No abstract

Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.

No abstract

Comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Our network modeling revealed that nonlinear enhancer-gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Utilizing hESC definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core endoderm lineage-specifying transcription factors, and many enhancers had strong effects mid-transition but weak effects post-transition. Through integrating enhancer activity measurements and three-dimensional enhancer-promoter interaction information, we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Our study provides generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.

No abstract

No abstract

Flake graphite has excellent explosive electron emission performance for its plenty surface micro-bulges and high graphitization degree, but its advantages have rarely been studied in relativistic magnetrons. In this paper, flake graphite cathodes with different fineness were used in coaxial diodes and relativistic magnetrons, and the influence of the surface microstructure of the flake graphite cathode on the relativistic magnetron performance is demonstrated for the first time. The result showed that the graphite microstructure mainly affected the initiation stage of explosive emission. Moreover, the delay time is determined by the degree of graphitization and the surface microstructure of graphite, and the surface microstructure plays a major role. Under the applied voltage of ∼ 330kV-∼ 490kV, The finer flake graphite possessed a shorter emission delay and facilitated the microwave excitation. The excitation time of finer flake graphite is ∼ 3ns, and ∼ 5ns for lager flake graphite. After several operations of the relativistic magnetron, the edges of flake graphite were blunted, and the surface of the flake graphite appeared droplet-like areas formed by anode atom sputtering. This work reveals the advantages of the finer flake graphite cathode in the fast priming of the relativistic magnetron, thus shedding new light on cathode design of the relativistic magnetron.

No abstract