bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender differences in naphthalene metabolism and naphthalene-induced acute lung injury
Authors: Van Winkle Laura S. , Gunderson Andrew D. , Shimizu Judith A. , Baker Gregory L. , Brown Collette D.
Published: March 2015

Humans are widely exposed to polycyclic aromatic hydrocarbons, commonly found in cigarette smoke and diesel exhaust. These can undergo site- and cell-specific metabolism to cytotoxic intermediates. Metabolism of naphthalene and Clara cell cytotoxicity have been extensively studied in male animals. To address whether male and female mice are equally susceptible to naphthalene, mice were injected with naphthalene, and lungs were examined 1, 2, 3, 6, and 24 h after treatment. By analysis of acute injury using differential permeability to fluorescent nuclear dyes and high-resolution histopathology, injury in female mice was found to be more extensive, occur earlier, and include permeable cells in proximal airways, including airway bifurcations. HPLC analysis of the products of cytochrome P-450 (CYP)-mediated metabolism in microdissected airways indicated that although both genders produced a predominance of products from CYP2F2, female mice produced more naphthalene dihydrodiol in distal airways, the primary sites of injury. We conclude that there are clear gender differences in susceptibility to naphthalene-induced injury and that differences in metabolism of naphthalene may play a role in elevated susceptibility in female mice.
p53 protects against LPS-induced lung endothelial barrier dysfunction
Authors: Barabutis Nektarios , Dimitropoulou Christiana , Birmpas Charalampos , Joshi Atul , Thangjam Gagan , Catravas John D.
Published: February 2015

New therapies toward heart and blood vessel disorders may emerge from the development of Hsp90 inhibitors. Several independent studies suggest potent anti-inflammatory activities of those agents in human tissues. The molecular mechanisms responsible for their protective effects in the vasculature remain unclear. The present study demonstrates that the transcription factor p53, an Hsp90 client protein, is crucial for the maintenance of vascular integrity, protects again LPS-induced endothelial barrier dysfunction, and is involved in the mediation of the anti-inflammatory activity of Hsp90 inhibitors in lung tissues. p53 silencing by siRNA decreased transendothelial resistance (a measure of endothelial barrier function). A similar effect was induced by the p53 inhibitor pifithrin, which also potentiated the LPS-induced hyperpermeability in human lung microvascular endothelial cells (HLMVEC). On the other hand, p53 induction by nutlin suppressed the LPS-induced vascular barrier dysfunction. LPS decreased p53 expression in lung tissues and that effect was blocked by pretreatment with Hsp90 inhibitors both in vivo and in vitro. Furthermore, the Hsp90 inhibitor 17-allyl-amino-demethoxy-geldanamycin suppressed the LPS-induced overexpression of the p53 negative regulator MDMX as well as p53 and MDM2 (another p53 negative regulator) phosphorylation in HLMVEC. Both negative p53 regulators were downregulated by LPS in vivo. Chemically induced p53 overexpression resulted in the suppression of LPS-induced RhoA activation and MLC2 phosphorylation, whereas p53 suppression caused the opposite effects. These observations reveal new mechanisms for the anti-inflammatory actions of Hsp90 inhibitors, i.e., the induction of the transcription factor p53, which in turn can orchestrate robust vascular anti-inflammatory responses both in vivo and in vitro.
IP3-induced tension and IP3-receptor expression in rat soleus muscle during postnatal development
Authors: Talon Sophie , Vallot Olivier , Huchet-Cadiou Corinne , Lompré Anne-Marie , Léoty Claude
Published: March 2015

The present study was designed to examine whether changes in Ca2+release by inositol-1,4,5-trisphosphate (IP3) in 8-, 15-, and 30-day-old rat skeletal muscles could be associated with the expression of IP3receptors. Experiments were conducted in slow-twitch muscle in which both IP3-induced Ca2+release and IP3-receptor (IP3R) expression have been shown to be larger than in fast-twitch muscle. In saponin-skinned fibers, IP3induced transient contractile responses in which the amplitude was dependent on the Ca2+-loading period with the maximal IP3contracture being at 20 min of loading. The IP3tension decreased during postnatal development, was partially inhibited by ryanodine (100 μM), and was blocked by heparin (20–400 μg/ml). Amplification of the DNA sequence encoding for IP3R isoforms (using the RT-PCR technique) showed that in slow-twitch muscle, the type 2 isoform is mainly expressed, and its level decreases during postnatal development in parallel with changes in IP3responses in immature fibers. IP3-induced Ca2+release would then have greater participation in excitation-contraction coupling in developing fibers than in mature muscle.
A two-barrier compartment model for volume flow across amphibian skin
Authors: Guo Peng , Hillyard Stanley D. , Fu Bingmei M.
Published: March 2015

