Gene/Protein Disease Symptom Drug Enzyme Compound
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In vivo cinemicroscopic studies of subpleural alveoli were conducted in dogs for 4 h after pulmonary lavage with 5% Tween 20 and after lavage with normal saline. Saline-lavaged alveoli showed little change in alveolar size during tidal ventilation, whereas Tween lavage resulted both in alveolar recruitment and marked variation in alveolar size from end expiration to peak inspiration, with total collapse frequently occurring by end expiration. Following Tween, alveolar stability decreased, but alveolar capillary perfusion increased. Marked recovery of stability by 4 h was noted in most alveoli. Wilhelmy balance studies on lung extracts showed a decrease in surfactant function 30 min after Tween and a partial recovery of surfactant activity after 4 h. This study provides in vivo evidence that normal surfactant function is critical to alveolar stability and that alveolar stability is markedly restored 4 h after acute deactivation or displacement by Tween. Surfactant deactivation and loss of alveolar stability are associated with increased alveolar capillary perfusion creating significant ventilation-perfusion ratio abnormalities.
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PMID:Alveolar function following surfactant deactivation. 689 68

FK506 can show efficacy in transplant rejection even after other immunosuppressive drugs have been ineffective. However, the lack of a suitable animal model has hindered the study of FK nephrotoxicity, which has been noted as a common adverse effect in human trials. In this paper, we report a model of chronic FK nephrotoxicity in which renal structure and function are worsened by sodium depletion. Pair-fed male Sprague-Dawley rats were given FK (6 mg/kg p.o.) or vehicle for 21 days on a low-salt or normal diet. There was no significant difference in body weight between FK and vehicle groups. The FK whole-blood trough levels (3-10 ng/ml) in rats are similar to those in FK treated transplant patients. In sodium-depleted rats, FK clearly decreased GFR (0.09 +/- 0.03 ml/min/100 g vs. 0.94 +/- 0.06 ml/min/100 g in the vehicle group, P < 0.01), urinary osmolarity (UOsm, P < 0.01) and plasma magnesium (P < 0.01) and increased plasma creatinine (Pcr, P < 0.01), fractional excretion of magnesium (P < 0.01), urine volume (P < 0.01), plasma renin activity (PRA, P < 0.05), and alanine aminopeptidase (AAP, P < 0.05) as compared with those in the vehicle group. Salt depletion significantly potentiated these functional changes as compared with those in the normal salt group (GFR, UOsm, Pcr, PRA, and AAP of the low salt group vs. those of the normal salt group, P < 0.05 by ANOVA). In the sodium-depleted rats, the main lesion in the rat kidneys was focal collapse and vacuolization in proximal tubules, but there was also significant interstitial fibrosis. In contrast, no injury was observed in the sodium-replete rat kidneys. In conclusion, an experimental model of FK nephrotoxicity in sodium-depleted rats has been developed that is characterized by reduced GFR and structural damage to the proximal tubule accompanied by interstitial fibrosis. Sodium depletion appears to potentiate these changes at blood levels similar to those achieved in patients receiving FK.
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PMID:Enhancement of FK506 nephrotoxicity by sodium depletion in an experimental rat model. 750 14

We ran and analyzed a total of eighteen, 10 ns molecular dynamics simulations of two C-terminal beta-hairpins from the B1 domain of Protein G: twelve runs for the last 16 residues and six runs for the last 15 residues, G41-E56 and E42-E56, respectively. Based on their CalphaRMS deviation from the starting structure and the pattern of stabilizing interactions (hydrogen bonds, hydrophobic contacts, and salt bridges), we were able to classify the twelve runs on G41-E56 into one of three general states of the beta-hairpin ensemble: 'Stable', 'Unstable', and 'Unfolded'. Comparing the specific interactions between these states, we find that on average the stable beta-hairpin buries 287 A(2) of hydrophobic surface area, makes 13 hydrogen bonds, and forms 3 salt-bridges. We find that the hydrophobic core prefers to make some specific contacts; however, this core does not require optimal packing. Side-chain hydrogen bonds stabilize the beta-hairpin turn with strong stabilizing interactions primarily due to the carboxyl of D46 with contributions from T49 hydroxyl. Buoyed by the strength of the hydrophobic core, other hydrogen bonds, primarily main-chain, guide the beta-hairpin into registration by forming a loose network of interactions, making an approximately constant number of hydrogen bonds from a pool of possible candidates. In simulations on E42-E56, where the salt bridge closing the termini is not favored, we observe that all the simulations show no 'Stable' behavior, but are 'Unstable' or 'Unfolded'. We can estimate that the salt-bridge between the termini provides approximately 1.3 kcal/mol. Altogether, the results suggest that the beta-hairpin folds beginning at the turn, followed by hydrophobic collapse, and then hydrogen bond formation. Salt bridges help to stabilize the folded conformations by inhibiting unfolded states.
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PMID:Evidence of turn and salt bridge contributions to beta-hairpin stability: MD simulations of C-terminal fragment from the B1 domain of protein G. 1248

