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.

关键词： amyloid-beta protein kinases collapsin response mediator protein microtubules kinesin tubulin

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Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick Heimel Markus Kerbl lászlóGál Sylvia Nürnberger Barbara Schaedl James Ferguson Nicole Swiadek Xavier Monforte Johannes C.Heinzel Antal Nógrádi Andreas H.Teuschl-Woller david Hercher Department life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk-based nerve guidance conduit vascularization

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph david Gimbel Jonathan Grossberg Daniel l.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Co-localization hypothesis:A mechanism for the intrapancreatic activation of digestive enzymes during the early phases of acute pancreatitis

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World Journal of Gastroenterology 2006年第13期12卷 1985-1990页

作者： Gijs JD van Acker George Perides Michael l.steer Department of Surgery and the Boston Pancreas Group Tufts-New England Medical Center 860 Washington StreetBostonMA 02111United States

Acute pancreatitis is generally believed to be a disease in which the pancreas is injured by digestive enzymes that it normally produces. Most of the potentially harmful digestive enzymes produced by pancreatic acinar cells are synthesized and secreted as inactive zymogens which are normally activated only upon entry into the duodenum but, during the early stages of acute pancreatitis, those zymogens become prematurely activated within the pancreas and, presumably, that activation occurs within pancreatic acinar cells. The mechanisms responsible for intracellular activation of digestive enzyme zymogens have not been elucidated with certainty but, according to one widely recognized theory （the ＂co-localization hypothesis＂）, digestive enzyme zymogens are activated by lysosomal hydrolases when the two types of enzymes become co-localized within the same intracellular compartment. This review focuses on the evidence supporting the validity of the m-localization hypothesis as an explanation for digestive enzyme activation during the early stages of pancreatitis. The findings, summarized in this review, support the conclusion that co-localization of lysosomal hydrolases with digestive enzyme zymogens plays a critical role in permitting the intracellular activation of digestive enzymes that leads to acinar cell injury and pancreatitis.

关键词： Acute pancreatitis Digestive enzymes Pancreatic acinar cells

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TOPOlOGY AND CASCADING lINE OUTAGES IN POWER GRIDS

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Journal of Systems Science and Systems Engineering 2007年第2期16卷 202-221页

作者： david l. PEPYNE University of Massachusetts Amherst MA USA

Motivated by the small world network research of Watts ＆ Strogatz, this paper studies relationships between topology and cascading line outages in electric power grids. Cascading line outages are a type of cascading collapse that can occur in power grids when the transmission network is congested. It is characterized by a self-sustaining sequence of line outages followed by grid breakup, which generally leads to widespread blackout. The main findings of this work are twofold： On one hand, the work suggests that topologies with more disorder in their interconnection topology tend to be robust with respect to cascading line outages in the sense of being able to support greater generation and demand levels than more regularly interconnected topologies. On the other hand, the work suggests that topologies with more disorder tend to be more fragile in that should a cascade get started, they tend to break apart after fewer outages than more regularly interconnected topologies. Thus, as has been observed in other complex networks, there appears to be a tradeoff between robustness and fragility. These results were established using synthetically generated power grid topologies and verified using the IEEE 57 bus and 188 bus power grid test cases.

关键词： Power grid blackout cascading line failure complex networks robust yet fragile

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OPTIMAl INVERSE lQG CONTROl FOR CERTAIN ODE AND PDE STATIONARY PROCESSES

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Journal of Systems Science & Complexity 2010年第3期23卷 584-599页

作者： david l.RUSSEll Department of Mathematics Virginia Tech

Following work carried out earlier on linear-quadratic optimal control for linear finitedimensional stationary systems we report,in this article,on extension of some of those results to certaininfinite dimensional systems;in particular a class of PDE systems of elliptic *** systems arestudied in the now familiar framework developed by *** and ***,specialized to asubclass of such systems important in a variety of *** an extended example this paperstudies an optimal redistribution problem in a groundwater flow system governed by Darcy's equation,presenting both analytic and computational work related to such problems.

关键词： Elliptic PDE linear feedback control stationary system.

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Dislocation Creep Accommodated by Grain Boundary Sliding in Dunite

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Journal of Earth Science 2010年第5期21卷 541-554页

作者： Yonghong Zhao david l Kohlstedt School of Earth and Space Sciences Peking University Department of Geology and Geophysics University of Minnesota

To investigate the role of grain boundary sliding during dislocation creep of dunite, a series of deformation experiments were carried out under anhydrous conditions on fine-grained （-15 μm） samples synthesized from powdered San Carlos olivine and powdered San Carlos olivine＋1.5 vol.% MORB. Triaxial compressive creep tests were conducted at a temperature of 1 473 K and confining pressures of 200 and 400 MPa using a high-resolution, gas-medium deformation apparatus. Each sample was deformed at several levels of differential stress between 100 and 250 MPa to yield strain rates in the range of 10^-6 to 10^-4 s^-1. Under these conditions, the dominant creep mechanism involves the motion of dislocations, largely on the easy slip system （010）[100], accommodated by grain boundary sliding （gbs）. This grain size-sensitive creep regime is characterized by a stress exponent of n=3.4±0.2 and a grain size exponent of p=2.0±0.2. The activation volume for this gbs-accommodated dislocation creep regime is V＊=（26±3）×10^-6 m2·mol^-1. Comparison of our flow law for gbs-accommodated dislocation creep with those for diffusion creep and for dislocation creep reveals that the present flow law is important for the flow of mantle rocks with grain sizes of 〈100μm at differential stresses 〉20 MPa. Hence, gbs-accommodated dislocation creep is likely to be an important deformation mechanism in deep-rooted, highly localized shear zones in the lithospheric upper mantle.

