Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.

Impact of social isolation on behavioral health in elderly: Systematic review

AIM: To examine and compare the effects of subjective and objective social isolation on behavioral health in elderly adults.METHODS: A systematic search of Pub Med was performed for original research articles from peerreviewed journals examining one of the following topics: "Social isolation and sleep disturbance", "social isolation and depression", or "social isolation and fatigue in older adults". Studies were selected following the criteria established based on the aim of this review. Data were extracted from the articles by two independent reviewers. Due to the heterogeneity in study designs and outcome measures of the included studies, qualitative and narrative analyses were conducted.RESULTS: The set criteria were used to select a total of 16 studies for the review. Of the 16, 13 were crosssectional studies. The characteristics of study populations were identified as follows. A total of 12 studies randomly selected subjects irrespective of pre-existing health conditions. Consequently, an unspecified number of the study subjects had chronic diseases in the studies compared. In addition, cultural and ethnic backgrounds of studies in this review were diverse, and included subjects living in North America, South America, Asia, Europe, and Oceania. Both subjective and objective types of social isolation increased behavioral symptoms, such as sleep disturbance, depressive symptoms, and fatigue in older adults. Furthermore, a few recent studies reported stronger effects of subjective social isolation than objective social isolation on sleep disturbance and depressive symptoms.CONCLUSION: Social isolation affects behavioral health in older adults. Compared to the objective social isolation, subjective social isolation contributes more significantly to sleep disturbance and depression.

Benzodiazepines and Amphetamines Use among Methadone Maintenance Participants and Their Associations with Treatment Adherence

It has been well documented that methadone maintenance treatment(MMT)can reduce illegal opioid use and drug-related crimes,and decrease the HIV infection risk[1].China initiated its MMT program in 2004,which was rapidly scaled up nationwide[2].By the end of 2016,there were 778 MMT clinics established in 29 provinces。

Modulation of protein tyrosine phosphorylation in gastric mucosa during re-epithelization processes

AIM:To investigate the role of protein tyrosine phosphorylation in gastric wound formation and repair following ulceration. METHODS:Gastric lesions were induced in rats using restraint cold stress.To investigate the effect of oxidative and nitrosative cell stress on tyrosine phosphorylation during wound repair,total activity of protein tyrosine kinase(PTK),protein tyrosine phosphatase (PTP),antioxidant enzymes,nitric oxide synthase (NOS), 2',5'-oligoadenylate synthetase,hydroxyl radical and zinc levels were assayed in parallel. RESULTS:Ulcer provocation induced an immediate decrease in tyrosine kinase(40% in plasma membranes and 56% in cytosol,(P<0.05) and phosphatase activity (threefold in plasma membranes and 3.3-fold in cytosol),followed by 2.3-2.4-fold decrease (P<0.05) in protein phosphotyrosine content in the gastric mucosa. Ulceration induced no immediate change in superoxide dismutase (SOD) activity,30% increase (P<0.05) in catalase activity,2.3-fold inhibition (P<0.05) of glutathione peroxidase,3.3-fold increase (P<0.05) in hydroxyl radical content,and 2.3-fold decrease (P<0.05) in zinc level in gastric mucosa.NOS activity was three times higher in gastric mucosa cells after cold stress. Following ulceration,PTK activity increased in plasma membranes and reached a maximum on day 4 after stress (twofold increase,P<0.05),but remained inhibited(1.6-3-fold decrease on days 3,4 and 5,P<0.05) in the cytosol.Tyrosine phosphatases remained inhibited both in membranes and cytosol(1.5-2.4-fold,P< 0.05).NOS activity remained increased on days 1,2 and 3(3.8-,2.6-,2.2-fold,respectively,P<0.05).Activity of SOD increased 1.6 times(P<0.05)days 4 and 5 after stress.Catalase activity normalized after day 2. Glutathione peroxidase activity and zinc level decreased (3.3-and 2-fold,respectively,P<0.05)on the last day. Activity of 2',5'-oligoadenylate synthethase increased 2.8-fold (P<0.05) at the beginning,and 1.6-2.3-fold (P<0.05) during ulcer recuperation,and normalized on day 5,consistent with slowing of inflammation processes. CONCLUSION:These studies show diverse changes in total tyrosine kinase activity in gastric mucosa during the recovery process.Oxidative and nitrosative stress during lesion formation might lead to the observed reduction in tyrosine phosphorylation during ulceration.

星形胶质细胞之间的接触和生长因子信号传导的正反馈回路对星形胶质细胞成熟的调节

星形胶质细胞对于中枢神经系统的发育和功能至关重要。在大脑发育过程中,未成熟的星形胶质细胞会发生形态、分子、细胞和功能的变化以至成熟。尽管已经广泛研究了调节中枢神经系统中其他主要细胞类型(如神经元和少突胶质细胞)成熟过程的机制,但对于控制星形胶质细胞成熟的细胞和分子机制知之甚少。本研究确定了星形胶质细胞成熟的分子标志物,并建立了研究星形胶质细胞成熟机制的离体检验方法。离体条件下,成熟的星形胶质细胞表现出与在体星形胶质细胞相似的分子变化及类似的多种分子亚型。使用该系统,我们发现星形胶质细胞之间的接触强烈促进星形胶质细胞的成熟。此外,来自小胶质细胞、少突胶质细胞前体细胞或内皮细胞的分泌信号影响星形胶质细胞的一小部分基因,但不会持续改变星形胶质细胞的成熟。为了确定星形胶质细胞成熟的分子机制,我们用影响肿瘤相关基因功能的分子处理了成熟中的星形胶质细胞。我们发现肝素结合表皮生长因子样生长因子(HBEGF)和表皮生长因子受体(EGFR)信号通路的正反馈回路调节星形胶质细胞的成熟。此外,HBEGF、EGFR和肿瘤蛋白53(TP53)影响一些基因的表达,这些基因对纤毛发育,昼夜节律和突触功能至关重要。这些结果揭示了星形胶质细胞成熟的细胞和分子机制,对理解胶质母细胞瘤具有重要意义。

Proteogenomic review of the changes in primate apoC-I during evolution

Apolipoprotein C-I has evolved more rapidly than any of the other soluble apolipoproteins. During the course of primate evolution, the gene for this apolipoprotein was duplicated. Prompted by our observation that the two resulting genes encode two distinct forms of apoC-I in great apes, we have reviewed both the genomic and proteomic data to examine what changes have occurred during the course of primate evolution. We have found data showing that one of the duplicated genes, known to be a pseudogene in humans, was also a pseudogene in Denisovans and Neandertals. Using genomic and proteomic data for primates, we will provide in this review evidence that the duplication took place after the divergence of New World monkeys from the human lineage and that the formation of the pseudogene took place after the divergence of the bonobos and chimpanzees from the human lineage.