Regulation of Protein Degradation in the Heart by AMP-Activated Protein Kinase

The degradation of proteins by the ubiquitin proteasome system is essential for cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). During nutrient deprivation, AMPK is activated and intracellular proteolysis is enhanced through the ubiquitin proteasome system (UPS). Whether AMPK plays a role in protein degradation through the UPS in the heart is not known. Here I present data in support of the hypothesis that AMPK transcriptionally regulates key players in the UPS, which, under extreme conditions can be detrimental to the heart. The ubiquitin ligases MAFbx /Atrogin-1 and MuRF1, key regulators of protein degradation, and AMPK activity are increased during nutrient deprivation. Pharmacologic and genetic activation of AMPK is sufficient for the induction of MAFbx/Atrogin-1 and MuRF1 in cardiomyocytes and in the heart in vivo. Comprehensive experiments demonstrate that the molecular mechanism by which AMPK regulates MuRF1 expression is through the transcription factor myocyte enhancer factor 2 (MEF2), which is involved in stress response and cardiomyocyte remodeling. MuRF1 is required for AMPK-mediated protein degradation through the UPS in cardiomyocytes. Consequently, the absence of MuRF1 during chronic fasting preserves cardiac function, possibly by limiting degradation of critical metabolic enzymes. Furthermore, during cardiac hypertrophy, chronic activation of AMPK also leads to cardiac dysfunction, possibly through enhanced protein degradation and metabolic dysregulation. Collectively, my findings demonstrate that AMPK regulates expression of ubiquitin ligases which are required for UPS-mediated protein degradation in the heart. Based on these results, I propose that specific metabolic signals may serve as modulators of intracellular protein degradation in the heart

Hypospadias and endocrine disruption: is there a connection?

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 250 newborns or roughly 1 in 125 live male births. It is the result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias, the majority of which have been classified as idiopathic. In this paper we briefly describe the normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations. Recent findings suggest that some hypospadias could be the result of disrupted gene expression. Discoveries about the antiandrogenic mechanisms of action of some contemporary-use chemicals have provided new knowledge about the organization and development of the urogenital system and may provide additional insight into the etiology of hypospadias and direction for prevention

Physiological Epicotyl Dormancy and Recalcitrant Storage Behaviour in Seeds of Two Tropical Fabaceae (Subfamily Caesalpinioideae) Species

BACKGROUND AND AIMS: Physiological epicotyl dormancy in which the epicotyl elongates inside the seed before the shoot emerges has been reported for only a few tropical rainforest species, all of which are trees that produce recalcitrant seeds. In studies on seeds of Fabaceae in Sri Lanka, we observed a considerable time delay in shoot emergence following root emergence in seeds of the introduced caesalpinioid legumes Brownea coccinea and Cynometra cauliflora. Thus, our aim was to determine if seeds of these two tropical rainforest trees have physiological epicotyl dormancy, and also if they are recalcitrant, i.e. desiccation sensitive. METHODOLOGY: Fresh seeds were (i) dried to various moisture levels, and (ii) stored at -1 and 5 °C to determine loss (or not) of viability and thus type of seed storage behaviour (orthodox, recalcitrant or intermediate). To identify the kind of dormancy, we tested the effect of scarification on imbibition and monitored radicle emergence and epicotyl growth (inside the seed) and emergence. PRINCIPAL RESULTS: FRESH SEEDS OF BOTH SPECIES HAD HIGH MOISTURE CONTENT (MC): 50 % for C. cauliflora and 30 % for B. coccinea. Further, all seeds of C. cauliflora and the majority of those of B. coccinea lost viability when dried to 15 % MC; most seeds of both species also lost viability during storage at -1 or 5 °C. Intact seeds of both species were water permeable, and radicles emerged in a high percentage of them inHowever, shoot emergence lagged behind root emergence by 77 ± 14 days in B. coccinea and by 38 ± 4 days in C. cauliflora. Further, plumule growth inside seeds of C. cauliflora began almost immediately after radicle emergence but not until ∼30-35 days in B. coccinea seeds. CONCLUSIONS: Seeds of both species are recalcitrant and have physiological epicotyl dormancy. The kind of physiological epicotyl dormancy in seeds of C. cauliflora has not been described previously; the formula is C(nd) (root)-[Formula: see text] (epicotyl)

