Voltage-gated sodium (Na
) channels are responsible for the initiation and propagation of action potentials. They are associated with a variety of channelopathies and are targeted by multiple ...pharmaceutical drugs and natural toxins. Here, we report the cryogenic electron microscopy structure of a putative Na
channel from American cockroach (designated Na
PaS) at 3.8 angstrom resolution. The voltage-sensing domains (VSDs) of the four repeats exhibit distinct conformations. The entrance to the asymmetric selectivity filter vestibule is guarded by heavily glycosylated and disulfide bond-stabilized extracellular loops. On the cytoplasmic side, a conserved amino-terminal domain is placed below VSD
, and a carboxy-terminal domain binds to the III-IV linker. The structure of Na
PaS establishes an important foundation for understanding function and disease mechanism of Na
and related voltage-gated calcium channels.
Urban spatial structure affects many aspects of urban functions and has implications for accessibility, environmental sustainability, and public expenditures. During the urbanization process, a ...careful and efficient examination of the urban spatial structure is crucial. Different from the traditional approach that relies on population or employment census data, this research exploits the nighttime light (NTL) intensity of the earth surface recorded by satellite sensors. The NTL intensity is represented as a continuous mathematical surface of human activities, and the elemental features of urban structures are identified by analogy with earth's topography. We use a topographical metaphor of a mount to identify an urban center or subcenter and the surface slope to indicate an urban land-use intensity gradient. An urban center can be defined as a continuous area with higher concentration or density of employments and human activities. We successfully identified 33 urban centers, delimited their corresponding boundaries, and determined their spatial relations for Shanghai metropolitan area, by developing a localized contour tree method. In addition, several useful properties of the urban centers have been derived, such as 9% of Shanghai administrative area has become urban centers. We believe that this method is applicable to other metropolitan regions at different spatial scales.
The glucose transporter GLUT1 catalyses facilitative diffusion of glucose into erythrocytes and is responsible for glucose supply to the brain and other organs. Dysfunctional mutations may lead to ...GLUT1 deficiency syndrome, whereas overexpression of GLUT1 is a prognostic indicator for cancer. Despite decades of investigation, the structure of GLUT1 remains unknown. Here we report the crystal structure of human GLUT1 at 3.2 Å resolution. The full-length protein, which has a canonical major facilitator superfamily fold, is captured in an inward-open conformation. This structure allows accurate mapping and potential mechanistic interpretation of disease-associated mutations in GLUT1. Structure-based analysis of these mutations provides an insight into the alternating access mechanism of GLUT1 and other members of the sugar porter subfamily. Structural comparison of the uniporter GLUT1 with its bacterial homologue XylE, a proton-coupled xylose symporter, allows examination of the transport mechanisms of both passive facilitators and active transporters.
Chronic diseases such as atherosclerosis and cancer are now the leading causes of morbidity and mortality worldwide. Inflammatory processes and oxidative stress underlie the pathogenesis of these ...pathological conditions. Bioactive peptides derived from food proteins have been evaluated for various beneficial effects, including anti-inflammatory and antioxidant properties. In this review, we summarize the roles of various food-derived bioactive peptides in inflammation and oxidative stress and discuss the potential benefits and limitations of using these compounds against the burden of chronic diseases.
The cation channel of sperm (CatSper) is essential for sperm motility and fertility
. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ...ε, ζ, and EFCAB9
. Here we report the cryo-electron microscopy (cryo-EM) structure of the CatSper complex isolated from mouse sperm. In the extracellular view, CATSPER1-4 conform to the conventional domain-swapped voltage-gated ion channel fold
, following a counterclockwise arrangement. The auxiliary subunits CATSPERβ, γ, δ and ε-each of which contains a single transmembrane segment and a large extracellular domain-constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively. Our EM map reveals several previously uncharacterized components, exemplified by the organic anion transporter SLCO6C1. We name this channel-transporter ultracomplex the CatSpermasome. The assembly and organization details of the CatSpermasome presented here lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives.