The amphibian skin has long been used as a model tissue for the study of ion transport and osmotic water movement across tight epithelia. To understand the mechanism of water uptake across amphibian skin, we model the skin as a well-stirred compartment bounded by an apical barrier and a tissue barrier. The compartment represents the lateral intercellular space between cells in the stratum granulosum. The apical barrier represents the stratum corneum, the principal/mitochondria-rich cells, and the junctional area between cells. This barrier is hypothesized to have the ability to actively transport solutes through Na+-K+-ATPase. The actively transported solute flux is assumed to satisfy the Michaelis-Menten relationship. The tissue barrier represents a composite barrier comprising the stratum spinosum, the stratum germinativum, the basal lamina, and the dermis. Our model shows that 1) the predicted rehydration rates from apical bathing solutions are in good agreement with the experiment results in Hillyard and Larsen ( J Comp Physiol 171: 283-292, 2001); 2) under their experimental conditions, there is a substantial volume flux coupled to the active solute flux and this coupled volume flux is nearly constant when the osmolality of the apical bathing solution is >100 mosmol/kgH2O; 3) the molar ratio of the actively transported solute flux to the coupled water flux is about 1:160, which is the same as that reported in Nielsen ( J Membr Biol 159: 61-69, 1997).
L-selectin is required for fMLP- but not C5a-induced margination of neutrophils in pulmonary circulation
Authors: Olson Timothy S. , Singbartl Kai , Ley Klaus
Published: March 2015

To study the role of L-selectin in neutrophil (PMN) margination and sequestration in the pulmonary microcirculation, maximally active concentrations of C5a (900 pmol/g) and N-formylmethionyl-leucyl-phenylalanine (fMLP; 0.34 pmol/g) were injected into the jugular vein of wild-type or L-selectin-deficient C57BL/6 mice. In wild-type mice administered C5a or fMLP, 92 ± 1% and 34 ± 9%, respectively, of peripheral blood PMN were trapped mostly in the pulmonary circulation as determined by immunohistochemistry and myeloperoxidase activity. In wild-type mice treated with F(ab′)2fragments of the L-selectin monoclonal antibody MEL-14 or in L-selectin-deficient mice, C5a-induced neutropenia was not significantly reduced, but the decrease in peripheral PMN in response to fMLP was completely abolished, indicating that L-selectin is necessary for fMLP- but not C5a-induced pulmonary margination. Immunostained lung sections of fMLP- or C5a-treated mice showed sequestered neutrophils in alveolar capillaries with no evidence of neutrophil aggregates. We conclude that chemoattractant-induced PMN margination in the pulmonary circulation can occur by two separate mechanisms, one of which requires L-selectin.
Anti-inflammatory agents inhibit the induction of leptin by tumor necrosis factor-α
Authors: Finck Brian N. , Johnson Rodney W.
Published: March 2015

Tumor necrosis factor (TNF)-α stimulates the secretion of the adipocyte-derived hormone leptin. However, the cellular mechanisms by which TNF-α influences leptin production are poorly understood. To examine this issue, epididymal fat pads were isolated from mice and cultured in recombinant murine TNF-α (100 ng/ml). Compared with medium-treated controls, steady-state leptin expression was increased in TNF-α-treated explants. Culture with inhibitors of translation (cycloheximide) or transcription (actinomycin-D) abrogated the induction of leptin following TNF-α. Explants were also cultured in the presence of the anti-inflammatory p38 mitogen-activated protein kinase inhibitor (SB-203580) or PG J2metabolite [15-deoxy-Δ12,14-PG J2(PGJ)] and then exposed to TNF-α. Both compounds completely abolished TNF-α-induced increases in leptin production. To test the relevance of this in vivo, mice were pretreated with PGJ and then given TNF-α. PGJ treatment markedly blunted the TNF-α-induced increase in leptin, TNF-α, and interleukin-6 gene expression in epididymal adipose tissue. Collectively, these data indicate that TNF-α acutely activates leptin expression and that anti-inflammatory agents can abrogate TNF-α-induced hyperleptinemia.
Recent advances in renal hemodynamics: insights from bench experiments and computer simulations
Authors: Layton Anita T.
Published: February 2015

It has been long known that the kidney plays an essential role in the control of body fluids and blood pressure and that impairment of renal function may lead to the development of diseases such as hypertension (Guyton AC, Coleman TG, Granger Annu Rev Physiol 34: 13–46, 1972). In this review, we highlight recent advances in our understanding of renal hemodynamics, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Renal Hemodynamics: Integrating with the Nephron and Beyond.
Mineralocorticoid regulation of epithelial Na+channels is maintained in a mouse model of Liddle's syndrome
Authors: Dahlmann Anke , Pradervand Sylvain , Hummler Edith , Rossier Bernard C. , Frindt Gustavo , Palmer Lawrence G.
Published: March 2015