Ventricular assist devices now clinically used for treatment of end-stage heart failure require responsive and reliable hemodynamic control to accommodate the continually changing demands of the body. This is an essential ingredient to maintaining a high quality of life. To satisfy this need, a control algorithm involving a trade-off between optimal perfusion and avoidance of ventricular collapse has been developed. An optimal control strategy has been implemented in vitro that combines two competing indices: representing venous return and prevalence of suction. The former is derived from the first derivative of diastolic flow with speed, and the latter derived from the harmonic spectra of the flow signal. The responsiveness of the controller to change in preload and afterload were evaluated in a mock circulatory simulator using a HeartQuest centrifugal blood pump (CF4b, MedQuest Products, Salt Lake City, UT). To avoid the need for flow sensors, a state estimator was used, based on the back-EMF of the actuator. The multiobjective algorithm has demonstrated more robust performance as compared with controllers relying on individual indices.
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PMID:In vitro evaluation of multiobjective hemodynamic control of a heart-assist pump. 1615 94

Salt marshes in the southeastern United States have recently experienced massive die-off, one of many examples of widespread degradation in marine and coastal ecosystems. Although intense drought is thought to be the primary cause of this die-off, we found snail grazing to be a major contributing factor. Survey of marsh die-off areas in three states revealed high-density fronts of snails on die-off edges at 11 of 12 sites. Exclusion experiments demonstrated that snails actively converted marshes to exposed mudflats. Salt addition and comparative field studies suggest that drought-induced stress and grazers acted synergistically and to varying degrees to cause initial plant death. After these disturbances, snail fronts formed on die-off edges and subsequently propagated through healthy marsh, leading to cascading vegetation loss. These results, combined with model analyses, reveal strong interactions between increasing climatic stress and grazer pressure, both potentially related to human environmental impacts, which amplify the likelihood and intensity of runaway collapse in these coastal systems.
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PMID:Drought, snails, and large-scale die-off of southern U.S. salt marshes. 1635 58

In this study we addressed initial laboratory observations of enhanced cardiovascular sensitivity to sodium pentobarbital (PTB) in normotensive Dahl Salt Sensitive rats (SS) compared to Brown Norway (BN) rats. We also used unique consomic (chromosomal substitution) strains to confirm preliminary observations that such differences were related to chromosome 13. Increasing concentrations of PTB were administered sequentially to SS, BN, and SS strains with BN chromosomal substitutions until the point of cardiovascular collapse. Both spontaneous and controlled ventilation were studied. The effect of large (450 microg/mL) and small (35 microg/mL) concentrations of PTB on in situ transmembrane potential of mesenteric arterial vascular smooth muscle (VSM) cells was also measured in these animals with local sympathetic innervation both intact and eliminated. An analysis of variance was used to identify significant differences among groups. Despite virtually identical plasma clearance of PTB, cardiovascular collapse occurred at approximately 35%-45% smaller cumulative doses of administered PTB in SS and other strains compared with BN and SS.13BN (introgression of BN chromosome 13 into an SS) in both spontaneous and controlled ventilation. In neurally intact preparations, large dose PTB-induced VSM hyperpolarization was 4-5 times greater than the small dose in SS and SS.16BN but not in BN and SS.13BN strains. Denervation eliminated this strain difference. These results suggest that enhanced cardiovascular sensitivity to PTB in SS rats is related to greater hyperpolarization of VSM transmembrane potential in resistance vessels and this effect is associated with chromosome 13.
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PMID:Chromosomal substitution-dependent differences in cardiovascular responses to sodium pentobarbital. 1649 31

In most in vitro studies of oral drug permeability, little attempt is made to reproduce the gastrointestinal lumenal environment. The aim of this study was to evaluate the compatibility of simulated intestinal fluid (SIF) solutions with Caco-2 cell monolayers and Ussing chamber-mounted rat ileum under standard permeability experiment protocols. In preliminary experiments, fasted-state simulated intestinal fluid (FaSSIF) and fed-state simulated intestinal fluid (FeSSIF) solutions based on the dissolution medium formulae of Dressman and co-workers (1998) were modified for compatibility with Caco-2 cells to produce FaS-SIF and FeSSIF "transport" solutions for use with in vitro permeability models. For Caco-2 cells exposed to FaSSIF and FESSIF transport solutions, the transepithelial electrical resistance was maintained for over 4 h and mannitol permeability was equivalent to that in control (Hank's Balanced Salt Solution-treated) cell layers. Scanning electron microscopy revealed that microvilli generally maintained a normal distribution, although some shortening of microvilli and occasional small areas of denudation were observed. For rat ileum in the Ussing chambers, the potential difference (PD) collapsed to zero over 120 min when exposed to the FaSSIF transport solution and an even faster collapse of the PD was observed when the FeSSIF transport solution was used. Electron micrographs revealed erosion of the villi tips and substantial denudation of the microvilli after exposure of ileal tissue to FaSSIF and FeSSIF solutions, and permeability to mannitol was increased by almost two-fold. This study indicated that FaSSIF and FeSSIF transport solutions can be used with Caco-2 monolayers to evaluate drug permeability, but rat ileum in Ussing chambers is adversely affected by these solutions. Metoprolol permeability in Caco-2 experiments was reduced by 33% using the FaSSIF and 75% using the FeSSIF compared to permeability measured using HBSS. This illustrates that using physiological solutions can influence permeability measurements.
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PMID:Use of simulated intestinal fluids with Caco-2 cells and rat ileum. 1653 96

