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Andrea M Zuhl, Charles E Nolan, Michael A Brodney, Sherry Niessen, Kevin Atchison, Christopher Houle, David A Karanian, Claude Ambroise, Jeffrey W Brulet, Elizabeth M Beck, Shawn D Doran, Brian T O'Neill, Christopher W Am Ende, Cheng Chang, Kieran F Geoghegan, Graham M West, Joshua C Judkins, Xinjun Hou, David R Riddell, Douglas S Johnson
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein...
October 11, 2016: Nature Communications
Calen P Ryan, Thomas W McDade, Lee T Gettler, Dan T A Eisenberg, Margarita Rzhetskaya, M Geoffey Hayes, Christopher W Kuzawa
OBJECTIVES: Testosterone (T), the primary androgenic hormone in males, is stimulated through pulsatile secretion of LH and regulated through negative feedback inhibition at the hypothalamus and pituitary. The hypothalamic-pituitary-gonadal (HPG) axis also controls sperm production through the secretion of follicle-stimulating hormone (FSH). Negative feedback in the HPG axis is achieved in part through the binding of T to the androgen receptor (AR), which contains a highly variable trinucleotide repeat polymorphism (AR-CAGn)...
July 15, 2016: American Journal of Human Biology: the Official Journal of the Human Biology Council
A Nickisch, M Gross, R Schönweiler, R Berger, T Wiesner, A Am Zehnhoff Dinnesen, M Ptok
The APD guideline of 2009 was supplemented by the statements listed here. The addition is based on current knowledge and findings. Otherwise, the Guideline 2009 remains valid. Here, a summary of the updated APD guideline is given, thus proving an overview of the definition of APD, diagnosis, differential diagnosis and recommended for APD management.
June 2015: HNO
Zahra Ghanian, Sepideh Maleki, Hannah Reiland, Daniel E Bütz, Grazia Chiellini, Fariba M Assadi-Porter, Fariba-Assadi Porter, Mahsa Ranji
This study used an optical technique to measure the effects of treating low (10 mg/kg) and high (25 mg/kg) doses of 3-iodothyronamine (T₁AM) on the metabolism in the kidney and heart of mice. The ratio of two intrinsic fluorophores in tissue, (NADH/FAD), called the NADH redox ratio (NADH RR), is a marker of the metabolic state of the tissue. A cryofluorescence imaging instrument was used to provide a quantitative assessment of NADH RR in both kidneys and hearts in mice treated with 3-iodothyronamine. We compared those results to corresponding tissues in control mice...
February 2014: Experimental Biology and Medicine
Sarah J Pyszczynski, Eric J Munson
We have identified and characterized a new solid form of trehalose, the δ form (Tδ) using (13)C solid-state NMR spectroscopy (SSNMR). Tδ is formed from dehydrations of trehalose dihydrate (T(h)) performed at or below 100 °C, and it is generated concurrently with the α form of trehalose (Tα) and amorphous trehalose (T(am)); the β form of trehalose (Tβ) has been observed in some dehydrated samples. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies of samples containing Tδ do not indicate the presence of the new form...
September 3, 2013: Molecular Pharmaceutics
Nina Hobi, Andrea Ravasio, Thomas Haller
Previous work from our group (Ravasio A, Hobi N, Bertocchi C, Jesacher A, Dietl P, Haller T. Am J Physiol Cell Physiol 300: C1456-C1465, 2011.) showed that contact of alveolar epithelial type II cells with an air-liquid interface (I(AL)) leads to a paradoxical situation. It is a potential threat that can cause cell injury, but also a Ca(2+)-dependent stimulus for surfactant secretion. Both events can be explained by the impact of interfacial tensile forces on cellular structures. Here, the strength of this mechanical stimulus became also apparent in microarray studies by a rapid and significant change on the transcriptional level...
July 2012: American Journal of Physiology. Lung Cellular and Molecular Physiology
Nduka Ikpo, Christian Hoffmann, Louise N Dawe, Francesca M Kerton
A series of lithium complexes were prepared from 2(N-piperazinyl-N'-methyl)-2-methylene-4-R'-6-R-phenols ([ONN](RR')) and characterized through elemental analysis, (1)H and (13)C{(1)H} NMR spectroscopy, and X-ray crystallography. Treatment of the ligands with n-butyllithium afforded {Li[ONN](RR')}(3) [R = Me, R' = (t)Bu, (1); R = R' = (t)Bu (2); R = R' = (t)Am, (3), (t)Am = C(CH(3))(2)CH(2)CH(3)], with trimetallic structures in the solid-state as shown by single-crystal X-ray diffraction. The reactivity of these complexes in the ring-opening polymerization of ε-caprolactone (ε-CL), as well as the influences of monomer concentration, monomer/Li molar ratio, polymerization temperature and time, was studied...
