The transmembrane voltage gradient is a general physico-chemical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains ...unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of the selectivity filter and ion permeation pathway with delayed rectifier properties and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464 and Q472 from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional potassium ion occupied at positions S6 confers the delayed rectifier property and Cole-Moore effects. These results provide insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.
Mechanosensitive (MS) ion channels are a ubiquitous type of molecular force sensor sensing forces from the surrounding bilayer. The profound structural diversity in these channels suggests that the ...molecular mechanisms of force sensing follow unique structural blueprints. Here we determine the structures of plant and mammalian OSCA/TMEM63 proteins, allowing us to identify essential elements for mechanotransduction and propose roles for putative bound lipids in OSCA/TMEM63 mechanosensation. Briefly, the central cavity created by the dimer interface couples each subunit and modulates dimeric OSCA/TMEM63 channel mechanosensitivity through the modulating lipids while the cytosolic side of the pore is gated by a plug lipid that prevents the ion permeation. Our results suggest that the gating mechanism of OSCA/TMEM63 channels may combine structural aspects of the 'lipid-gated' mechanism of MscS and TRAAK channels and the calcium-induced gating mechanism of the TMEM16 family, which may provide insights into the structural rearrangements of TMEM16/TMC superfamilies.
To study organic matter and pore characteristics of the Lower Cambrian Niutitang organic-rich shales, 166 shale samples from the Niutitang Formation were collected from the studied well, drilled in ...Kaiyang county in the Northern Guizhou area, Upper Yangtze region. All of the 166 shale cores were analysed for total organic carbon (TOC), total sulfur (TS), and the stable carbon isotope of kerogen (δ13Corg). Shale samples with varying TOC values were chosen for mineral composition analysis, helium porosity measurement and low pressure nitrogen adsorption measurement. The Lower Cambrian Niutitang Formation features high organic matter content, type I oil-prone organic matter, ultra-thick organic-rich shales, and an abundance of brittle minerals exhibiting favourable characteristics for the Lower Cambrian shale gas exploration in the Upper Yangtze region. Helium porosity measurement and low pressure nitrogen adsorption measurements were performed on selected shale samples with varying TOC content in order to analyse and characterize pore characteristics. Significant differences in mineral composition and pore characteristics were found between clay-rich and clay-poor Niutitang shales. Quartz weakly correlated with TOC content in clay-rich shales, which contained minor biogenically contributed quartz and performed better in terms of reservoir properties than clay-poor shales, and exhibited higher porosity, maximum nitrogen quantity adsorbed, pore volume, and specific surface area. In clay-rich shales, the maximum nitrogen quantity adsorbed, total pore volume, and specific surface area positively correlated with TOC content (R2=0.77, 0.79, and 0.75, respectively). The pore volume of clay-rich shales was dominated by mesopores, and both micropore and mesopore volume of clay-rich shales correlated significantly with TOC content. In clay-poor shales, quartz positively correlated with TOC content, indicating biogenic contribution to quartz. Micropore volume and mesopore volume of clay-poor shales were weakly positively correlated with TOC content. Pore volume, especially mesopore volume, may be affected by the recrystallization of biogenic silica, exhibiting identical micropore volume with clay-rich shales but lower mesopore volume.
•The Lower Cambrian shales displayed high-quality organic matter concentrations.•The quartz content positively correlated with TOC content in the clay-poor shales.•Organic matter plays a positive role in the pore structure of Niutitang shales.•Significant differences exist in the pore characteristics of clay-rich and clay-poor shales.
We sought to evaluate the risk effect of tanning bed use on skin cancers among teenage and young adults. We also expected to determine whether a dose-response relationship was evident.
We observed ...73,494 female nurses for 20 years (from 1989 to 2009) in a large and well-characterized cohort in the United States and investigated whether frequency of tanning bed use during high school/college and at ages 25 to 35 years were associated with a risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. We used Cox proportional hazards models and carefully adjusted for host risk factors, ultraviolet index of residence, and sun exposure behaviors at a young age.
During follow-up, 5,506 nurses were diagnosed with BCC, 403 with SCC, and 349 with melanoma. The multivariable-adjusted hazard ratio (HR) of skin cancer for an incremental increase in use of tanning beds of four times per year during both periods was 1.15 (95% CI, 1.11 to 1.19; P < .001) for BCC, 1.15 (95% CI, 1.01 to 1.31; P = .03) for SCC, and 1.11 (95% CI, 0.97 to 1.27; P = .13) for melanoma. Compared with tanning bed use at ages 25 to 35 years, we found a significantly higher risk of BCC for use during high school/college (multivariable-adjusted HR for use more than six times per year compared with no use was 1.73 during high school/college v 1.28 at ages 25 to 35 years; P for heterogeneity < .001).
Our data provide evidence for a dose-response relationship between tanning bed use and the risk of skin cancers, especially BCC, and the association is stronger for patients with a younger age at exposure.