Currents through epithelial Na channels (ENaCs) were measured in the cortical collecting tubule (CCT) of mice expressing truncated β-subunits of ENaC, reproducing one of the mutations found in human patients with Liddle's syndrome. Tubules were isolated from mice homozygous for the Liddle mutation (L/L) and from wild-type (WT) littermates. Amiloride-sensitive currents ( INa) from single cells were recorded under whole cell clamp conditions. CCTs from mice kept under control conditions and fed a diet with normal levels of Na had very small INas (WT: 18 ± 13 pA; L/L: 22 ± 8 pA at Vm= –100 mV) that were not different in WT and L/L animals. However, the L/L mice had much larger currents when the animals were fed a low-Na diet (WT: 256 ± 127 pA; L/L: 1,820 ± 330 pA) or infused with aldosterone (WT: 285 ± 63 pA; L/L: 1,600 ± 280 pA). Currents from L/L mice were also larger when animals were pretreated with a high-K diet but not when the CCTs were stimulated in vitro with 8-CTP-cAMP. Noise analysis of amiloride-induced fluctuations in INashowed that single-channel currents at Vm= 0 mV were slightly smaller in L/L mice (WT: 0.33 pA; L/L: 0.24 pA). This difference could be attributed to a decrease in driving force since current-voltage analysis indicated that intracellular Na was increased in the L/L animals. Analysis of spontaneous channel noise indicated that the open probability was similar in the two genotypes(WT: 0.77; L/L: 0.80). Thus the increase in whole cell current is attributed to a difference in the density of conducting channels.
Urea stress is more akin to EGF exposure than to hypertonic stress in renal medullary cells
Authors: Tian Wei , Cohen David M.
Published: March 2015

Although urea is considered to be a cell stressor even in renal medullary cells perpetually exposed to this solute in vivo by virtue of the renal concentrating mechanism, aspects of urea signaling resemble that of a peptide mitogen. Urea was compared with epidermal growth factor and hypertonic NaCl or hypertonic mannitol using a large-scale expression array-based approach. The expression profile in response to urea stress more closely resembled that of EGF treatment than hypertonic stress, as determined by hierarchical cluster analysis; the effect of urea+NaCl was equidistant from that of either solute applied individually. Among the most highly urea- and hypertonicity-responsive transcripts were genes that had previously been shown to be responsive to these solutes, validating this approach. Increased expression of the activating transcription factor 3 by urea was newly detected via expression array and confirmed via immunoblot analysis. Earlier, we noted an abrogation of tonicity-dependent gene regulation by urea, primarily in a transient transfection-based model (Tian W and Cohen DM. Am J Physiol Renal Physiol 280: F904–F912, 2001). Here we applied K-means cluster analysis to demonstrate that the genes most profoundly up- or downregulated by hypertonic stress were partially restored toward basal levels in the presence of urea pretreatment. These global expression data are consistent with our earlier biochemical studies suggesting that urea affords cytoprotection in this context. In the aggregate, these data strongly support the hypothesis that the urea effect in renal medullary cells resembles that of a peptide mitogen in terms of the adaptive program of gene expression and in terms of cytoprotection from hypertonicity.
Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron
Authors: Wang Hong , D'Ambrosio Martin A. , Ren YiLin , Monu Sumit R. , Leung Pablo , Kutskill Kristopher , Garvin Jeffrey L. , Janic Branislava , Peterson Edward L. , Carretero Oscar A.
Published: February 2015

Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (−7.9 ± 0.2 mmHg) was blocked by furosemide (−0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: −0.2 ± 0.1 vs. furosemide+benzamil: −4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: −1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors.
Excess prenatal corticosterone exposure results in albuminuria, sex-specific hypotension, and altered heart rate responses to restraint stress in aged adult mice
Authors: O'Sullivan Lee , Cuffe James S. M. , Koning Anselm , Singh Reetu R. , Paravicini Tamara M. , Moritz Karen M.
Published: February 2015

Exposure to excess glucocorticoids programs susceptibility to cardiovascular and renal dysfunction in later life although the mechanisms have not been clearly elucidated. We administered corticosterone (CORT; 33 μg·kg−1·h−1) to pregnant mice for 60 h from embryonic day ( E) 12.5. Prenatal CORT resulted in postnatal growth restriction and reduced nephron endowment at postnatal day 30 in both male and female offspring. The reduction in nephron number was associated with increased expression of apoptotic markers in the kidney at E14.5. In offspring of both sexes at 12 mo of age, there were no differences in kidney weights, urine output, or urinary sodium excretion; however, prenatal CORT exposure increased the urinary albumin/creatinine ratio and 24-h urinary albumin excretion. Surprisingly, at 12 mo male but not female offspring exposed to prenatal CORT were hypotensive, with mean arterial blood pressures ∼10 mmHg lower than untreated controls ( P < 0.001). Finally, we examined how offspring responded to a renal or cardiovascular challenge (saline load or restraint stress). When given 0.9% NaCl as drinking water for 7 days, there were no differences in blood pressures or urinary parameters between groups. Restraint stress (15 min) caused a tachycardic response in all animals; however the increase in heart rate was not sustained in male offspring exposed to CORT ( P < 0.01), suggesting that autonomic control of cardiovascular function may be altered. These data demonstrate that excess prenatal CORT impairs kidney development and increases the risk of cardiovascular dysfunction especially in males.
Effect of surface tension on alveolar surface area
Authors: Butler James P. , Brown Richard E. , Stamenović Dimitrije , Morris John P. , Topulos George P. ,   (With the Technical Assistance of Lydia S. Stickneyand Shasta Kielbasa)
Published: March 2015

