Persistent alterations in heart rate variability, baroreflex sensitivity, and anxiety-like behaviors during development of heart failure in the rat

Depressed heart rate variability and mood are associated with increased mortality in patients with congestive heart failure (CHF). Here autonomic indexes were assessed 3 and 7 wk after left coronary artery ligation in telemetered rats, after which anxiety-like behaviors were assessed in an elevated plus maze. Low frequency (LF) and high frequency (HF) heart rate variability were reduced in CHF rats 3 wk after infarction (LF, 1.60 +/- 0.52 vs. 6.97 +/- 0.79 ms(2); and HF, 1.53 +/- 0.39 vs. 6.20 +/- 1.01 ms(2); P < 0.01). The number of sequences of interbeat intervals that correlated with arterial pressure was decreased in CHF rats at 3 and 7 wk (week 3, 26.60 +/- 10.85 vs. 59.75 +/- 11.4 sequences, P < 0.05; and week 7, 20.80 +/- 8.97 vs. 65.38 +/- 5.89 sequences, P < 0.01). Sequence gain was attenuated in CHF rats by 7 wk (1.34 +/- 0.06 vs. 2.70 +/- 0.29 ms/mmHg, P < 0.01). Coherence between interbeat interval and mean arterial blood pressure variability in the LF domain was reduced in CHF rats at 3 (0.12 +/- 0.03 vs. 0.26 +/- 0.05 k(2), P < 0.05) and 7 (0.16 +/- 0.02 vs. 0.31 +/- 0.05 k(2), P < 0.05) wk. CHF rats invariably entered the open arm of the elevated plus maze first and spent more time in the open arms (36.0 +/- 15% vs. 4.6 +/- 1.9%, P < 0.05). CHF rats also showed a tendency to jump head first off the apparatus, whereas controls did not. Together the data indicate that severe autonomic dysfunction is accompanied by escape-seeking behaviors in rats with verified CHF.     

Walking back the cat: Unsupervised classification as an aid in “remote” fossil prospecting

Counterintelligence analysts use a technique called “walking back the cat'' to reveal “moles” or others passing on disinformation in which they compare what they now know as fact against what their agents or informers had told them to expect about certain persons or events. 1 Thus, “walking back the cat” is a perfect metaphor for working backwards; that is, retracing the complex development of an event and examining the “run up” to it in order to gain useful insights about how that event unfolded. Perhaps paleoanthropology can profit from such an approach.     

Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.     

Variation for resistance to aphids (Homoptera: Aphididae) among tomato inbred backcross lines derived from wild Lycopersicon species

Two tomato inbred backcross line (IBL) populations, derived from crosses between aphid-susceptible Lycopersicon esculentum Mill. 'Peto 95-43' X resistant wild L. pennellii Corr (D'arcy) accession LA716, and Peto 95-43 X resistant wild L. hirsutum f. glabratum Mull accession LA407, were evaluated in replicated field experiments for resistance to potato aphid, Macrosiphum euphorbiae (Thomas), and green peach aphid, Myzus persicae (Sulzer). Aphid infestation scores for each IBL and control (LA716, LA407, Peto 95-43, and susceptible 'Alta') plot were recorded weekly for 5 and 9 wk during the summers of 2000 and 2001, respectively. Aphid infestation scores from leaflets were used to calculate area under the infestation pressure curve (AUIPC), a measure of aphid infestation throughout the growing season, for each IBL and control. Score AUIPC was highly correlated with actual aphid count AUIPC, indicating that scores accurately reflected aphid infestation. Score AUIPC was also highly correlated across both years (2000 and 2001) and locations. Low score AUIPC was significantly correlated with larger plant size and sprawling, indeterminate plant growth habit. Seven IBLs, LA716, and LA407 were significantly more resistant to aphids (lower score AUIPC) than susceptible parent Peto 95-43 in both years. Two IBLs, 1034 and 1051, were not significantly different from resistant LA407 for score AUIPC in both years. The seven aphid-resistant IBLs identified here can be useful as donor parent material for resistance breeding efforts in cultivated tomato.     

Drug Withdrawal Syndromes: A Literature Review

Drug withdrawal syndromes reportedly have been caused by numerous pharmacological agents, but only a few drugs have been adequately studied in this regard. Criteria for evaluating drug withdrawal syndromes have been proposed. Sedative-hypnotic agents, opiates, corticosteroids, clonidine, tricyclic antidepressant medications and beta-adrenergic blocking agents meet the criteria for such syndromes. Gradual tapering of the dose of these drugs is recommended when therapy must be discontinued. Whether or not other drugs cause rebound reactions is questionable, but caution should be used when discontinuing drugs for which numerous reports of withdrawal syndromes exist.     

Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents

Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3β substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a–b, which have affinities of 17 and 12 μM, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design.     

Maintenance of the epithelial barrier in a bronchial epithelial cell line is dependent on functional E-cadherin local to the tight junctions

Tight junctions (TJ) are essential components of polarized epithelia, and E-cadherin is important for their formation and maintenance. The bronchial epithelial cell line, 16HBE14o- expresses E- and P-cadherin, but not N-cadherin. E- and P-cadherin levels changed during culture, the former increasing after confluence, and the latter were markedly reduced. All detectable E-cadherin was bound to β- and γ-catenins. We investigated involvement of E-cadherin with epithelial integrity using an E-cadherin specific, function-blocking antibody, SHE78-7. Surprisingly, apical SHE78-7 exposure caused a prompt fall in transepithelial resistance (TER), while TER remained unchanged for 8 hrs after basal exposure then dropped. SHE78-7 exposure increased epithelial permeability to mannitol, inulin, and 9.5 kDa and 77 kDa dextrans and caused fragmentation and loss of the tight junction protein, ZO-1, from the cell borders in some areas. Ultrastructural studies showed that all junctional intercellular contact was lost in the center of SHE78-7 induced lesions. Near the lesion periphery, epithelial structure was maintained, but TJs were dysfunctional as shown by ruthenium red penetration. Analysis of epithelial penetration by SHE78-7 revealed discrete, local defects in the apical barrier at the top of some cell hills that permitted rapid access of the antibody to E-cadherin near the apical surface. In contrast, after basal exposure, antibody initially engaged with E-cadherin nearer the basal surface and only accessed apical E-cadherin later. Taken together with the TER measurements, these data suggest compartmentalization of E-cadherin function within 16HBE14o- cells, with only the apical E-cadherin adjacent to the tight junctions contributing to the function of the latter.     

The Positive Correlations Between the Activity of Superoxide Dismutase and Dehydration Tolerance in Wheat Seedlings

Damage to crops by drought is still a serious problem in large areas of the world. Considerable research has been undertaken to discover the mechanisms of drought injury and drought resistance of plants. However, the critical features of drought injury have not yet been identified. In the past ten years a free radical hypothesis has been suggested to account for subcellular damage caused by severe environments. Superoxide (oxygen radical) is normally produced in hydrated tissues. It is controlled by free radical scavenging reactions. One such scavenger is the enzyme superoxide dismutase (SOD). Under water stress, production of excess free radicals may occur in dehydrated plant tissues and this probably damages the membranes by causing peroxidation of the lipid components. So far few studies have been done to determine if drought injury is correlated with the free radical mechanism. In the present study, the SOD activities in wheat seedlings under water stress have been investigated by measuring the photoreduction of nitro blue tetrazolium using a spectrometric method. Meanwhile, the viabilities of wheat seedlings during drying were followed by tetrazolium test. These results provided information on the relationship between SOD activity and the dehydration tolerance of the plant. Results indicated that SOD activity changed with the time after germination. The activity of SOD of 24 h seedlings was 1.9 times higher than those of 72 h seedlings based on fresh weight. SOD activity in shoot was also higher than in root. These results were consistent with the results obtained from rating of the viabilities of seedlings during drying. The 24h seedlings were more tolerant of dehydration than 72 h seedlings and root were more sensitive of drought than shoot. In addition, shoot and root tips showed the higher SOD activities than non-tip region and they also showed a higher survival ability upon dehydration. In dehydration and subsequent rehydration, SOD activity, different from many other enzymes in plants, increased rather than declined during drying. After rehydration SOD activity returned to nearly the original level. Therefore, the positive correlations were found to exist between SOD activity and dehydration tolerance. It is reasonable to suggest that SOD enzyme may play a protective role against damage caused by free radicals which may be produced excessively during dehydration in wheat seedling.