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Sensorimotor dysfunctions as primary features of autism spectrum disorders

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Science China(Life Sciences) 2015年第10期58卷 1016-1023页

作者： Matthew W.MOSCONI John A.SWEENEY departments of Psychiatry and pediatrics University of Texas Southwestern Medical Center

Motor impairments in autism spectrum disorders(ASD) have received far less research attention than core social- communication and cognitive features. Yet, behavioral, neurophysiological, neuroimaging and histopathological studies have documented abnormal motor system development in the majority of individuals with ASD suggesting that these deficits may be primary to the disorder. There are several unique advantages to studying motor development in ASD. First, the neurophysiological substrates of motor skills have been well-characterized via animal and human lesion studies. Second, many of the single-gene disorders associated with ASD also are characterized by motor dysfunctions. Third, recent evidence suggests that the onset of motor dysfunctions may precede the emergence of social and communication deficits during the first year of life in ASD. Motor deficits documented in ASD indicate disruptions throughout the neuroaxis affecting cortex, striatum, the cerebellum and brainstem. Questions remain regarding the timing and development of motor system alterations in ASD, their association with defining clinical features, and their potential for parsing heterogeneity in ASD. Pursuing these questions through neurobiologically informed translational research holds great promise for identifying gene-brain pathways associated with ASD.

关键词： autism motor cerebellum dyspraxia oculomotor

mTOR signaling in skeletal development and disease

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Bone Research 2018年第1期6卷 32-37页

作者： Jianquan Chen Fanxin Long orthopedic Institute Soochow University Suzhou Department of Orthopaedics The First Affiliated Hospital Soochow University departments of Orthopaedic surgery Medicine and Developmental Biology Washington University School of Medicine

The mammalian/mechanistic target of rapamycin(m TOR) is a serine/threonine protein kinase that integrates inputs from nutrients and growth factors to control many fundamental cellular processes through two distinct protein complexes m TORC1 and m *** mouse genetic studies have established that m TOR pathways play important roles in regulating multiple aspects of skeletal development and homeostasis. In addition, m TORC1 has emerged as a common effector mediating the bone anabolic effect of Igf1,Wnt and Bmp. Dysregulation of m TORC1 could contribute to various skeletal diseases including osteoarthritis and *** we review the current understanding of m TOR signaling in skeletal development and bone homeostasis, as well as in the maintenance of articular cartilage. We speculate that targeting m TOR signaling may be a valuable approach for treating skeletal diseases.

关键词： mammalian/mechanistic mTOR approach

Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation

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Bone Research 2015年第3期3卷 173-181页

作者： Edward Maharam Miguel Yaport Nathaniel L Villanueva Takintope Akinyibi Damien Laudier Zhiyong He Daniel J Leong Hui B Sun Leni and Peter W.May Department of orthopedics Icahn School of Medicine at Mount Sinai departments of orthopedic surgery Albert Einstein College of Medicine Radiation Oncology Albert Einstein College of Medicine

Mesenchymal stem cell （MSC）-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin （two other components of the pathway） using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope-like silk scaffolds.

关键词： MSCs Figure Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation

Yin and Yang of mesenchymal stem cells and aplastic anemia

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World Journal of Stem Cells 2017年第12期9卷 219-226页

作者： Larisa Broglie David Margolis Jeffrey A Medin Department of pediatrics Medical College of Wisconsin departments of pediatrics and Biochemistry Medical College of Wisconsin

Acquired aplastic anemia(AA) is a bone marrow failure syndrome characterized by peripheral cytopenias and bone marrow hypoplasia. It is ultimately fatal without treatment, most commonly from infection or hemorrhage. Current treatments focus on suppressing immune-mediated destruction of bone marrow stem cells or replacing hematopoietic stem cells(HSCs) by transplantation. Our incomplete understanding of the pathogenesis of AA has limited development of targeted treatment options. Mesenchymal stem cells(MSCs) play a vital role in HSC proliferation; they also modulate immune responses and maintain an environment supportive of hematopoiesis. Some of the observed clinical manifestations of AA can be explained by mesenchymal dysfunction. MSC infusions have been shown to be safe and may offer new approaches for the treatment of this disorder. Indeed, infusions of MSCs may help suppress auto-reactive, T-cell mediated HSC destruction and help restore an environment that supports hematopoiesis. Small pilot studies using MSCs as monotherapy or as adjuncts to HSC transplantation have been attempted as treatments for AA. Here we review the current understanding of the pathogenesis of AA and the function of MSCs, and suggest that MSCs should be a target for further research and clinical trials in this disorder.

关键词： Hematopoiesis Targeted therapies Stem cells Hematopoietic stem cell transplantation Aplastic anemia Mesenchymal stem cells

Distal femoral extension and shortening osteotomy as a part of multilevel surgery in children with cerebral palsy

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World Journal of pediatrics 2017年第4期13卷 353-359页

作者： Matthias C.M.Klotz Klemens Hirsch Daniel Heitzmann Michael W.Maier Sebastien Hagmann Thomas Dreher Department of orthopedic and Trauma surgery Heidelberg University ClinicsHeidelbergGermany

Background:There are several reports describing an increase in anterior pelvic tilt after hamstring lengthening in children with cerebral palsy (CP).Distal femoral extension and shortening osteotomy (DFESO) is an alternative treatment for correction of flexed knee gait,but investigations analyzing outcome and influence on adjacent joint are few in the *** purpose of this study was to analyze the influence of DFESO on knee and pelvis in children with ***,it was of interest if an additional patellar tendon advancement (PA) influences ***:In this retrospective study,31 limbs of 22 children (GMFCS Ⅰ-Ⅲ;mean age:12.1±3.1 years),who received DFESO were included and kinematic parameters (knee,pelvis) measured by 3-D-gait analysis were compared before and at least 1 year after surgery (mean follow-up period:15.6 months).Results:After surgery,during stance phase minimum knee flexion improved significantly by 20.5° (P<0.001) and mean anterior pelvic tilt increased by 4.0 degrees (P=0.045).In 16 limbs,the postoperative increase in maximum anterior pelvic tilt was more than 5°.Limbs who received an additional PA showed the biggest increase in anterior pelvic ***:DFESO is an effective method for correction of flexed knee gait in children with ***,the results of this study indicate that DFESO may lead to an increase in anterior pelvic tilt,which may lead to a recurrence of flexed knee *** this context,PA seemed to aggravate the effect on the pelvis.

关键词： cerebral palsy femoral extension osteotomy motion analysis

Molecular physiology of vesicular glutamate transporters in the digestive system

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World Journal of Gastroenterology 2005年第12期11卷 1731-1736页

作者： Fayez K.Ghishan departments of pediatrics and Medicine

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Packaging and storage of glutamate into glutamatergic neuronal vesicles require ATP-dependent vesicular glutamate uptake systems, which utilize the electrochemical proton gradient as a driving force. Three vesicular glutamate transporters (VGLUT1-3) have been recently identified from neuronal tissue where they play a key role to maintain the vesicular glutamate level. Recently, it has been demonstrated that glutamate signaling is also functional in peripheral neuronal and non-neuronal tissues, and occurs in sites of pituitary, adrenal, pineal glands, bone, GI tract, pancreas,skin, and testis. The glutamate receptors and VGLUTs in digestivesystem have been found in both neuronal and endocrinal cells. The glutamate signaling in the digestive system may have significant relevance to diabetes and GI tract motility disorders. This review will focus on the most recent update of molecular physiology of digestive VGLUTs.