At fixed lung volume (Vl), alterations in surface tension change alveolar surface area (S) and lung recoil (Pl). Wilson (26), using data from fixed lungs (1, 9), quantified the isovolume change in S with Pl. We reexamined this question in fresh excised rabbit lungs, with two important differences. First, we measured fractional changes in S by using diffuse light scattering, avoiding the potential upset of the balance of tissue and surface forces during fixation. Second, we altered surface tension by ventilating the lungs with nebulized polydimethylsiloxane, with much less residual fluid compared with lavage. We found that S decreased at low and mid Vl(treatment surface tension > control) by about half of Wilson's estimates and was nearly unaffected by treatment at high Vl. This suggests that with increased surface tension there is 1) greater septal retraction in lungs fixed by vascular perfusion compared with unfixed lungs and 2) a greater increase in Pl and less loss of S than would have been predicted.
Inspiratory loading does not accelerate dystrophy inmdxmouse diaphragm: implications for regenerative therapy
Authors: Krupnick Alexander S. , Zhu Jianliang , Nguyen Taitan , Kreisel Daniel , Balsara Keki R. , Lankford Edward B. , Clark Charles C. , Levine Sanford , Stedman Hansell H. , Shrager Joseph B.
Published: March 2015

Since the finding that the mdx mouse diaphragm, in contrast to limb muscles, undergoes progressive degeneration analogous to that seen in Duchenne muscular dystrophy, the relationship between the workload on a muscle and the pathogenesis of dystrophy has remained controversial. We increased the work performed by the mdx mouse diaphragm in vivo by tracheal banding and evaluated the progression of dystrophic changes in that muscle. Despite the establishment of dramatically increased respiratory workload and accelerated myofiber damage documented by Evans blue dye, no change in the pace of progression of dystrophy was seen in banded animals vs. unbanded, sham-operated controls. At the completion of the study, more centrally nucleated fibers were evident in the diaphragms of banded mdx mice than in sham-operated mdx controls, indicating that myofiber regeneration increases to meet the demands of the work-induced damage. These data suggest that there is untapped regenerative capacity in dystrophin-deficient muscle and validates experimental efforts aimed at augmenting regeneration within skeletal muscle as a therapeutic strategy in the treatment of dystrophinopathies.
High-impact exercise strengthens bone in osteopenic ovariectomized rats with the same outcome as Sham rats
Authors: Honda Akiko , Sogo Naota , Nagasawa Seigo , Shimizu Takuya , Umemura Yoshihisa
Published: March 2015

The effect of jump exercise on middle-aged osteopenic rats was investigated. Forty-two 9-mo-old female rats were either sham-operated (Sham) or ovariectomized (OVX). Three months after surgery, the rats were divided into the following groups: Sham sedentary, Sham exercised, OVX sedentary, and OVX exercised. Rats in the exercise groups jumped 10 times/day, 5 days/wk, for 8 wk, with a jumping height of 40 cm. Less than 1 min was required for the jump training. After the experiment, the right tibia and femur were dissected, and blood was obtained from each rat. OVX rats were observed to have increased body weights and decreased bone mass in their tibiae and femurs. Jump-exercised rats, on the other hand, had significantly increased tibial bone mass, strength, and cortical areas. The bone mass and strength of OVX exercised rats increased to approximately the same extent as Sham exercised rats, despite estrogen deficiency or osteopenia. Our data suggest that jump exercise has beneficial effects on lower limb bone mass, strength, bone mineral density, and morphometry in middle-aged osteopenic rats, as well as in Sham rats.
Characterization of LPS-induced lung inflammation incftr−/−mice and the effect of docosahexaenoic acid
Authors: Freedman Steven D. , Weinstein Deborah , Blanco Paola G. , Martinez-Clark Pedro , Urman Serge , Zaman Munir , Morrow Jason D. , Alvarez Juan G.
Published: March 2015

The mechanism by which Pseudomonas causes excessive inflammation in the cystic fibrosis lung is unclear. We have reported that arachidonic acid is increased and docosahexaenoic acid (DHA) decreased in lung, pancreas, and ileum from cftr−/−mice. Oral DHA corrected this defect and reversed the pathology. To determine which mediators regulate inflammation in lungs from cftr−/−mice and whether inhibition occurs with DHA, cftr−/−and wild-type (WT) mice were exposed to aerosolized Pseudomonas lipopolysaccharide (LPS). After 2 days of LPS, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2, and KC levels in bronchoalveolar lavage fluid were increased in cftr−/−compared with WT mice and not suppressed by pretreatment with oral DHA. Neutrophil levels were not different between cftr−/−and WT mice. After 3 days of aerosolized LPS, neutrophil concentration, TNF-α, and the eicosanoids 6-keto-PGF1α, PGF2α, PGE2, and thromboxane B2were all increased in bronchoalveolar lavage fluid from cftr−/−mice compared with WT controls. Oral DHA had no significant effect on TNF-α levels in cftr−/−mice. In contrast, neutrophils and eicosanoids were decreased in cftr−/−but not in WT mice treated with DHA, indicating that the effects of DHA on these inflammatory parameters may be related to correction of the membrane lipid defect.
Double-stranded RNA causes airway hyperreactivity and neuronal M2muscarinic receptor dysfunction
Authors: Bowerfind William M. L. , Fryer Allison D. , Jacoby David B.
Published: March 2015