Salt marsh ecosystems are widely considered to be controlled exclusively by bottom-up forces, but there is mounting evidence that human disturbances are triggering consumer control in western Atlantic salt marshes, often with catastrophic consequences. In other marine ecosystems, human disturbances routinely dampen (e.g., coral reefs, sea grass beds) and strengthen (e.g., kelps) consumer control, but current marsh theory predicts little potential interaction between humans and marsh consumers. Thus, human modification of top-down control in salt marshes was not anticipated and was even discounted in current marsh theory, despite loud warnings about the potential for cascading human impacts from work in other marine ecosystems. In spite of recent experiments that have challenged established marsh dogma and demonstrated consumer-driven die-off of salt marsh ecosystems, government agencies and nongovernmental organizations continue to manage marsh die-offs under the old theoretical framework and only consider bottom-up forces as causal agents. This intellectual dependency of many coastal ecologists and managers on system-specific theory (i.e., marsh bottom-up theory) has the potential to have grave repercussions for coastal ecosystem management and conservation in the face of increasing human threats. We stress that marine vascular plant communities (salt marshes, sea grass beds, mangroves) are likely more vulnerable to runaway grazing and consumer-driven collapse than is currently recognized by theory, particularly in low-diversity ecosystems like Atlantic salt marshes.
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PMID:Consumer control of salt marshes driven by human disturbance. 1857 90

Salt marshes are highly productive coastal wetlands that provide important ecosystem services such as storm protection for coastal cities, nutrient removal and carbon sequestration. Despite protective measures, however, worldwide losses of these ecosystems have accelerated in recent decades. Here we present data from a nine-year whole-ecosystem nutrient-enrichment experiment. Our study demonstrates that nutrient enrichment, a global problem for coastal ecosystems, can be a driver of salt marsh loss. We show that nutrient levels commonly associated with coastal eutrophication increased above-ground leaf biomass, decreased the dense, below-ground biomass of bank-stabilizing roots, and increased microbial decomposition of organic matter. Alterations in these key ecosystem properties reduced geomorphic stability, resulting in creek-bank collapse with significant areas of creek-bank marsh converted to unvegetated mud. This pattern of marsh loss parallels observations for anthropogenically nutrient-enriched marshes worldwide, with creek-edge and bay-edge marsh evolving into mudflats and wider creeks. Our work suggests that current nutrient loading rates to many coastal ecosystems have overwhelmed the capacity of marshes to remove nitrogen without deleterious effects. Projected increases in nitrogen flux to the coast, related to increased fertilizer use required to feed an expanding human population, may rapidly result in a coastal landscape with less marsh, which would reduce the capacity of coastal regions to provide important ecological and economic services.
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PMID:Coastal eutrophication as a driver of salt marsh loss. 2307 84

In any living species, stress adaptation is closely linked with major changes of the gene expression profile. As a substrate protein of the rapidly stress-induced mitogen-activated protein kinase MPK3, Arabidopsis transcription factor MYB44 likely acts at the front line of stress-induced re-programming. We recently characterized MYB44 as phosphorylation-dependent positive regulator of salt stress signaling. Molecular events downstream of MYB44 are largely unknown. Although MYB44 binds to the MBSII element in vitro, it has no discernible effect on MBSII-driven reporter gene expression in plant co-transfection assays. This may suggest limited abundance of a synergistic co-regulator. MYB44 carries a putative transcriptional repression (Ethylene responsive element binding factor-associated Amphiphilic Repression, EAR) motif. We employed a dominant repressor strategy to gain insights into MYB44-conferred stress resistance. Overexpression of a MYB44-REP fusion markedly compromised salt and drought stress tolerance--the opposite was seen in MYB44 overexpression lines. MYB44-mediated resistance likely results from induction of tolerance-enhancing, rather than from repression of tolerance-diminishing factors. Salt stress-induced accumulation of destructive reactive oxygen species is efficiently prevented in transgenic MYB44, but accelerated in MYB44-REP lines. Furthermore, heterologous overexpression of MYB44-REP caused tissue collapse in Nicotiana. A mechanistic model of MAPK-MYB-mediated enhancement in the antioxidative capacity and stress tolerance is proposed. Genetic engineering of MYB44 variants with higher trans-activating capacity may be a means to further raise stress resistance in crops.
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PMID:Dominant repression by Arabidopsis transcription factor MYB44 causes oxidative damage and hypersensitivity to abiotic stress. 2453 Nov 38


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