关键词： Glutamate Vesicular glutamate transporters Digestive system

Modifying oxygen tension affects bone marrow stromal cell osteogenesis for regenerative medicine

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World Journal of Stem Cells 2017年第7期9卷 98-106页

作者： Yusuke Inagaki Manabu Akahane Takamasa Shimizu Kazuya Inoue Takuya Egawa Tsutomu Kira Munehiro Ogawa Kenji Kawate Yasuhito Tanaka Department of orthopedic surgery Nara Medical University Department of Public Health Health Management and PolicyNara Medical UniversityFaculty of Medicine departments of Artificial Joint and Regenerative Medicine for Bone and Cartilage Nara Medical University

AIM To establish a hypoxic environment for promoting osteogenesis in rat marrow stromal cells(MSCs) using osteogenic matrix cell sheets(OMCSs).METHODS Rat MSCs were cultured in osteogenic media under one of four varying oxygen conditions: Normoxia(21% O_2) for 14 d(NN), normoxia for 7 d followed by hypoxia(5% O_2) for 7 d(NH), hypoxia for 7 d followed by normoxia for 7 d(HN), or hypoxia for 14 d(HH). Osteogenesis was evaluated by observing changes in cell morphology and calcium deposition, and by measuring osteocalcin secretion(ELISA) and calcium content. In vivo syngeneic transplantation using OMCSs and β-tricalcium phosphate discs, preconditioned under NN or HN conditions, was also evaluated by histology, calcium content measurements,and real-time quantitative *** In the NN and HN groups, differentiated, cuboidal-shaped cells were readily observed, along with calcium deposits. In the HN group, the levels of secreted osteocalcin increased rapidly from day 10 as compared with the other groups, and plateaued at day 12(P < 0.05). At day 14, the HN group showed the highest amount of calcium deposition. In vivo, the HN group showed histologically prominent new bone formation, increased calcium deposition, and higher collagen type Ⅰ?messenger RNA expression as compared with the NN *** The results of this study indicate that modifying oxygen tension is an effective method to enhance the osteogenic ability of MSCs used for OMCSs.

关键词： Hypoxia Osteogenesis Tissue engineering Marrow stromal cells Regenerative medicine

Towards creation of national cerebral palsy registries in Arab countries:what is missing?

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World Journal of pediatrics 2022年第3期18卷 222-224页

作者： Sahar M.A.Hassanein Tamer A.El-Sobky Division of Pediatric Neurology Department of PediatricsFaculty of MedicineAin Shams UniversityCairoEgypt Division of Pediatric orthopedics Department of Orthopedic SurgeryFaculty of MedicineAin Shams UniversityCairoEgypt

Cerebral palsy(CP)is a global,complex and lifelong health issue with a relatively high disease burden in low-resource *** benefits of a national disease registry in general and a national CP registry in particular are twofold,namely the public health and the clinical disease-related benefits.A national CP quality registry has the potential to inform health planning and spending at national,regional and continental *** turn,this can help allocate and manage the relevant material and human resources in a more predictable and efficient manner.

关键词： benefits palsy creation

Regulation of pancreatic cancer metastasis through the Gli2-YAP1 axis via regulation of anoikis

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Genes & Diseases 2022年第6期9卷 1427-1430页

作者： Beiqin Yu Dongsheng Gu Xiaoli Zhang Bingya Liu Jingwu Xie Department of General surgery Shanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025PR China departments of pediatrics Biochemistry and Molecular BiologyPharmacology and ToxicologyThe Wells Center for Pediatrics ResearchIndiana University School of MedicineIndianapolisIN 46202USA

Pancreatic cancer,mostly pancreatic ductal adenocarcinoma(PDAC),is often metastatic upon the initial diagnosis,and has a high mortality ***,the primary and the matched metastatic cancers often share the same driver gene mutations.1,2 Gene expression comparison between primary and metastatic PDAC tissues revealed high expression of Gli2 and YAP1 in the metastatic ***2 is an important player in non-canonical hedgehog signaling,and YAP1 is an essential cell polarity *** this study,we investigated the effects of Gli2 and YAP1 on pancreatic cancer cell function in 3D culture and in mouse *** further determined the relationship between Gli2 and *** studies further our understanding of pancreatic cancer metastasis.

关键词： YAP1 Gli2 metastasis