Viral infection causes dysfunction of inhibitory M2muscarinic receptors (M2Rs) on parasympathetic nerves, leading to airway hyperreactivity. The mechanisms of M2R dysfunction are incompletely understood. Double-stranded RNA (dsRNA), a product of viral replication, promotes the expression of interferons. Interferon-γ decreases M2R gene expression in cultured airway parasympathetic neurons. In this study, guinea pigs were treated with dsRNA (1 mg/kg ip) on 2 consecutive days. Twenty-four hours later, anesthetized guinea pigs had dysfunctional M2Rs and were hyperresponsive to electrical stimulation of the vagus nerves, in the absence of inflammation. DsRNA did not affect either cholinesterase or the function of postjunctional M3muscarinic receptors on smooth muscle. M2Rs on the nerves supplying the heart were also dysfunctional, but M2Rs on the heart muscle itself functioned normally. Thus dsRNA causes increased bronchoconstriction and bradycardia via increased release of ACh from the vagus nerves because of loss of M2R function on parasympathetic nerves in the lungs and heart. Production of dsRNA may be a mechanism by which viruses cause dysfunction of neuronal M2Rs and airway hyperreactivity.
Exercise training alleviates MCT1 and MCT4 reductions in heart and skeletal muscles of STZ-induced diabetic rats
Authors: Enoki Taisuke , Yoshida Yuko , Hatta Hideo , Bonen Arend
Published: March 2015

We compared the changes in monocarboxylate transporter 1 (MCT1) and 4 (MCT4) proteins in heart and skeletal muscles in sedentary control and streptozotocin (STZ)-induced diabetic rats (3 wk) and in trained (3 wk) control and STZ-induced diabetic animals. In nondiabetic animals, training increased MCT1 in the plantaris (+51%; P < 0.01) but not in the soleus (+9%) or the heart (+14%). MCT4 was increased in the plantaris (+48%; P < 0.01) but not in the soleus muscles of trained nondiabetic animals. In sedentary diabetic animals, MCT1 was reduced in the heart (−30%), and in the plantaris (−31%; P < 0.01) and soleus (−26%) muscles. MCT4 content was also reduced in sedentary diabetic animals in the plantaris (−52%; P < 0.01) and soleus (−25%) muscles. In contrast, in trained diabetic animals, MCT1 and MCT4 in heart and/or muscle were similar to those of sedentary, nondiabetic animals ( P > 0.05) but were markedly greater than in the sedentary diabetic animals [MCT1: plantaris +63%, soleus +51%, heart +51% ( P > 0.05); MCT4: plantaris +107%, soleus +17% ( P > 0.05)]. These studies have shown that 1) with STZ-induced diabetes, MCT1 and MCT4 are reduced in skeletal muscle and/or the heart and 2) exercise training alleviated these diabetes-induced reductions.
Anti-inflammatory agent, dexamethasone, does not affect exercise-induced arterial hypoxemia in Thoroughbreds
Authors: Manohar Murli , Goetz Thomas E. , Hassan Aslam S. , Depuy Tracy , Humphrey Sarah
Published: March 2015

In view of the suggestion that pulmonary injury-induced release of histamine and/or other chemical mediators from airway inflammatory and mast cells contribute to the exercise-induced arterial hypoxemia (EIAH) in human athletes, we examined the effects of pretreatment with a potent anti-inflammatory agent, dexamethasone, on EIAH and desaturation of hemoglobin in horses. Seven healthy, sound, exercise-trained Thoroughbreds were studied in the control (no medications) experiments, followed in 7 days by intravenous dexamethasone (0.11 mg·kg−1·day−1for 3 consecutive days) studies. Blood-gas measurements were made at rest and during incremental exercise leading to maximal exertion at 14 m/s on a 3.5% uphill grade. Galloping at this workload induced pulmonary hemorrhage in all horses in both treatments, thereby indicating that stress failure of pulmonary capillaries had occurred. In both treatments, significant EIAH, desaturation of hemoglobin, hypercapnia, acidosis, and hyperthermia developed during maximal exercise, but significant differences between the control and dexamethasone treatments were not discerned. The failure of pretreatment with dexamethasone to significantly affect EIAH suggests that pulmonary injury-evoked airway inflammatory response may not play a major role in EIAH in racehorses. However, our observations in both treatments that EIAH developed quickly (being evident at 30 s of exertion) and that its severity remained unaffected by increasing exercise duration (to 120 s) suggest that EIAH has a functional basis, probably related to significant shortening of the transit time for blood in the pulmonary capillaries as cardiac output increases dramatically.
Fatigue depresses maximal in vitro skeletal muscle Na+-K+-ATPase activity in untrained and trained individuals
Authors: Fraser Steve F. , Li Jia L. , Carey Michael F. , Wang Xiao N. , Sangkabutra Termboon , Sostaric Simon , Selig Steve E. , Kjeldsen Keld , McKenna Michael J.
Published: March 2015