关键词： grain boundary sliding creep olivine flow law.

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Colorectal cancer and dysplasia in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第17期14卷 2662-2669页

作者： Timothy l Zisman david T Rubin Clinical Research Fellow in Gastro-enterology the University of Chicago Medical Center The University of Chicago Medical Center

Both ulcerative colitis and Crohn’s disease carry an increased risk of developing colorectal cancer. Established risk factors for cancer among patients with inflammatory bowel disease (IBD) include the younger age at diagnosis, greater extent and duration of disease, increased severity of inflammation, family history of colorectal cancer and coexisting primary sclerosing cholangitis. Recent evidence suggests that current medical therapies and surgical techniques for inflammatory bowel disease may be reducing the incidence of this complication. Nonetheless heightened vigilance and a careful, comprehensive approach to prevent or minimize the complications of invasive cancer are warranted in this unique cohort of patients. Current guidelines for the prevention and early detection of cancer in this high risk population are grounded in the concept of an inflammation-dysplasia- carcinoma sequence. A thorough understanding of the definition and natural history of dysplasia in IBD, as well as the challenges associated with detection and interpretation of dysplasia are fundamental to developing an effective strategy for surveillance and prevention, and understanding the limitations of the current approach to prevention. This article reviews the current consensus guidelines for screening and surveillance of cancer in IBD, as well as presenting the evidence and rationale for chemoprevention of cancer and a discussion of emerging technologies for the detection of dysplasia.

关键词： Cancer Dysplasia Inflammatory Bowel Disease Ulcerative Colitis Crohn's Disease Chemoprevention

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MEMS-in-the-lens architecture for a miniature high-NA laser scanning microscope

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light(Science & Applications) 2019年第1期8卷 665-675页

作者： Tianbo liu Milind Rajadhyaksha david l.Dickensheets Electrical and Computer Engineering Department Montana State UniversityBozemanMT 59715USA Dermatology Department Memorial Sloan Kettering Cancer CenterNew YorkNY 10022USA

laser scanning microscopes can be miniaturized for in vivo imaging by substituting optical microelectromechanical system(MEMS)devices in place of larger *** emergence of multifunctional active optical devices can support further miniaturization beyond direct component replacement because those active devices enable diffraction-limited performance using simpler optical system *** this paper,we propose a catadioptric microscope objective lens that features an integrated MEMS device for performing biaxial scanning,axial focus adjustment,and control of spherical *** MEMS-in-the-lens architecture incorporates a reflective MEMS scanner between a low-numerical-aperture back lens group and an aplanatic hyperhemisphere front refractive element to support high-numerical-aperture *** implemented this new optical system using a recently developed hybrid polymer/silicon MEMS three-dimensional scan mirror that features an annular aperture that allows it to be coaxially aligned within the objective lens without the need for a beam *** optical performance of the active catadioptric system is simulated and imaging of hard targets and human cheek cells is demonstrated with a confocal microscope that is based on the new objective lens design.

关键词： scanning scanner mirror

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Sources and significance of variation in basal,summit and maximal metabolic rates in birds

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Current Zoology 2010年第6期56卷 741-758页

作者： Andrew E. MCKECHNIE david l. SWANSON DST/NRF Centre of Excellence at the Percy FitzPatrick Institute Department of Zoology and EntomologyUniversity of Pretoria Department of Biology University of South Dakota

The rates at which birds use energy may have profound effects on fitness, thereby influencing physiology, behavior, ecology and evolution. Comparisons of standardized metabolic rates （e.g., lower and upper limits of metabolic power output） present a method for elucidating the effects of ecological and evolutionary factors on the interface between physiology and life history in birds. In this paper we review variation in avian metabolic rates [basal metabolic rate （BMR; minimum normothermic metabolic rate）, summit metabolic rate （Msum; maximal thermoregulatory metabolic rate）, and maximal metabolic rate （MMR; maximal exercise metabolic rate）], the factors associated with this variation, the evidence for functional links between these metabolic traits, and the ecological and evolutionary significance of avian metabolic diversity. Both lower and upper limits to metabolic power production are phenotypically flexible traits, and vary in association with numerous ecological and evolutionary factors. For both inter- and intraspecific comparisons, lower and upper limits to metabolic power production are generally upregulated in response to energetically demanding conditions and downregulated when energetic demands are relaxed, or under conditions of energetic scarcity. Positive correlations have been documented between BMR, Msum and MMR in some, but not all studies on birds, providing partial support for the idea of a functional link between lower and upper limits to metabolic power production, but more intraspecific studies are needed to determine the robustness of this conclusion. Correlations between BMR and field metabolic rate （or daily energy expenditure） in birds are variable, suggesting that the linkage between these traits is subject to behavioral adjustment, and studies of the relationship between field and maximal metabolic rates are lacking. Our understanding of avian metabolic diversity would benefit from future studies of：（1） the functional and mechanistic li

关键词： Phenotypic flexibility Reaction norms Basal metabolic rate Maximal metabolic rate Birds

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