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Molecular Underpinnings (molecular + underpinning)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration,

HEPATOLOGY, Issue 2 2007
Yongzhi Cui
Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1,/, mice with a hepatocyte-specific deletion of Stat5. Concomitant loss of both Stat5 and Stat1 restored cell proliferation upon PHx but did not reverse fatty liver development. Thus the molecular underpinnings of some defects observed in the absence of Stat5 are the consequence of a deregulated activation of other signal transducers and activators of transcription (STAT) family members. Conclusion: Aberrant cytokine-Stat5 signaling in hepatocytes alters their physiology through increased activity of Stat1 and Stat3. Such cross-talk between different pathways could add to the complexity of syndromes observed in disease. (HEPATOLOGY 2007.) [source]

Endocrine parameters of cystic fibrosis: Back to basics

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009
Michael S. Stalvey
Abstract Dramatic changes in the life expectancy of cystic fibrosis (CF) patients are occurring, creating a cohort of aging individuals experiencing long-term complications of this chronic disease. The two most common of these complications include CF-related diabetes and CF bone disease. The clinical implications of each have become better understood, as have potential therapies. However, data obtained from the basic science studies of both diseases have not been widely recognized. In this review, we focus on the known and hypothesized pathogenesis of these two disorders. Additionally, the molecular underpinnings of CF will be explained along with the potential interactions with endocrine disease phenotypes. J. Cell. Biochem. 108: 353,361, 2009. © 2009 Wiley-Liss, Inc. [source]

Longitudinal Brain Metabolic Characterization of Chronic Alcoholics With Proton Magnetic Resonance Spectroscopy

ALCOHOLISM, Issue 9 2002
Mitchell H. Parks
Background Proton magnetic resonance spectroscopy may elucidate the molecular underpinnings of alcoholism-associated brain shrinkage and the progression of alcohol dependence. Methods Using proton magnetic resonance spectroscopy, we determined absolute concentrations of N -acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline (Cho)-containing compounds and myo -inositol (mI) in the anterior superior cerebellar vermis and frontal lobe white matter in 31 alcoholics and 12 normal controls. All patients were examined within 3 to 5 days of their last drink. Patients who did not relapse were again studied after 3 weeks and 3 months of abstinence by using an on-line repositioning technique that allows reliable localization of volumes of interest (VOIs). Results At 3 to 5 days after the last drink, frontal white matter metabolite concentrations were not significantly different from those of normal controls, whereas brain tissue in the VOI was reduced. Cerebellar [NAA] and [Cho] and brain and cerebellar volumes were decreased, but [Cr], [mI], and VOI brain tissue volume were not significantly different. Eight patients relapsed before 3 weeks (ER), 12 relapsed between 3 weeks and 3 months (LR), and 11 did not relapse (NR) during 3 months. Cerebellar [NAA] was reduced only in ER patients, despite the fact that ER patients drank for significantly fewer years and earlier in life than LR or NR patients. After 3 months, in the 11 continuously abstinent patients, cerebellar [NAA] and brain and cerebellar volumes increased; cerebellar [Cho], [Cr], and [mI] and VOI brain tissue did not change significantly. Conclusions Decreased [NAA] and [Cho] in cerebellar vermis indicate a unique sensitivity to alcohol-induced brain injury. Cerebellar [NAA] increased with abstinence, but reduced [Cho] persisted beyond 3 months. Further studies are needed to determine whether low cerebellar [NAA] is a risk factor for, or consequence of, malignant, early-onset alcoholism. [source]

Relating Chemical and Biological Diversity Space: A Tunable System for Efficient Gene Transfection

CHEMBIOCHEM, Issue 12 2008
Liisa D. Van Vliet Dr.
Abstract Polyethyleneimine (PEI), a well-established nonviral transfection reagent, was combinatorially modified with varying proportions of methyl, benzyl, and n -dodecyl groups to create a library of 435 derivatized polymers. Screening of this library for transfection, DNA binding, and toxicity allows systematic correlation of the biological properties of our polymers to their derivatizations. Combinations of derivatizations bring about a 100-fold variation in transfection efficiency between library members. The best PEI derivatives exhibit increases in transfection efficiency of more than 80-fold over unmodified PEI (up to 28±7,% of cells transfected) and rival commercial reagents such as Lipofectamine 2000 (21±10,%) and JetPEI (32±5.0,%). In addition, we can identify compounds that are specifically tuned for efficient transfection in CHO-K1 over Ishikawa cells and vice versa, demonstrating that the approach can lead to cell-type selectivity of at least one order of magnitude. This work demonstrates that multivalent derivatization of a polymeric framework can create functional diversity substantially greater than the structural diversity of the derivatization building blocks and suggests an approach to a better understanding of the molecular underpinnings of transfection as well as their exploitation. [source]