Owing to cognitive radar breaking the open-loop receiving-transmitting mode of traditional radar, adaptive waveform design for cognitive radar has become a central issue in radar system research. In ...this paper, the method of radar transmitted waveform design in the presence of clutter is studied. Since exact characterizations of the target and clutter spectra are uncommon in practice, a single-robust transmitted waveform design method is introduced to solve the problem of the imprecise target spectrum or the imprecise clutter spectrum. Furthermore, considering that radar cannot simultaneously obtain precise target and clutter spectra, a novel double-robust transmitted waveform design method is proposed. In this method, the signal-to-interference-plus-noise ratio and mutual information are used as the objective functions, and the optimization models for the double-robust waveform are established under the transmitted energy constraint. The Lagrange multiplier method was used to solve the optimal double-robust transmitted waveform. The simulation results show that the double-robust transmitted waveform can maximize SINR and MI in the worst case; the performance of SINR and MI will degrade if other transmitted waveforms are employed in the radar system.
This paper studies a persistent tracking problem, which is to design a control strategy for a unicycle-type mobile vehicle to track a moving target and to maintain the tracking distance within a ...detection range all the time, regardless of the target's motion. In a proposed framework based on the game theory, a bounded and closed region encircling the tracking vehicle is identified to enable persistent tracking and a tracking algorithm is constructed accordingly. The proposed approach is successfully verified through experiments using two ground vehicles, one serving as the autonomous tracking vehicle and the other as the target vehicle.
The construction of super large section (SLS) shallow buried tunnels involves challenges related to their large span, high flat rate, and complex construction process. Selecting an appropriate ...excavation method is crucial for ensuring stability, controlling costs, and managing the construction timeline. This study focuses on the selection of excavation methods and the mechanical responses of SLS tunnels in different types of surrounding rock. The research is based on the Yangjiashan tunnel project in Zhejiang Province, China, which is a four-line highway tunnel with a span of 21.3 m. Three sequential excavation methods were proposed and simulated using the three-dimensional finite difference method: the "upper first and lower later" side drift (SD) method, the central diaphragm method, and the top heading and bench (HB) method. The mechanical response characteristics of tunnel construction under these methods were investigated, including rock deformation, rock pressure, and the internal forces acting on the primary support. By comparing the performance of the three construction methods in rock masses of Grades III to V, the study aimed to determine the optimal construction method for SLS tunnels considering factors such as safety, cost, and schedule. Field tests were conducted to evaluate the effectiveness of the optimized construction scheme. The results of the field monitoring indicated that the "upper first and lower later" SD method in Grade V rock mass and the HB method in Grade III to IV rock mass are feasible and cost-effective under certain conditions. The research findings provide valuable insights for the design and construction of SLS tunnels in complex conditions, serving as a reference for engineers and project managers.
Semi-confined pyrolysis experiments were performed on core and powdered samples taken from type-II lacustrine mudstone to investigate the effects of sample rock fabrics on hydrocarbon generation and ...porosity changes when shale is subjected to pyrolysis. The generated hydrocarbons were analysed by organic geochemical methods to reflect differences in constituents and carbon isotopes. Gas (N2 and CO2) adsorption tests were applied to solid residues to characterize the formation and development of pores after the two series of pyrolysis experiments. Simple calculations indicate that hydrocarbons prefer to expulse as intact rock fabric is destroyed. Secondary cracking gas accounted for approximately 23–30% and 28–49% of all gaseous hydrocarbons in the powdered and core samples, respectively. Side reactions, such as mineral catalytic and recombination reactions, prevailed during the semi-closed pyrolysis of powdered sample at 300–500 °C, causing generated C3+ hydrocarbon yields to be lower than those of the core sample. Additionally, gaseous hydrocarbons generated from the powdered sample were characterized by more positive δ13C and higher iso-/n-C4,5 and C1/C1-5 values. Side reactions ceased at 500–550 °C, and corresponding ratios tended to equalize. For the powdered samples, a higher expulsive ratio of hydrocarbons led to better pore development, the mesopore volume increased with increasing temperatures, and micropore volume decreased above 450 °C. Comparatively, the mesopore volume decreased above 450 °C for the core sample, and the micropore volume decreased above 500 °C. These results are helpful for revealing the genetic characteristics of shale gas and for understanding the origins of organic-hosted pores of the Cambrian Niutitang shale in southern China. The study suggests that samples with intact rock fabric should be used in future laboratory pyrolysis tests to generate results that better reflect natural conditions.
•Semi-closed pyrolysis results for core and powdered samples of a same mudstone were compared.•The expulsion-retention mechanisms of hydrocarbons are affected by rock fabrics.•Rock fabrics have important effects on porosity development of samples.•Samples with intact rock fabrics should be used for future laboratory pyrolysis.
Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks ...that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2
mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2
mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
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