June 14, 2012: Dalton Transactions: An International Journal of Inorganic Chemistry
Wen Liu, Núria M Pastor-Soler, Carlos Schreck, Beth Zavilowitz, Thomas R Kleyman, Lisa M Satlin
Epithelial Na(+) channel (ENaC)-mediated Na(+) absorption and BK channel-mediated K(+) secretion in the cortical collecting duct (CCD) are modulated by flow, the latter requiring an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), microtubule integrity, and exocytic insertion of preformed channels into the apical membrane. As axial flow modulates HCO(3)(-) reabsorption in the proximal tubule due to changes in both luminal Na(+)/H(+) exchanger 3 and H(+)-ATPase activity (Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, Wang T...
January 1, 2012: American Journal of Physiology. Renal Physiology
A J Miller, D F Twomey, R H Davies, C J Teale, S M Williamson, R Reichel, C A Featherstone, A J C Cook, L C Snow, J D Armstrong
Following the introduction of a national abattoir-based monitoring programme for Salmonella in pigs, advisory visits were made to pig farms in England and Wales with high Salmonella seroprevalence assessed by muscle tissue fluid (meat juice) ELISA. Samples (n = 15 790), including pooled pen floor faeces (n = 12 136), were collected for Salmonella culture from 296 farms, between October 2003 and February 2008. Salmonella was isolated from 4489 (28%) of all samples collected, including 3301 (27%) of pooled pen floor faecal samples, from 270 (91%) of farms visited...
December 2011: Zoonoses and Public Health
J B Gaughan, S Bonner, I Loxton, T L Mader, A Lisle, R Lawrence
A 120-d feedlot study using 164 Angus steers (BW = 396.7 ± 7.0 kg) was undertaken in Queensland Australia (24°84' S, 149°78' N) to determine the effect of shade on body temperature (T(B)) and performance. Cattle were allocated to 20 pens: 16 with an area of 144 m(2) (8 steers/pen) and 4 with an area of 168 m(2) (9 steers/pen). Treatments (10 pens/treatment) were unshaded (NS) vs. shaded (SH). Shade (3.3 m(2)/steer) was provided by 80% solar block shade cloth. Before the study (d -31), 63 steers were implanted (between the internal abdominal muscle and the peritoneum at the right side flank) with a T(B) transmitter...
December 2010: Journal of Animal Science
Virginia J Vitzthum, Carol M Worthman, Cynthia M Beall, Jonathan Thornburg, Enrique Vargas, Mercedes Villena, Rudy Soria, Esperanza Caceres, Hilde Spielvogel
Testosterone (T) plays a key role in the increase and maintenance of muscle mass and bone density in adult men. Life history theory predicts that environmental stress may prompt a reallocation of such investments to those functions critical to survival. We tested this hypothesis in two studies of rural Bolivian adult men by comparing free T levels and circadian rhythms during late winter, which is especially severe, to those in less arduous seasons. For each pair of salivary T(AM)/T(PM) samples (collected in a approximately 12-h period), circadian rhythm was considered classic (C(CLASSIC)) if T(AM) > 110%T(PM), reverse (C(REVERSE)) if T(PM) > 110%T(AM), and flat (C(FLAT)) otherwise...
November 2009: American Journal of Human Biology: the Official Journal of the Human Biology Council
S Piehl, T Heberer, G Balizs, T S Scanlan, R Smits, B Koksch, J Köhrle
3-Iodothyronamine (3-T 1 AM) and thyronamine (T AM) are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T(3)) actions. Their proposed biosynthesis from thyroid hormones would require decarboxylation and more or less extensive deiodination. Deiodinases (Dio1, Dio2, and Dio3) catalyze the removal of iodine from their substrates. Because a role of deiodinases in thyronamine biosynthesis requires their ability to accept thyronamines as substrates, we investigated whether thyronamines are converted by deiodinases...
June 2008: Endocrinology
Michael I Lewis, Mario Fournier, Thomas W Storer, Shalender Bhasin, Janos Porszasz, Song-Guang Ren, Xiaoyu Da, Richard Casaburi
We recently reported increased leg lean mass and strength in men with chronic obstructive pulmonary disease (COPD) receiving 10 wk of testosterone (T) and leg resistance training (R) (Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis M, Fournier M, Storer T. Am J Respir Crit Care Med 170: 870-878, 2004). The present study evaluates the role of muscle IGF and related factors as potential mechanisms for our findings, using quadriceps muscle biopsies from the same cohort. Patient groups were 1) weekly placebo (P) injections + no R; 2) P and R; 3) weekly injections of T + no R; and 4) T + R (TR)...
