Decreased Level of Nurr1 in Heterozygous Young Adult Mice Leads to Exacerbated Acute and Long-Term Toxicity after Repeated Methamphetamine Exposure

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals

Electrically Addressable Hybrid Architectures of Zinc Oxide Nanowires Grown on Aligned Carbon Nanotubes

The fabrication and characterization of hybrid architectures of ZnO nanowires (ZNWs) grown on organized carbon nanotubes (CNTs), by a two-step chemical vapor deposition (CVD) process involving CNT growth from a hydrocarbon source followed by ZNW growth using a Zn metal source, is reported. The ZNWs grow uniformly and radially from individual CNTs and CNT bundles, and the aligned morphology of the CNTs is not disturbed by the ZNW growth process. The nucleation and growth of ZnO crystals on CNTs are analyzed in relation to the classical vapor–solid mechanism. Importantly, the CNTs make uniform and distributed electrical contact to the ZNWs, with up to a 1000-fold yield advantage over conventional ZNW growth on a flat substrate. Hybrid ZNW/CNT sheets are fabricated by scalable CVD, rolling, and printing methods; and their electrical properties, which are governed by transport through the anisotropic CNT network, are characterized. Functional interaction between the ZNWs and CNTs is demonstrated by photoconductive behavior and photocurrent generation of the hybrid material under UV illumination. There is significant future opportunity to extend these processing methods to fabricate other functional oxides on CNTs, and to build devices that harness the attractive properties of ZNWs and CNTs with high volumetric efficiency over large areas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77980/1/2470_ftp.pd

Activation of the Fas/Fas ligand pathway in hypertensive renal disease in Dahl/Rapp rats

BACKGROUND: Hypertensive nephrosclerosis is the second most common cause of end-stage renal failure in the United States. The mechanism by which hypertension produces renal failure is incompletely understood. Recent evidence demonstrated that an unscheduled and inappropriate increase in apoptosis occurred in the Dahl/Rapp rat, an inbred strain of rat that uniformly develops hypertension and hypertensive nephrosclerosis; early correction of the hypertension prevents the renal injury. The present study examined the role of the Fas/FasL pathway in this process. METHODS: Young male Dahl/Rapp salt-sensitive (S) and Sprague-Dawley rats were fed diets that contained 0.3% or 8.0% NaCl diets. Kidneys were examined at days 7 and 21 of the study. RESULTS: An increase in Fas and FasL expression was observed in glomerular and tubular compartments of kidneys of hypertensive S rats, whereas dietary salt did not change expression of either of these molecules in normotensive Sprague-Dawley rats. Associated with this increase was cleavage of Bid and activation of caspase-8, the initiator caspase in this apoptotic pathway, by day 21 of the study. CONCLUSIONS: Augmented expression of apoptotic signaling by the Fas/FasL pathway occurred during development of end-stage renal failure in this model of hypertensive nephrosclerosis

Does unemployment in family affect pregnancy outcome in conditions of high quality maternity care?

BACKGROUND: The influence of unemployment in the family on pregnancy outcome is controversial. Only a few studies have involved investigation of the effect of unemployment of the father on pregnancy. The objective of this study was to assess the effects of unemployment of one or both parents on obstetric outcome in conditions of free antenatal care attended by the entire pregnant population. METHODS: The data of 24 939 pregnancies included maternal risk factors, pregnancy characteristics and outcome, and was based on a self administered questionnaire at 20 weeks of pregnancy and on clinical records. RESULTS: Unemployment was associated with adolescent maternal age, unmarried status and overweight, anemia, smoking, alcohol consumption and prior pregnancy terminations. Multivariate logistic regression analysis indicated that after controlling for these maternal risk factors small differences only were found in pregnancy outcomes between unemployed and employed families. Unemployed women had significantly more often small-for-gestational-age (SGA) infants, at an OR of 1.26 (95% CI: 1.12 – 1.42) whereas, in families where both parents were unemployed, the risk of SGA was even higher at an OR of 1.43 (95% CI: 1.18 – 1.73). Otherwise, pregnancy outcome was comparable in the groups studied. CONCLUSION: Free antenatal care was unable to fully overcome the adverse pregnancy outcomes associated with unemployment, SGA risk being highest when both parents are unemployed

Cardio-metabolic risk factors and prehypertension in persons without diabetes, hypertension, and cardiovascular disease

10.1186/1471-2458-13-730BMC Public Health131

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Gradient lithography of engineered proteins to fabricate 2D and 3D cell culture microenvironments

Spatial patterning of proteins is a valuable technique for many biological applications and is the prevailing tool for defining microenvironments for cells in culture, a required procedure in developmental biology and tissue engineering research. However, it is still challenging to achieve protein patterns that closely mimic native microenvironments, such as gradient protein distributions with desirable mechanical properties. By combining projection dynamic mask lithography and protein engineering with non-canonical photosensitive amino acids, we demonstrate a simple, scalable strategy to fabricate any user-defined 2D or 3D stable gradient pattern with complex geometries from an artificial extracellular matrix (aECM) protein. We show that the elastic modulus and chemical nature of the gradient profile are biocompatible and allow useful applications in cell biological research

ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation

Selective treatments for myocardial infarction (MI) induced cardiac fibrosis are lacking. In this study, we focus on the therapeutic potential of a synthetic cardio-protective agent named ZYZ-168 towards MI-induced cardiac fibrosis and try to reveal the underlying mechanism. ZYZ-168 was administered to rats with coronary artery ligation over a period of six weeks. Ecocardiography and Masson staining showed that ZYZ-168 substantially improved cardiac function and reduced interstitial fibrosis. The expression of α–smooth muscle actin (α-SMA) and Collagen I were reduced as was the activity of matrix metalloproteinase 9 (MMP-9). These were related with decreased phosphorylation of ERK1/2 and expression of Rho-associated coiled-coil containing protein kinase 1 (ROCK1). In cardiac fibroblasts stimulated with TGF-β1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed. Inhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-β1 induced fibrotic responses. ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent manner, in part via a decrease in ROCK 1 expression through inhibition of the phosphorylation status of ERK1/2. For inhibition of ERK1/2 phosphorylation with a specific inhibitor reduced the activation of ROCK1. Considering its anti-apoptosis activity in MI, ZYZ-168 may be a potential drug candidate for treatment of MI-induced cardiac fibrosis