This study investigated whether fatiguing dynamic exercise depresses maximal in vitro Na+-K+-ATPase activity and whether any depression is attenuated with chronic training. Eight untrained (UT), eight resistance-trained (RT), and eight endurance-trained (ET) subjects performed a quadriceps fatigue test, comprising 50 maximal isokinetic contractions (180°/s, 0.5 Hz). Muscle biopsies (vastus lateralis) were taken before and immediately after exercise and were analyzed for maximal in vitro Na+-K+-ATPase (K+-stimulated 3- O-methylfluoroscein phosphatase) activity. Resting samples were analyzed for [3H]ouabain binding site content, which was 16.6 and 18.3% higher ( P < 0.05) in ET than RT and UT, respectively (UT 311 ± 41, RT 302 ± 52, ET 357 ± 29 pmol/g wet wt). 3- O-methylfluoroscein phosphatase activity was depressed at fatigue by −13.8 ± 4.1% ( P < 0.05), with no differences between groups (UT −13 ± 4, RT −9 ± 6, ET −22 ± 6%). During incremental exercise, ET had a lower ratio of rise in plasma K+ concentration to work than UT ( P < 0.05) and tended ( P = 0.09) to be lower than RT (UT 18.5 ± 2.3, RT 16.2 ± 2.2, ET 11.8 ± 0.4 nmol · l−1 · J−1). In conclusion, maximal in vitro Na+-K+-ATPase activity was depressed with fatigue, regardless of training state, suggesting that this may be an important determinant of fatigue.
The effect of force feedback delay on stiffness perception and grip force modulation during tool-mediated interaction with elastic force fields
Authors: Leib Raz , Karniel Amir , Nisky Ilana
Published: February 2015

During interaction with objects, we form an internal representation of their mechanical properties. This representation is used for perception and for guiding actions, such as in precision grip, where grip force is modulated with the predicted load forces. In this study, we explored the relationship between grip force adjustment and perception of stiffness during interaction with linear elastic force fields. In a forced-choice paradigm, participants probed pairs of virtual force fields while grasping a force sensor that was attached to a haptic device. For each pair, they were asked which field had higher level of stiffness. In half of the pairs, the force feedback of one of the fields was delayed. Participants underestimated the stiffness of the delayed field relatively to the nondelayed, but their grip force characteristics were similar in both conditions. We analyzed the magnitude of the grip force and the lag between the grip force and the load force in the exploratory probing movements within each trial. Right before answering which force field had higher level of stiffness, both magnitude and lag were similar between delayed and nondelayed force fields. These results suggest that an accurate internal representation of environment stiffness and time delay was used for adjusting the grip force. However, this representation did not help in eliminating the bias in stiffness perception. We argue that during performance of a perceptual task that is based on proprioceptive feedback, separate neural mechanisms are responsible for perception and action-related computations in the brain.
Weak orientation and direction selectivity in lateral geniculate nucleus representing central vision in the gray squirrelSciurus carolinensis
Authors: Zaltsman Julia B. , Heimel J. Alexander , Van Hooser Stephen D.
Published: February 2015

Classic studies of lateral geniculate nucleus (LGN) and visual cortex (V1) in carnivores and primates have found that a majority of neurons in LGN exhibit a center-surround organization, while V1 neurons exhibit strong orientation selectivity and, in many species, direction selectivity. Recent work in the mouse and the monkey has discovered previously unknown classes of orientation- and direction-selective neurons in LGN. Furthermore, some recent studies in the mouse report that many LGN cells exhibit pronounced orientation biases that are of comparable strength to the subthreshold inputs to V1 neurons. These results raise the possibility that, in rodents, orientation biases of individual LGN cells make a substantial contribution to cortical orientation selectivity. Alternatively, the size and contribution of orientation- or direction-selective channels from LGN to V1 may vary across mammals. To address this question, we examined orientation and direction selectivity in LGN and V1 neurons of a highly visual diurnal rodent: the gray squirrel. In the representation of central vision, only a few LGN neurons exhibited strong orientation or direction selectivity. Across the population, LGN neurons showed weak orientation biases and were much less selective for orientation compared with V1 neurons. Although direction selectivity was weak overall, LGN layers 3abc, which contain neurons that express calbindin, exhibited elevated direction selectivity index values compared with LGN layers 1 and 2. These results suggest that, for central visual fields, the contribution of orientation- and direction-selective channels from the LGN to V1 is small in the squirrel. As in other mammals, this small contribution is elevated in the calbindin-positive layers of the LGN
Brain-mediated antidiabetic, anorexic, and cardiovascular actions of leptin require melanocortin-4 receptor signaling
Authors: da Silva Alexandre A. , Spradley Frank T. , Granger Joey P. , Hall John E. , do Carmo Jussara M.
Published: February 2015

We previously demonstrated that leptin has powerful central nervous system (CNS)-mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 ± 2 vs. 111 ± 2 mmHg) and HR was lower in MC4R-KO rats (320 ± 6 vs. 347 ± 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (∼17 mmHg) and HR (∼61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ∼10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 ± 10 to 136 ± 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 ± 16 to 326 ± 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions.
Hand placement near the visual stimulus improves orientation selectivity in V2 neurons
Authors: Perry Carolyn J. , Sergio Lauren E. , Crawford J. Douglas , Fallah Mazyar
Published: February 2015