October 2007: Journal of Applied Physiology
Christophe Jayle, Frederic Favreau, Kequiang Zhang, Carole Doucet, Jean Michel Goujon, William Hebrard, Michel Carretier, Michel Eugene, Gerard Mauco, Jean Paul Tillement, Thierry Hauet
Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T...
March 2007: American Journal of Physiology. Renal Physiology
Ken Watanabe, Toshio Nishikimi, Motoki Takamuro, Kenji Yasuda, Yuichi Ishikawa, Saori Tanabe, Osamu Yamada, Toshikatsu Yagihara, Shinichi Suga, Kenji Kangawa, Hiroaki Matsuoka, Shigeyuki Echigo
OBJECTIVE: We investigated the pathophysiological significance of molecular forms of adrenomedullin (AM) in patients after the Fontan procedure. METHODS: Plasma concentrations of mature AM (AM-m), an active form, glycine-extended AM (AM-Gly), an inactive form, and total AM (AM-T: AM-m+AM-Gly) were measured by specific immunoradiometric assay in the femoral vein, pulmonary artery and femoral artery of 29 consecutive patients after the Fontan procedure. The eleven patients who had history of Kawasaki disease and have normal coronary and hemodynamics served as control...
June 7, 2007: Regulatory Peptides
Alan M Weinstein, Sheldon Weinbaum, Yi Duan, Zhaopeng Du, Qingshang Yan, Tong Wang
The mathematical model of rat proximal tubule has been extended to include calculation of microvillous torque and to incorporate torque-dependent solute transport in a compliant tubule. The torque calculation follows that of Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, and Wang T (Am J Physiol 290: F289-F296, 2006). In the model calculations, torque-dependent scaling of luminal membrane transporter density [either as an ensemble or just type 3 Na(+)/H(+) exchanger (NHE3) alone] had a relatively small impact on overall Na(+) reabsorption and could produce a lethal derangement of cell volume; coordinated regulation of luminal and peritubular transporters was required to represent the overall impact of luminal flow on Na(+) reabsorption...
April 2007: American Journal of Physiology. Renal Physiology
Aihua Zhang, Zheng Dong, Tianxin Yang
In a separate study, we identified PGE2 as a potent inhibitor of TGF-beta1induced epithelial-mesenchymal transition (EMT) in cultured Madin-Darby canine kidney (MDCK) cells (Zhang A, Wang M-H, Dong Z, and Yang T. Am J Physiol Renal Physiol 291: F1323-F1331, 2006). This finding prompted us to examine the roles of other prostanoids: PGD2, PGF(2alpha), PGI2, and thromboxane A2 (TXA2). Treatment with 10 ng/ml TGF-beta1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and activation of alpha-smooth muscle actin (alpha-SMA)...
December 2006: American Journal of Physiology. Renal Physiology
Xin Wang, Nishikimi Toshio, Zhi-zhong Li, Qing-xiang Li, Xiao-ling Zhu, Shu-gong Bai
OBJECTIVE: To investigate the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand and amidating activity in the hypertrophied heart in severe hypertension. METHODS: The following four groups were studied: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), 8 weeks captopril-treated SHR-SP, and 8 weeks trichlormethiazide-treated SHR-SP. AM precursor was converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly was converted to active mature AM (AM-m) by enzymatic amidation...
January 2005: Zhonghua Xin Xue Guan Bing za Zhi
Jun Murata, Kanji Matsukawa, Hidehiko Komine, Hirotsugu Tsuchimochi, Tomoko Nakamoto
Animals decerebrated at the precollicular-premammillary body level exhibit spontaneous locomotion without any artificial stimulation. Our laboratory reported that the cardiovascular and autonomic responses at the onset of spontaneous locomotor events are evoked by central command, generated from the caudal diencephalon and the brain stem (Matsukawa K, Murata J, and Wada T. Am J Physiol Heart Circ Physiol 275: H1115-H1121, 1998). In this study, we examined whether central command and/or a reflex resulting from muscle afferents modulates arterial baroreflex function using a decerebrate cat model...
October 2004: Journal of Applied Physiology
Yasutaka Kurata, Ichiro Hisatome, Sunao Imanishi, Toshishige Shibamoto
To elucidate the dynamical mechanisms of the sinoatrial (SA) node pacemaker activity, we investigated the roles of L-type Ca2+ (ICa,L) and delayed-rectifier K+ (IKr) currents in pacemaking by stability and bifurcation analyses of our rabbit SA node model (Kurata Y, Hisatome I, Imanishi S, and Shibamoto T. Am J Physiol Heart Circ Physiol 283: H2074-H2101, 2002). Equilibrium points (EPs), periodic orbits, stability of EPs, and Hopf bifurcation points were calculated as functions of conductance or gating time constants of the currents for constructing bifurcation diagrams...
December 2003: American Journal of Physiology. Heart and Circulatory Physiology
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