Honorary and ghost authorship

Has not substantially declined, suggesting that standards need tightening u

Regulation of Protein Degradation in the Heart by AMP-Activated Protein Kinase

The degradation of proteins by the ubiquitin proteasome system is essential for cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). During nutrient deprivation, AMPK is activated and intracellular proteolysis is enhanced through the ubiquitin proteasome system (UPS). Whether AMPK plays a role in protein degradation through the UPS in the heart is not known. Here I present data in support of the hypothesis that AMPK transcriptionally regulates key players in the UPS, which, under extreme conditions can be detrimental to the heart. The ubiquitin ligases MAFbx /Atrogin-1 and MuRF1, key regulators of protein degradation, and AMPK activity are increased during nutrient deprivation. Pharmacologic and genetic activation of AMPK is sufficient for the induction of MAFbx/Atrogin-1 and MuRF1 in cardiomyocytes and in the heart in vivo. Comprehensive experiments demonstrate that the molecular mechanism by which AMPK regulates MuRF1 expression is through the transcription factor myocyte enhancer factor 2 (MEF2), which is involved in stress response and cardiomyocyte remodeling. MuRF1 is required for AMPK-mediated protein degradation through the UPS in cardiomyocytes. Consequently, the absence of MuRF1 during chronic fasting preserves cardiac function, possibly by limiting degradation of critical metabolic enzymes. Furthermore, during cardiac hypertrophy, chronic activation of AMPK also leads to cardiac dysfunction, possibly through enhanced protein degradation and metabolic dysregulation. Collectively, my findings demonstrate that AMPK regulates expression of ubiquitin ligases which are required for UPS-mediated protein degradation in the heart. Based on these results, I propose that specific metabolic signals may serve as modulators of intracellular protein degradation in the heart

Hole-hole interaction in a strained Inx_xGa1−x_{1-x}As two dimensional system

The interaction correction to the conductivity of 2D hole gas in strained GaAs/In$_x$Ga$_{1-x}$As/GaAs quantum well structures was studied. It is shown that the Zeeman splitting, spin relaxation and ballistic contribution should be taking into account for reliable determination of the Fermi-liquid constant $F_0^\sigma$. The proper consideration of these effects allows us to describe both th temperature and magnetic field dependences of the conductivity and find the value of $F_0^\sigma$.Comment: 7 pages, 6 figure

Microwave photoresistance of a high-mobility two-dimensional electron gas in a triangular antidot lattice

The microwave (MW) photoresistance has been measured on a high-mobility two-dimensional electron gas patterned with a shallow triangular antidot lattice, where both the MW-induced resistance oscillations (MIRO) and magnetoplasmon (MP) resonance are observed superposing on sharp commensurate geometrical resonance (GR). Analysis shows that the MIRO, MP, and GR are decoupled from each other in these experiments.Comment: 5 pages, 4 figures, paper accepted by PR

Quasiclassical negative magnetoresistance of a 2D electron gas: interplay of strong scatterers and smooth disorder

We study the quasiclassical magnetotransport of non-interacting fermions in two dimensions moving in a random array of strong scatterers (antidots, impurities or defects) on the background of a smooth random potential. We demonstrate that the combination of the two types of disorder induces a novel mechanism leading to a strong negative magnetoresistance, followed by the saturation of the magnetoresistivity $\rho_{xx}(B)$ at a value determined solely by the smooth disorder. Experimental relevance to the transport in semiconductor heterostructures is discussed.Comment: 4 pages, 2 figure