Slo3 K+ Channels: Voltage and pH Dependence of Macroscopic Currents

The mouse Slo3 gene (KCNMA3) encodes a K+ channel that is regulated by changes in cytosolic pH. Like Slo1 subunits responsible for the Ca2+ and voltage-activated BK-type channel, the Slo3 α subunit contains a pore module with homology to voltage-gated K+ channels and also an extensive cytosolic C terminus thought to be responsible for ligand dependence. For the Slo3 K+ channel, increases in cytosolic pH promote channel activation, but very little is known about many fundamental properties of Slo3 currents. Here we define the dependence of macroscopic conductance on voltage and pH and, in particular, examine Slo3 conductance activated at negative potentials. Using this information, the ability of a Horrigan-Aldrich–type of general allosteric model to account for Slo3 gating is examined. Finally, the pH and voltage dependence of Slo3 activation and deactivation kinetics is reported. The results indicate that Slo3 differs from Slo1 in several important ways. The limiting conductance activated at the most positive potentials exhibits a pH-dependent maximum, suggesting differences in the limiting open probability at different pH. Furthermore, over a 600 mV range of voltages (−300 to +300 mV), Slo3 conductance shifts only about two to three orders of magnitude, and the limiting conductance at negative potentials is relatively voltage independent compared to Slo1. Within the context of the Horrigan-Aldrich model, these results indicate that the intrinsic voltage dependence (zL) of the Slo3 closed–open equilibrium and the coupling (D) between voltage sensor movement are less than in Slo1. The kinetic behavior of Slo3 currents also differs markedly from Slo1. Both activation and deactivation are best described by two exponential components, both of which are only weakly voltage dependent. Qualitatively, the properties of the two kinetic components in the activation time course suggest that increases in pH increase the fraction of more rapidly opening channels

Species-specific Differences among KCNMB3 BK β3 Auxiliary Subunits: Some β3 N-terminal Variants May Be Primate-specific Subunits

The KCNMB3 gene encodes one of a family of four auxiliary β subunits found in the mammalian genome that associate with Slo1 α subunits and regulate BK channel function. In humans, the KCNMB3 gene contains four N-terminal alternative exons that produce four functionally distinct β3 subunits, β3a–d. Three variants, β3a–c, exhibit kinetically distinct inactivation behaviors. Since investigation of the physiological roles of BK auxiliary subunits will depend on studies in rodents, here we have determined the identity and functional properties of mouse β3 variants. Whereas β1, β2, and β4 subunits exhibit 83.2%, 95.3%, and 93.8% identity between mouse and human, the mouse β3 subunit, excluding N-terminal splice variants, shares only 62.8% amino acid identity with its human counterpart. Based on an examination of the mouse genome and screening of mouse cDNA libraries, here we have identified only two N-terminal candidates, β3a and β3b, of the four found in humans. Both human and mouse β3a subunits produce a characteristic use-dependent inactivation. Surprisingly, whereas the hβ3b exhibits rapid inactivation, the putative mβ3b does not inactivate. Furthermore, unlike hβ3, the mβ3 subunit, irrespective of the N terminus, mediates a shift in gating to more negative potentials at a given Ca2+ concentration. The shift in gating gradually is lost following patch excision, suggesting that the gating shift involves some regulatory process dependent on the cytosolic milieu. Examination of additional genomes to assess conservation among splice variants suggests that the putative mβ3b N terminus may not be a true orthologue of the hβ3b N terminus and that both β3c and β3d appear likely to be primate-specific N-terminal variants. These results have three key implications: first, functional properties of homologous β3 subunits may differ among mammalian species; second, the specific physiological roles of homologous β3 subunits may differ among mammalian species; and, third, some β3 variants may be primate-specific ion channel subunits

Ce3+, Mn2+ Co-doped Red–light Long–Lasting Phosphor: BaMg2Si2O7 Through Energy Transfer

AbstractThe red light long-lasting phosphors BaMg2Si2O7: Ce3+, Mn2+, Dy3+ were synthesized by solid-state reactions under a weak reductive atmosphere. The energy transfer between Ce3+ and Mn2+ in BaMg2Si2O7 was systematically investigated. Through co-dope with Ce3+ in BaMg2Si2O7:Mn2+, Dy3+, the red phosphorescence of Mn2+ can prolong to more than 2h. Two types of traps were existed in BaMg2Si2O7

pH-regulated Slo3 K+ Channels: Properties of Unitary Currents

Here we have examined the voltage and pH dependence of unitary Slo3 channels and used analysis of current variance to define Slo3 unitary current properties over a broader range of voltages. Despite complexity in Slo3 channel openings that precludes simple definition of the unitary conductance, average current through single Slo3 channels varies linearly with voltage at positive activation potentials. Furthermore, the average Slo3 unitary current at a given activation potential does not change with pH. Consistent with macroscopic conductance estimates, the apparent open probability of Slo3 channel exhibits a pH-dependent maximum, with limiting values around 0.3 at the most elevated pH and voltage. Estimates of Slo3 conductance at negative potentials support a weaker intrinsic voltage dependence of gating than is observed for Slo1. For the pH-regulated Slo3 K+ channel, the dependence of macroscopic conductance on pH suggests that the pH-sensitive mechanism regulates gating in an allosteric manner qualitatively similar to regulation of Slo1 by Ca2+. Together, the results support the view that the regulation of macroscopic Slo3 currents by pH reflects regulation of gating equilibria, and not a direct effect of pH on ion permeation. Specifically, both voltage and pH regulate a closed–open conformational change in a largely independent fashion

Implicit Diffusion Models for Continuous Super-Resolution

Image super-resolution (SR) has attracted increasing attention due to its wide applications. However, current SR methods generally suffer from over-smoothing and artifacts, and most work only with fixed magnifications. This paper introduces an Implicit Diffusion Model (IDM) for high-fidelity continuous image super-resolution. IDM integrates an implicit neural representation and a denoising diffusion model in a unified end-to-end framework, where the implicit neural representation is adopted in the decoding process to learn continuous-resolution representation. Furthermore, we design a scale-controllable conditioning mechanism that consists of a low-resolution (LR) conditioning network and a scaling factor. The scaling factor regulates the resolution and accordingly modulates the proportion of the LR information and generated features in the final output, which enables the model to accommodate the continuous-resolution requirement. Extensive experiments validate the effectiveness of our IDM and demonstrate its superior performance over prior arts.Comment: 8 pages, 9 figures, published to CVPR202

Comprehensive analysis identifies novel targets of gemcitabine to improve chemotherapy treatment strategies for colorectal cancer

BackgroundGemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to the lack of clarity of the exact action targets.MethodsThe half maximal inhibitory concentration (IC50) of GEM treatment for 42 CRC cell lines were accessed from the Genomics of Drug sensitivity in Cancer (GDSC) database. High-throughput sequencing data of CRC patients were captured in The Cancer Genome Atlas (TCGA) and Weighted correlation network analysis (WGCNA) was conducted. Pearson correlations were derived for GEM potency-related genes. Differential analysis was conducted in the TCGA cohort to obtain CRC development-related genes (CDRGs), and univariate COX model analysis was performed on CDRGs overlapping with GEM potency-related genes to obtain CDRGs affecting CRC prognosis. Hub genes affecting GEM potency were identified by Spearman correlation.ResultsCALB2 and GPX3 were identified as potential targets for GEM treatment of CRC via prognostic analysis, which we also observed to be elevated with elevated clinical stage in CRC patients. The enhanced expression of CALB2 and GPX3 genes identified in the pathway analysis might inhibit the body metabolism as well as activate immune and inflammation related pathways. In addition, we found that CALB2 and GPX3 could also be considered as prognostic biomarkers in pan-cancer. Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and Z-LNle-CHO, which were expected to be the drugs of choice for GEM combination.ConclusionCALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies

Summer soil drying exacerbated by earlier spring greening of northern vegetation

Earlier vegetation greening under climate change raises evapotranspiration and thus lowers spring soil moisture, yet the extent and magnitude of this water deficit persistence into the following summer remain elusive. We provide observational evidence that increased foliage cover over the Northern Hemisphere, during 1982–2011, triggers an additional soil moisture deficit that is further carried over into summer. Climate model simulations independently support this and attribute the driving process to be larger increases in evapotranspiration than in precipitation. This extra soil drying is projected to amplify the frequency and intensity of summer heatwaves. Most feedbacks operate locally, except for a notable teleconnection where extra moisture transpired over Europe is transported to central Siberia. Model results illustrate that this teleconnection offsets Siberian soil moisture losses from local spring greening. Our results highlight that climate change adaptation planning must account for the extra summer water and heatwave stress inherited from warming-induced earlier greening