Activity-dependent heteromerization of the hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels: role of N-linked glycosylation.

Formation of heteromeric complexes of ion channels via co-assembly of different subunit isoforms provides an important mechanism for enhanced channel diversity. We have previously demonstrated co-association of the hyperpolarization activated cyclic-nucleotide gated (HCN1/HCN2) channel isoforms that was regulated by network (seizure) activity in developing hippocampus. However, the mechanisms that underlie this augmented expression of heteromeric complexes have remained unknown. Glycosylation of the HCN channels has been implicated in the stabilization and membrane expression of heteromeric HCN1/HCN2 constructs in heterologous systems. Therefore, we used in vivo and in vitro systems to test the hypothesis that activity modifies HCN1/HCN2 heteromerization in neurons by modulating the glycosylation state of the channel molecules. Seizure-like activity (SA) increased HCN1/HCN2 heteromerization in hippocampus in vivo as well as in hippocampal organotypic slice cultures. This activity increased the abundance of glycosylated HCN1 but not HCN2-channel molecules. In addition, glycosylated HCN1 channels were preferentially co-immunoprecipitated with the HCN2 isoforms. Provoking SA in vitro in the presence of the N-linked glycosylation blocker tunicamycin abrogated the activity-dependent increase of HCN1/HCN2 heteromerization. Thus, hippocampal HCN1 molecules have a significantly higher probability of being glycosylated after SA, and this might promote a stable heteromerization with HCN2

Stability and enzymatic studies with omeprazole: hydroxypropyl-β-cyclodextrin

The original publication is available at www.springerlink.com. A publicação original está disponível em www.springerlink.comOmeprazole (OME) exhibits low stability to light, heat and humidity. In stress conditions OME stability should improve under inclusion complex form with hydroxypropyl-b-cyclodextrin (HPbCD). Stability of OME, its physical mixture (PM) with HPbCD and OME:HPbCD inclusion complex was assessed during 60 days. The inclusion complexes were prepared by kneading and freezedrying techniques and characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). A molecular modelling was also held to predict the most probable tridimensional conformation of inclusion complex OME:HPbCD. The inhibitory activity of free and complexed OME on selected enzymes, namely, papain (protease model of the proton pump) and acetylcholinesterase (enzyme present in cholinergic neurons and also involved in Alzheimer’s disease) was compared. The results obtained show that HPbCD do not protect against OME degradation, in any prepared powder, in the presence of light, heat and humidity. This may indicate that the reactive group of OME is not included in the HPbCD cavity. This fact is supported by molecular modelling data, which demonstrated that 2-pyridylmethyl group of OME is not included into the cyclodextrin cavity. In relation to enzymatic assays it was observed that free OME and OME in the binary systems showed identical inhibitory activity on papain and acethylcolinesterase, concluding that HPbCD do not affect OME activity on these two enzymes

Understanding concurrent earcons: applying auditory scene analysis principles to concurrent earcon recognition

Two investigations into the identification of concurrently presented, structured sounds, called earcons were carried out. One of the experiments investigated how varying the number of concurrently presented earcons affected their identification. It was found that varying the number had a significant effect on the proportion of earcons identified. Reducing the number of concurrently presented earcons lead to a general increase in the proportion of presented earcons successfully identified. The second experiment investigated how modifying the earcons and their presentation, using techniques influenced by auditory scene analysis, affected earcon identification. It was found that both modifying the earcons such that each was presented with a unique timbre, and altering their presentation such that there was a 300 ms onset-to-onset time delay between each earcon were found to significantly increase identification. Guidelines were drawn from this work to assist future interface designers when incorporating concurrently presented earcons

Abundances of 'secondary' elements among the ultraheavy cosmic rays: Results from HEAO-3

The HEAO-3 Heavy Nuclei Experiment has measured elemental abundances of ultraheavy cosmic rays near earth. The elements with atomic number (Z) in the intervals 44≤Z≤48 and 62≤Z≤74 arriving at earth are expected to have significant secondary components. However, their source abundances are unlikely to be low enough to warrant treating them as pure secondaries. Our results are consistent with solar system abundances modified for first ionization potential with possibly some enhancement of tho r to s ratio