Often, the brain receives more sensory input than it can process simultaneously. Spatial attention helps overcome this limitation by preferentially processing input from a behaviorally-relevant location. Recent neuropsychological and psychophysical studies suggest that attention is deployed to near-hand space much like how the oculomotor system can deploy attention to an upcoming gaze position. Here we provide the first neuronal evidence that the presence of a nearby hand enhances orientation selectivity in early visual processing area V2. When the hand was placed outside the receptive field, responses to the preferred orientation were significantly enhanced without a corresponding significant increase at the orthogonal orientation. Consequently, there was also a significant sharpening of orientation tuning. In addition, the presence of the hand reduced neuronal response variability. These results indicate that attention is automatically deployed to the space around a hand, improving orientation selectivity. Importantly, this appears to be optimal for motor control of the hand, as opposed to oculomotor mechanisms which enhance responses without sharpening orientation selectivity. Effector-based mechanisms for visual enhancement thus support not only the spatiotemporal dissociation of gaze and reach, but also the optimization of vision for their separate requirements for guiding movements.
New Roles for Connexons
Authors: Ebihara Lisa
Published: March 2015

Connexons or gap junction hemichannels are large, nonselective ion channels that reside in the nonjunctional plasma membrane before their assembly into gap junction channels. Increasing evidence suggests that these channels can open under certain conditions and may participate in a number of cellular processes, including the release of small metabolites such as ATP and NAD+, which are involved in paracrine signaling.
Improved significance test for DNA microarray data: temporal effects of shear stress on endothelial genes
Authors: Zhao Yihua , Chen Benjamin P. C. , Miao Hui , Yuan Suli , Li Yi-Shuan , Hu Yingli , Rocke David M. , Chien Shu
Published: March 2015

Statistical methods for identifying differentially expressed genes from microarray data are evolving. We developed a test for the statistical significance of differential expression as a function of time. When applied to microarray data obtained from endothelial cells exposed to shearing for different durations, the new multi-group test ( G-test) identified three times as many genes as the one-way ANOVA at the same significance level. Using simulated data, we showed that this increase in sensitivity was achieved without sacrificing specificity. Several genes known to respond to shear stress by Northern blotting were identified by the G-test at P ≤ 0.01 (but not by ANOVA), with similar temporal patterns. The validity and utility of the G-test were further supported by the examination of a few more example genes in relation to the present knowledge of their regulatory mechanisms. This new significance test may have broad application for the analysis of gene-expression studies and, in fact, to other biological studies in general.
Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse
Authors: Cvetkovic Branimir , Keen Henry L. , Zhang Xiaoji , Davis Deborah , Yang Baoli , Sigmund Curt D.
Published: March 2015

Angiotensinogen (AGT) was the first gene to be genetically linked to hypertension in humans. Analysis of the gene sequence identified a number of polymorphisms, several of which were reported associated with increased blood pressure (BP) or other cardiovascular diseases. One haplotype of the human AGT (hAGT) gene consisting of an allele at the −6 (A vs. G) position in the promoter and the sequence encoding amino acid 235 (Thr vs. Met) attracted the most attention and has been the subject of numerous association studies. In this report, we addressed the physiological relevance of alleles at these two positions using an experimental mouse model system. Transgenic mice were generated by targeting each haplotype [−6G/235Met (GM) and −6A/235Thr (AT)] as a single copy transgene to the mouse hypoxanthine phosphoribosyl transferase locus, allowing direct comparison of the two transgenes in vivo. Our results indicate that both transgenes exhibit the same transcriptional activity and produce similar levels of hAGT protein in the plasma of the transgenic mice. BP analysis was performed in double transgenic mice generated by breeding each hAGT line to mice expressing a human renin gene. A small but significant increase in BP and relative heart weight was demonstrated by mice carrying the GM haplotype. Moreover, compensatory downregulation of endogenous renin expression was more pronounced in mice containing the GM variant. Our findings suggest that the AT and GM haplotypes of the hAGT gene have no effect on gene expression, but may affect the cardiovascular system and the regulation of BP differently.
Downregulation of growth hormone 1 gene in the cerebellum and prefrontal cortex of rats with depressive-like behavior
Authors: Yamamoto Yuta , Ueyama Takashi , Ito Takao , Tsuruo Yoshihiro
Published: February 2015

Depressive-like behaviors in animals are usually assessed by standardized behavioral tests such as the forced swimming test (FST). However, individual variation in test performance may obscure group differences and thereby hinder the discovery of genes responsible for depression. Few reports have shown the influence of individual variability in identifying the genes associated with depressive-like behaviors. In this study, we conducted microarray analysis to identify genes differentially expressed in the prefrontal cortex (PFC) and cerebellum of rats stratified by FST immobility ratio (% immobility in 5 min) into a control group [immobility ratio: −1 to +1 standard deviation (SD) from the mean] and a depressive group (immobility ratio: +1 to +2 SDs above the mean). Genes differentially expressed in both the cerebellum and PFC of the depressive group were Alas2, Gh1, Hba-a2, Hbb, Hbb-b1, Hbe2, LOC689064, Mrps10, Mybpc, Olf6415, and Pfkb1. Ingenuity Pathway Analysis identified Gh1 as a hub gene in the networks of differentially expressed genes in both brain regions. This study indicates that the depressive-like behavior may be related to the decrease of Gh1 expression in the cerebellum and PFC.
Associations between cardiorespiratory responses to exercise and the C34TAMPD1gene polymorphism in the HERITAGE Family study
Authors: Rico-Sanz J. , Rankinen T. , Joanisse D. R. , Leon A. S. , Skinner J. S. , Wilmore J. H. , Rao D. C. , Bouchard C.
Published: March 2015

