Recent advances in our understanding of the structure and function of more unusual cation channels.

As their name implies, cation channels allow the regulated flow of cations such as sodium, potassium, calcium, and magnesium across cellular and intracellular membranes. Cation channels have long been known for their fundamental roles in controlling membrane potential and excitability in neurons and muscle. In this review, we provide an update on the recent advances in our understanding of the structure-function relationship and the physiological and pathophysiological role of cation channels. The most exciting developments in the last two years, in our opinion, have been the insights that cryoelectron microscopy has provided into the inner life and the gating of not only voltage-gated channels but also mechanosensitive and calcium- or sodium-activated channels. The mechanosensitive Piezo channels especially have delighted the field not only with a fascinating new type of structure but with important roles in blood pressure regulation and lung function

Piloted-simulation study of effects of vortex flaps on low-speed handling qualities of a Delta-wing airplane

A piloted-simulation study was conducted to investigate the effects of vortex flaps on low-speed handling qualities of a delta-wing airplane. The simulation math model was developed from wind tunnel tests of a 0.15 scale model of the F-106B airplane. Pilot evaluations were conducted using a six-degree-of-freedom motion base simulator. The results of the investigation showed that the reduced static longitudinal stability caused by the vortex flaps significantly degraded handling qualities in the approach-to-landing task. Acceptable handling qualities could be achieved by limiting the aft center-of-gravity location, consequently reducing the operational envelope of the airplane. Further improvement were possible by modifying the flight control force-feel system to reduce pitch-control sensitivity

Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system

This is the final version of the article. Available from the publisher via the DOI in this record.The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.M. Kurihara was supported by a Medical Research Council Industrial collaborative studentship in collaboration with Pfizer, who also supported aspects of DISC1-related work in A. D. Randall’s laborator

The Trials and Tribulations of Structure Assisted Design of KCa Channel Activators.

Calcium-activated K+ channels constitute attractive targets for the treatment of neurological and cardiovascular diseases. To explain why certain 2-aminobenzothiazole/oxazole-type KCa activators (SKAs) are KCa3.1 selective we previously generated homology models of the C-terminal calmodulin-binding domain (CaM-BD) of KCa3.1 and KCa2.3 in complex with CaM using Rosetta modeling software. We here attempted to employ this atomistic level understanding of KCa activator binding to switch selectivity around and design KCa2.2 selective activators as potential anticonvulsants. In this structure-based drug design approach we used RosettaLigand docking and carefully compared the binding poses of various SKA compounds in the KCa2.2 and KCa3.1 CaM-BD/CaM interface pocket. Based on differences between residues in the KCa2.2 and KCa.3.1 models we virtually designed 168 new SKA compounds. The compounds that were predicted to be both potent and KCa2.2 selective were synthesized, and their activity and selectivity tested by manual or automated electrophysiology. However, we failed to identify any KCa2.2 selective compounds. Based on the full-length KCa3.1 structure it was recently demonstrated that the C-terminal crystal dimer was an artefact and suggested that the "real" binding pocket for the KCa activators is located at the S4-S5 linker. We here confirmed this structural hypothesis through mutagenesis and now offer a new, corrected binding site model for the SKA-type KCa channel activators. SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine) is binding in the interface between the CaM N-lobe and the S4-S5 linker where it makes van der Waals contacts with S181 and L185 in the S45A helix of KCa3.1

Structure and expression of two nuclear receptor genes in marsupials: insights into the evolution of the antisense overlap between the α-thyroid hormone receptor and Rev-erbα

<p>Abstract</p> <p>Background</p> <p>Alternative processing of α-thyroid hormone receptor (TRα, NR1A1) mRNAs gives rise to two functionally antagonistic nuclear receptors: TRα1, the α-type receptor, and TRα2, a non-hormone binding variant that is found only in mammals. TRα2 shares an unusual antisense coding overlap with mRNA for Rev-erbα (NR1D1), another nuclear receptor protein. In this study we examine the structure and expression of these genes in the gray short-tailed opossum, <it>Monodelphis domestica</it>, in comparison with that of eutherian mammals and three other marsupial species, <it>Didelphis virginiana, Potorous tridactylus </it>and <it>Macropus eugenii</it>, in order to understand the evolution and regulatory role of this antisense overlap.</p> <p>Results</p> <p>The sequence, expression and genomic organization of mRNAs encoding TRα1 and Rev-erbα are very similar in the opossum and eutherian mammals. However, the sequence corresponding to the TRα2 coding region appears truncated by almost 100 amino acids. While expression of TRα1 and Rev-erbα was readily detected in all tissues of <it>M. domestica </it>ages 0 days to 18 weeks, TRα2 mRNA was not detected in any tissue or stage examined. These results contrast with the widespread and abundant expression of TRα2 in rodents and other eutherian mammals. To examine requirements for alternative splicing of TRα mRNAs, a series of chimeric minigenes was constructed. Results show that the opossum TRα2-specific 5' splice site sequence is fully competent for splicing but the sequence homologous to the TRα2 3' splice site is not, even though the marsupial sequences are remarkably similar to core splice site elements in rat.</p> <p>Conclusions</p> <p>Our results strongly suggest that the variant nuclear receptor isoform, TRα2, is not expressed in marsupials and that the antisense overlap between TRα and Rev-erbα thus is unique to eutherian mammals. Further investigation of the TRα and Rev-erbα genes in marsupial and eutherian species promises to yield additional insight into the physiological function of TRα2 and the role of the associated antisense overlap with Rev-erbα in regulating expression of these genes.</p

Factors Correlating Perceptions of HPV and Vaccine Uptake among High School Students

Background: Human papillomavirus (HPV) is arguably the most prevalent sexually transmitted infection, and has been linked to a variety of health complications including cervical cancer, anal cancer, and anogenital warts. The HPV vaccine can prevent these health complications, but few studies have investigated the specific factors that impact HPV vaccine uptake. Methods: Two hundred seventy-five male and female high school students were surveyed in an ethnically diverse school district in southern California regarding HPV vaccine uptake and perceptions. Results: Less than one third of students reported their physician had discussed HPV vaccine with them, and fewer still for males (p&lt;0.01). Students who did discuss HPV vaccination with their physician were significantly more likely to get vaccinated (p&lt;0.01). Conclusion: These findings suggest the merit of the physician taking on a more active role during office visits to promote knowledge of HPV and HPV vaccine to all youth in this age group

Real-time segmentation and tracking of brain metabolic state in ICU EEG recordings of burst suppression

We provide a method for estimating brain metabolic state based on a reduced-order model of EEG burst suppression. The model, derived from previously suggested biophysical mechanisms of burst suppression, describes important electrophysiological features and provides a direct link to cerebral metabolic rate. We design and fit the estimation method from EEG recordings of burst suppression from a neurological intensive care unit and test it on real and synthetic data.National Institutes of Health (U.S.) (Grant DP1-OD003646

Propofol and sevoflurane induce distinct burst suppression patterns in rats

Burst suppression is an EEG pattern characterized by alternating periods of high-amplitude activity (bursts) and relatively low amplitude activity (suppressions). Burst suppression can arise from several different pathological conditions, as well as from general anesthesia. Here we review current algorithms that are used to quantify burst suppression, its various etiologies, and possible underlying mechanisms. We then review clinical applications of anesthetic-induced burst suppression. Finally, we report the results of our new study showing clear electrophysiological differences in burst suppression patterns induced by two common general anesthetics, sevoflurane and propofol. Our data suggest that the circuit mechanisms that generate burst suppression activity may differ among general anesthetics