Renal artery reconstruction for the preservation of renal function

AbstractPurpose: We reviewed a 13-year experience with an emphasis on long-term survival and renal function response when renal artery reconstruction (RAR) was performed primarily for the preservation or restoration of renal function in patients who had atherosclerotic renovascular disease.Methods: From January 1, 1980, to June 30, 1993, 139 patients underwent RAR for renal function salvage and were retrospectively reviewed. Inclusion criteria were either preoperative serum creatinine level >2.0 mg/dl (67% of patients) or RAR to the entire functioning renal mass irrespective of baseline renal function. Patient survival was calculated by life-table methods. Cox regression analysis was used to determine relative risk (RR) estimates for the late outcomes of continued deterioration of renal function and late survival after RAR. A logistic regression model was used to evaluate variables associated with perioperative complications.Results: Clinical characteristics of the cohort were notable for advanced cardiac (history of congestive heart failure, 27%; angina, 22%; previous myocardial infarction, 19%) and renal disease (serum creatinine level <2.0 mg/dl, 33%; 2.0 mg/dl to 3.0 mg/dl, 40%, >3.0 mg/dl, 27%). Cardiac disease was the principle cause of early (6 of 11 operative deaths) and late death. Operative management consisted of aortorenal bypass in 47%, extraanatomic bypass in 45%, and endarterectomy in 8%; 45% of patients required combined aortic and RAR. The operative mortality rate was 8%; significant perioperative renal dysfunction occurred in 10%. Major operative morbidity was associated with increasing azotemia (RR = 2.1; p = 0.001; 95% confidence interval [CI], 1.3 to 4.7 for each 1.0 mg/dl increase in baseline creatinine level). Of those patients who had a baseline creatinine level ≥2.0 mg/dl, 54% had ≥20% reduction in creatinine level after RAR. Late follow-up data were available for 87% of operative survivors at a mean duration of 4 years (range, 6 weeks to 12.6 years). Actuarial survival at 5 years was 52% ± 5%. Continued deterioration in renal function occurred in 24% of patients who survived operation, and eventual dialysis was required in 15%. Deterioration of renal function after RAR was associated with increasing levels of preoperative creatinine (RR = 1.6; 95% CI, 1.2 to 1.8; p = 0.001 for each 1.0 mg/dl increment in baseline creatinine level), and inversely related to early postoperative improvement in creatinine level (RR = 0.41; 95% CI, 0.2 to 0.9; p = 0.04).Conclusions: Intervention before major deterioration in renal function and an aggressive posture toward the frequently associated coronary artery disease are necessary to improve long-term results when RAR is performed for renal function salvage. (J Vasc Surg 1996;24:371-82.

Temporal Modulation of Traveling Waves in the Flow Between Rotating Cylinders With Broken Azimuthal Symmetry

The effect of temporal modulation on traveling waves in the flows in two distinct systems of rotating cylinders, both with broken azimuthal symmetry, has been investigated. It is shown that by modulating the control parameter at twice the critical frequency one can excite phase-locked standing waves and standing-wave-like states which are not allowed when the system is rotationally symmetric. We also show how previous theoretical results can be extended to handle patterns such as these, that are periodic in two spatial direction.Comment: 17 pages in LaTeX, 22 figures available as postscript files from http://www.esam.nwu.edu/riecke/lit/lit.htm

A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a persistence detector in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis

Excavation of Barrow III, Irton Moor, North Yorkshire.

YesIrton Moor was excavated by Derek Simpson in 1973 but remained unpublished at the time of his death in 2006. Material from the excavation including a skeletal report and some publication drawings were located in DDAS’s archives and brought back to Bradford for archiving. Sufficient work had been done by DDAS to bring the report to publication though clearly the archive had suffered over the years. Irton Moor represents a small structured round cairn of the Early Bronze Age producing evidence for long-term occupation of the site from the Early Neolithic though this occupation does not appear to have been continuous. The cairn was used for Food Vessel and Collared Urn-associated cremations