The associations of the C34T polymorphism of the adenosine monophosphate deaminase 1 ( AMPD1) gene with cardiorespiratory phenotypes were tested during cycling exercise at absolute and relative power outputs progressing to exhaustion before and after endurance training for 20 wk in the HERITAGE Family Study cohort ( n = 779). Since no blacks were mutant homozygotes (TT), only whites were considered for analysis (400 normal homozygotes, CC; 97 heterozygotes, CT; and 6 TT). For sedentary state, cycling at the absolute power output of 50 W resulted in a higher rating of perceived exertion in TT ( P < 0.0001). At the relative intensity of 60% of V̇o2 max, stroke volume was lower in TT ( P < 0.05). Maximal values for power output, systolic blood pressure, heart rate, V̇co2, and respiratory exchange ratio were lower in TT ( P < 0.05). The cardiorespiratory training response at 50 W and at 60% of V̇o2 maxwas similar across C34T-AMPD1 genotypes. However, the maximal values for ventilation, V̇o2, and V̇co2during exercise increased less in TT ( P < 0.01). The results indicate that subjects with the TT genotype at the C34T AMPD1 gene have diminished exercise capacity and cardiorespiratory responses to exercise in the sedentary state. Furthermore, the training response of ventilatory phenotypes during maximal exercise is more limited in TT.
Four Years Analysis of Cancer Genetic Clinics Activity in France from 1994 to 1997: A Survey on 801 Patients
Authors: Sobol Hagay , Bignon Yves-Jean , Bonaiti Catherine , Cuisenier Jean , Lasset Christine , Lortholary Alain , Noguès Catherine , Stoppa-Lyonnet Dominique , Eisinger François , The French Cooperative Network/Groupe Génétique et Cancer de
Published: February 2015

AIM: In order to evaluate the characteristics and the evolution of cancer genetics activity in France, a survey was conducted at the national level during a period of 4 years from 1994 to 1997 through the French Cooperative Network, a multidisciplinary group formed to investigate inherited tumors.

METHOD: A questionnaire was sent to all the 29 French non‐specialized cancer genetic clinics to evaluate activity during a period of 4 consecutive weeks each year from 1994 to 1997. Items concerning the cancer genetic clinics, the consultees and the types of consultation were explored.

RESULTS: A total number of 801 consultees were seen during the period of analysis. Some prominent characteristics of patients attending cancer genetic clinics were found. The majority of these are women (88%), and the mean age of consultees is 48 years. Fifty five percent of consultees are affected with cancer, and breast (personal and/or family history) is the most frequent site involved (63%). A genetic predisposition is certain or likely in about 53% of cases and unlikely in only 13% of consultations. The majority of consultations are devoted to new families (71%). The mean duration of consultations is 50 minutes, but 40% have a duration of at least 1 hour. Variations of several parameters during the 4 years period were observed and analyzed. Finally, since duration of consultations (more or equal to 1 hour) and personal or family history of breast/ovarian cancer appeared as pivotal elements in our study and consequently may affect the organization of clinics and the structuring as well as the evolution of cancer genetic activity in France, we analyzed more precisely the factors significantly associated with these 2 elements.

CONCLUSION: Study compliance was fair (60% of centers) and these results give a good measure of cancer genetic activity in France. The variation of parameters from one year to another may reflect modifications in medical practice (medical orientation rather than research focus and content of cancer genetic clinics) and/or scientific breakthroughs in cancer genetics such as identification of genes predisposing to cancer.
Motions of Curves in the Pseudo-Galilean SpaceG31
Authors: Cengiz Suleyman , Koc Ozturk Esra Betul , Ozturk Ufuk
Published: February 2015

We study the flows of curves in the pseudo-Galilean 3-space and its equiform geometry without any constraints. We find that the Frenet equations and intrinsic quantities of the inelastic flows of curves are independent of time. We show that the motions of curves in the pseudo-Galilean 3-space and its equiform geometry are described by the inviscid and viscous Burgers’ equations.
Analog Beamforming and Digital Beamforming on Receive for Range Ambiguity Suppression in Spaceborne SAR
Authors: Huang Pingping , Xu Wei
Published: February 2015

For future spaceborne synthetic aperture radar (SAR) missions, digital beamforming (DBF) on receive in elevation to form a sharp high receive beam will be adopted to improve the signal to noise ratio (SNR) level and suppress range ambiguities. However, in some special cases, range ambiguities may be received by grating lobes with the high receive beam gain, and range ambiguities would not be well suppressed and even may be increased. In this paper, a new receiving approach based on analog beamforming (ABF) and DBF is proposed. According to the spaceborne SAR imaging geometry and the selected pulse repetition frequency (PRF), the antenna patterns of all subapertures of the whole receive antenna in elevation are adjusted by ABF at first. Afterwards, signals from all subapertures in elevation are combined by a real time DBF processor onboard. Since grating lobes could be suppressed by the antenna pattern of the subapertures via ABF, range ambiguities would be well suppressed even if ambiguities are received by grating lobes. Simulation results validate the proposed approach.