Role of ERK1/2 and p38 mitogen-activated protein kinases in the regulation of thrombospondin-1 by TGF-beta1 in rat proximal tubular cells and mouse fibroblasts

Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-beta1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-beta1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-beta1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-beta1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-beta1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-beta1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-beta1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-beta1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-beta1, this provides an important insight to the mechanism by which TGF-beta1 may mediate interstitial fibrosis and progressive renal disease.     

The uncoupling protein 2 Ala55Val polymorphism is associated with diabetes mellitus: the CARDIA study

BACKGROUND: Uncoupling proteins (UCPs) reduce ATP generation with concomitant increased release of heat. The activities of UCPs have been related to obesity and energy metabolism. METHODS: We investigated the association of the commonly observed UCP2 Ala55Val (V) polymorphism with diabetes mellitus and impaired fasting glucose (IFG) among 3684 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. RESULTS: The V frequency was approximately 45% in blacks and 42% in whites. Those with the Val/Val (VV) genotype had a higher incidence of diabetes than those having the Ala/Ala (AA) genotype (5.8% vs 3.3%; P = 0.02). Similarly, the incidences of diabetes in participants without abdominal obesity were 2.8% and 1.0% (P = 0.03) in the VV and AA groups, and 12.4% and 8.3% (P = 0.15) in participants with abdominal obesity. The incidence of IFG was higher in VV vs AA only in those without abdominal obesity (12.9% vs 9.2%). These trends persisted in minimally and fully adjusted models, and in strata of blacks and whites and men and women. The homeostasis model assessment for insulin resistance was highest in VV in the combined group of those with IFG or untreated diabetes, but not in those with normal fasting glucose. CONCLUSION: The VV genotype of the UCP2 polymorphism was positively related to diabetes. It may involve increased insulin resistance in those with impaired glucose homeostasis.     

Short-term adaptation of auditory receptive fields to dynamic stimuli

Short-term adaptation and recovery from adaptation have a strong impact on the processing of dynamic stimuli. Adaptive effects on neuronal activity have been studied most commonly for changes in first-order statistics of stimuli such as stepwise increments or decrements in stimulus amplitude. However, changes in higher moment statistics, such as the variance of the amplitude distribution in visual stimuli, also can invoke pronounced adaptation behavior. We demonstrate here that neurons in the inferior colliculus (ICC) of the cat show adaptation to dynamic auditory stimuli that differ in the variance of their modulation depth distribution. In addition, it is shown that neurons show adaptation to other higher moment statistics (e.g., kurtosis) of the modulation envelope. The time course of adaptation is specific for the altered stimulus property and the direction of parameter change. The use of dynamic stimuli allows an estimate of the effects of the adaptation on the temporal response properties of the neurons. We demonstrate that temporal receptive fields of neurons undergo change during the course of adaptation. We show that adaptation to variance in the ICC has many similarities to that in the retina and suggest that adaptation to variance is a general property of sensory systems that allows them to effectively deal with a nonstationary environment.     

Attrition, abrasion, corrosion and abfraction revisited: a new perspective on tooth surface lesions

OVERVIEW: The authors propose updated and revised nomenclature, definitions and classification for tooth surface lesions. Their objective is standardization, clarity and clinical utility for the dental practitioner. The article presents a schema of the pathodynamic mechanisms in the formation of tooth surface lesions--three basic physical and chemical mechanisms, their interactions and their dental manifestations. CONCLUSIONS AND CLINICAL IMPLICATIONS: The use of precise definitions will assist the practitioner in determining the etiology of various tooth surface lesions. Understanding the pathodynamic mechanisms and their many possible interactions, as set forth in the schema, will enable the practitioner to make an accurate differential diagnosis and to provide effective prevention and treatment. It also will assist dentists in communicating more effectively with their colleagues as well as with their patients. In addition, the schema helps identify areas in which future research is indicated.     

Associative learning shapes the neural code for stimulus magnitude in primary auditory cortex

Since the dawn of experimental psychology, researchers have sought an understanding of the fundamental relationship between the amplitude of sensory stimuli and the magnitudes of their perceptual representations. Contemporary theories support the view that magnitude is encoded by a linear increase in firing rate established in the primary afferent pathways. In the present study, we have investigated sound intensity coding in the rat primary auditory cortex (AI) and describe its plasticity by following paired stimulus reinforcement and instrumental conditioning paradigms. In trained animals, population-response strengths in AI became more strongly nonlinear with increasing stimulus intensity. Individual AI responses became selective to more restricted ranges of sound intensities and, as a population, represented a broader range of preferred sound levels. These experiments demonstrate that the representation of stimulus magnitude can be powerfully reshaped by associative learning processes and suggest that the code for sound intensity within AI can be derived from intensity-tuned neurons that change, rather than simply increase, their firing rates in proportion to increases in sound intensity.     

Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling

Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.     

Long-term prediction of incident hip fracture risk in elderly white women: study of osteoporotic fractures

OBJECTIVES: To identify independent risk factors for first hip fracture over 10 years of follow-up. DESIGN: Prospective cohort study. SETTING: Four U.S. clinical centers. PARTICIPANTS: A total of 6,787 women aged 66 and older in the Study of Osteoporotic Fractures. MEASUREMENTS: Total hip bone mineral density (BMD) using dual-energy x-ray absorptiometry and a comprehensive set of potential risk factors were collected. Incident hip fractures were identified prospectively and confirmed using radiographic report. RESULTS: Six hundred two women (8.9%) had a hip fracture during a mean +/- standard deviation (SD) follow-up of 10.1 +/- 3.2 years. Older age, previous self-reported fracture after age 50, maternal history of hip fracture after age 50, greater height at age 25, impaired cognition, slower walking speed, nulliparity, type II diabetes mellitus, Parkinson's disease, and depth perception each independently predicted a 1.17- to 1.83-fold increase in hip fracture risk, whereas each SD (0.13 g/cm2) decrease in hip BMD was independently associated with a 1.84-fold increase in risk. Lower body mass index also was associated with an increased risk of hip fracture, although lower hip BMD largely explained this association. CONCLUSION: Although hip BMD is strongly related to hip fracture risk in elderly white women, other clinical risk factors also are independent predictors of long-term risk and provide additional insight into the prevention of fracture in high-risk women. Clinicians should be alert to factors other than BMD that place older women at a high risk of hip fracture.