New Insights Into Interactions of Presynaptic Calcium Channel Subtypes and SNARE Proteins in Neurotransmitter Release

Action potential (AP) induces presynaptic membrane depolarization and subsequent opening of Ca2+ channels, and then triggers neurotransmitter release at the active zone of presynaptic terminal. Presynaptic Ca2+ channels and SNARE proteins (SNAREs) interactions form a large signal transfer complex, which are core components for exocytosis. Ca2+ channels serve to regulate the activity of Ca2+ channels through direct binding and indirect activation of active zone proteins and SNAREs. The activation of Ca2+ channels promotes synaptic vesicle recruitment, docking, priming, fusion and neurotransmission release. Intracellular calcium increase is a key step for the initiation of vesicle fusion. Various voltage-gated calcium channel (VGCC) subtypes exert different physiological functions. Until now, it has not been clear how different subtypes of calcium channels integrally regulate the release of neurotransmitters within 200 μs of the AP arriving at the active zone of synaptic terminal. In this mini review, we provide a brief overview of the structure and physiological function of Ca2+ channel subtypes, interactions of Ca2+ channels and SNAREs in neurotransmitter release, and dynamic fine-tune Ca2+ channel activities by G proteins (Gβγ), multiple protein kinases and Ca2+ sensor (CaS) proteins

The Spatiotemporal Patterns and Interrelationships of Snow Cover and Climate Change in Tianshan Mountains

To reveal the spatiotemporal patterns of the asymmetry in the Tianshan mountains’ climatic warming, in this study, we analyzed climate and MODIS snow cover data (2001–2019). The change trends of asymmetrical warming, snow depth (SD), snow coverage percentage (SCP), snow cover days (SCD) and snow water equivalent (SWE) in the Tianshan mountains were quantitatively determined, and the influence of asymmetrical warming on the snow cover activity of the Tianshan mountains were discussed. The results showed that the nighttime warming rate (0.10 °C per decade) was greater than the daytime, and that the asymmetrical warming trend may accelerate in the future. The SCP of Tianshan mountain has reduced by 0.9%. This means that for each 0.1 °C increase in temperature, the area of snow cover will reduce by 5.9 km2. About 60% of the region’s daytime warming was positively related to SD and SWE, and about 48% of the region’s nighttime warming was negatively related to SD and SWE. Temperature increases were concentrated mainly in the Pamir Plateau southwest of Tianshan at high altitudes and in the Turpan and Hami basins in the east. In the future, the western and eastern mountainous areas of the Tianshan will continue to show a warming trend, while the central mountainous areas of the Tianshan mountains will mainly show a cooling trend

Comparison of lens thickness measurements using the anterior segment optical coherence tomography and A-scan ultrasonography. Invest Ophthalmol Vis Sci

PURPOSE. To assess lens thickness (LT) measurements with anterior segment optical coherence tomography (AS-OCT) in comparison with A-scan ultrasonography (A-scan US). METHODS. Enrolled were 66 eyes of 48 phakic elderly volunteers aged Ն50 years and 56 eyes of 56 young participants aged 18 to 40 years. LT was measured with the internal manual caliper tools in AS-OCT. The A-scan US measurements were based on an average of 10 consecutive automatic measurements. Reproducibility was assessed by three measurements each with AS-OCT and A-scan US independently obtained by two observers who were masked to one another's results. RESULTS. The failure rates of AS-OCT and A-scan US were 9.1% and 7.6%, respectively, in elderly subjects, but no failure was observed in young subjects. The LT values measured by AS-OCT were significantly greater than A-scan US; the paired difference was 0.135 mm in elderly and 0.101 mm in young subjects (P Ͻ 0.001). These differences did not correlate with the nuclear cataract grades (r ϭ 0.078, P ϭ 0.558). Intraobserver agreement on AS-OCT (95% limits of agreement [LoA]: Ϫ0.049 to ϩ0.045 mm; ICC: 0.999) was better than A-scan US (95%LoA: Ϫ0.194 to ϩ0.218 mm; ICC: 0.974). The 95% LoA of interobserver agreement using AS-OCT and A-scan were Ϫ0.084 to ϩ0.073 and Ϫ0.278 to ϩ0.239 mm, respectively, and the ICCs were 0.996 and 0.960, respectively. CONCLUSIONS. AS-OCT can be used to measure lens thickness in most eyes with clear or opacified lenses. It appears to be an alternative means of measuring lens thickness, particularly when a noncontact method is needed. (Invest Ophthalmol Vis Sci

Ligand-Independent and Tissue-Selective Androgen Receptor Inhibition by Pyrvinium

Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling

Ligand-Independent and Tissue-Selective Androgen Receptor Inhibition by Pyrvinium

Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the <i>in vivo</i> growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling