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The laboratory rat was the first mammal domesticated for research purposes. It is descended from wild Norway rats, Rattus norvegicus, which despite their name likely originated in Asia. Exceptionally adaptable, these rodents now inhabit almost all environments on Earth, especially near human settlements where they are often seen as pests. The laboratory rat thrives in captivity, and its domestication has produced many inbred and outbred lines that are used for different purposes, including medical trials and behavioral studies. Differences between wild Norway rats and their laboratory counterparts were first noted in the early 20th century and led some researchers to later question its value as a model organism. While these views are probably unjustified, the advanced domestication of the laboratory rat does suggest that resuming studies of wild rats could benefit the wider research community.

Current thalassemia gene therapy protocols require the collection of hematopoietic stem/progenitor cells (HSPCs), in vitro culture, lentivirus vector transduction, and retransplantation into myeloablated patients. Because of cost and technical complexity, it is unlikely that such protocols will be applicable in developing countries, where the greatest demand for a β-thalassemia therapy lies. We have developed a simple in vivo HSPC gene therapy approach that involves HSPC mobilization and an intravenous injection of integrating HDAd5/35++ vectors. Transduced HSPCs homed back to the bone marrow, where they persisted long-term. HDAd5/35++ vectors for in vivo gene therapy of thalassemia had a unique capsid that targeted primitive HSPCs through human CD46, a relatively safe SB100X transposase-based integration machinery, a micro-LCR-driven γ-globin gene, and an MGMT(P140K) system that allowed for increasing the therapeutic effect by short-term treatment with low-dose O6-benzylguanine plus bis-chloroethylnitrosourea. We showed in \"healthy\" human CD46-transgenic mice and in a mouse model of thalassemia intermedia that our in vivo approach resulted in stable γ-globin expression in the majority of circulating red blood cells. The high marking frequency was maintained in secondary recipients. In the thalassemia model, a near-complete phenotypic correction was achieved. The treatment was well tolerated. This cost-efficient and \"portable\" approach could permit a broader clinical application of thalassemia gene therapy.

The characteristic brain pathology and motor and nonmotor symptoms of Parkinson’s disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH-positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD.

Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use (\"addiction\") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms Yiying Zhang 1 2 , Kaiying Guo 1 , Robert E. LeBlanc 1 , Daniella Loh 1 , Gary J. Schwartz 3 and Yi-Hao Yu 4 1 Department of Pediatrics, Division of Molecular Genetics, Columbia University, New York, New York 2 Naomi Berrie Diabetes Center, Columbia University, New York, New York 3 Department of Medicine and Neuroscience, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 4 Department of Medicine, Division of Preventive Medicine, Columbia University, New York, New York Address correspondence and reprint requests to Yiying Zhang, PhD, Division of Molecular Genetics, Department of Pediatrics, Columbia University, Russ Berrie Pavilion, Rm. 620, 1150 St. Nicholas Ave., New York, NY 10032. E-mail: yz84{at}columbia.edu . Or Yi-Hao Yu, MD, PhD, Division of Preventive Medicine, Department of Medicine, Columbia University, 630 W. 168th St., PH 10-305J, New York, NY 10032. E-mail: yy102{at}columbia.edu Abstract Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain ( P < 0.05) and a 25% decrease in adiposity ( P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% ( P < 0.001) and 53% ( P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms. BAT, brown adipose tissue G6P, glucose-6-phosphatase HFD, high-fat diet HOMA-IR, homeostasis model assessment of insulin resistance mTOR, mammalian target of rapamycin UCP, uncoupling protein WAT, white adipose tissue Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db07-0123. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 19, 2007. Received January 27, 2007. DIABETES

The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R). A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators. Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1β and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining. The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.

In young animals, monocular deprivation leads to an ocular dominance shift, whereas in adults after the critical period there is no such shift. Chondroitin sulphate proteoglycans (CSPGs) are components of the extracellular matrix (ECM) inhibitory for axonal sprouting. We tested whether the developmental maturation of the ECM is inhibitory for experience-dependent plasticity in the visual cortex. The organization of CSPGs into perineuronal nets coincided with the end of the critical period and was delayed by dark rearing. After CSPG degradation with chondroitinase-ABC in adult rats, monocular deprivation caused an ocular dominance shift toward the nondeprived eye. The mature ECM is thus inhibitory for experience-dependent plasticity, and degradation of CSPGs reactivates cortical plasticity.

Compulsive drug use in the face of adverse consequences is a hallmark feature of addiction, yet there is little preclinical evidence demonstrating the actual progression from casual to compulsive drug use. Presentation of an aversive conditioned stimulus suppressed drug seeking in rats with limited cocaine self-administration experience, but no longer did so after an extended cocaine-taking history. In contrast, after equivalent extended sucrose experience, sucrose seeking was still suppressed by an aversive conditioned stimulus. Persistent cocaine seeking in the presence of signals of environmental adversity after a prolonged cocaine-taking history was not due to impaired fear conditioning, nor to an increase in the incentive value of cocaine, and may reflect the establishment of compulsive behavior.

Carbamazepine (CBZ), an effective drug for epilepsy and other neurological diseases, and its metabolites are one of the most frequently detected substances in the aquatic environment. Although these are doses of very low concentrations, chronic exposure to them can affect the physiological processes of living organisms. This experiment may clarify if carbamazepine, under an environmental and a therapeutic concentration, can affect the behaviour of higher vertebrates, especially mammals, and gene expressions of Ugt1a6 and Ugt1a7 in the brain compared to the control group without exposure to CBZ. Three groups of thirteen rats were randomly formed, and each group was treated either with carbamazepine 12 mg/kg (therapeutic), carbamazepine 0.1 mg/kg (environmental), or by 10% DMSO solution (control). The memory, anxiety, and social behaviour of the rats were assessed by the test Elevated Plus Maze, the novel object recognition test, and the social chamber paradigm. After testing, they were euthanised and brain tissue samples were collected and analysed for mRNA expression of Ugt1a6 and Ugt1a7 genes. The tests did not show significant differences in the behaviour of the rats between the groups. However, there were significant changes at the gene expression level of Ugt1a7.