Angiotensin converting enzyme (ACE) is a key enzyme in the renin angiotensin system (RAS) responsible for conversion of angiotensin (Ang) I into Ang II, a vasoconstrictor leading to elevated blood ...pressure. ACE inhibitory (ACEi) peptides derived from food proteins have shown potential in the prevention and management of hypertension. Although most ACEi peptides were characterized based on in vitro ACEi activity, a relationship between ACE inhibition and physiological antihypertensive effect is not apparent, indicating the involvement of other mechanisms of action.
This paper focuses on emerging antihypertensive mechanisms of ACEi peptides. As an alternate arm of the classic RAS, ACE2 cleaves Ang II into Ang (1–7) and thus counterbalances the harmful effects of Ang II. Endothelial dysfunction is now recognized as an early feature in the pathophysiology of metabolic syndrome and cardiovascular disorders including hypertension; endothelial dysfunction, vascular oxidative stress and inflammation are interplayed. Future perspectives on mechanistic study of ACEi peptides are forecasted.
Apart from classic ACE inhibition, emerging evidence suggests that food peptides can exert antihypertensive activity through upregulation of ACE2 (an ACE homologue that counterbalances the detrimental effect of elevated ACE), improvement of endothelial function, as well as reduced vascular oxidation and inflammation. Future research is expected to look into the effects of bioaccessibility, bioavailability, stability and reactivity of the peptides with food and gut matrices, as well as the gut microbiota, on blood pressure reduction.
•ACE inhibition is a well-known mechanism of antihypertensive peptides.•Food peptides also exert antihypertensive activity through upregulation of ACE2.•Peptide effect on ACE2 counterbalances the detrimental effect of elevated ACE.•Other alternative mechanisms can help explain the in vivo effects of the peptides.•Peptide bioaccessibility and role of the gut microbiota should also be considered.
The aim of this study was to develop a hybrid model (Geo-RFE-RF) for Landslide Susceptibility Mapping (LSM) predicated on GeoDetector and Random Forest (RF) using the Recursive Feature Elimination ...(RFE-RF) method for eliminating redundant and noise factors. At the outset, for the sample of 1522 investigated landslides and 1522 non-landslides, twenty-two factors were chosen as the initial landslide-conditioning factors to construct a spatial database. Subsequently, the GeoDetector and RFE-RF methods were adopted to eliminate the least effective factors, respectively, with the Geo-RFE-RF model being formulated with the combination factors of these two methods. Finally, the performance of the Geo-RFE-RF and RF model with twenty-two initial factors (In-RF) were compared and assessed, and the higher accuracy model was employed to generate a LSM in a case study area, Fengjie County (China). The results indicate that, the Area Under Curve, Accuracy, Precision, and F1 Score of the test dataset is increased by 0.9%, 0.4%, 1.5%, and 0.3%, respectively, under the Geo-RFE-RF model, as compared to the In-RF model. The conditioning factors used to construct the model have been reduced from twenty-two to thirteen, but the predictive ability of the Geo-RFE-RF model performs better, proving the effectiveness of the hybrid model that combines the factors from GeoDetector and RFE-RF methods. This hybrid model not only considers the spatial pattern characteristics of spatial data for screening factors, but the selected factors are also in good agreement with the adopted machine learning method, offering potential use as a general framework for eliminating redundant and noise factors in LSM across the globe.
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•LSM Random Forest model based on factor screening•Hybrid optimization method based on GeoDetector and Recursive Feature Elimination•Considered both spatial pattern characteristics and the agreement with the adopted model
The L-type voltage-gated Ca2+ (Cav) channels are modulated by various compounds exemplified by 1,4-dihydropyridines (DHP), benzothiazepines (BTZ), and phenylalkylamines (PAA), many of which have been ...used for characterizing channel properties and for treatment of hypertension and other disorders. Here, we report the cryoelectron microscopy (cryo-EM) structures of Cav1.1 in complex with archetypal antagonistic drugs, nifedipine, diltiazem, and verapamil, at resolutions of 2.9 Å, 3.0 Å, and 2.7 Å, respectively, and with a DHP agonist Bay K 8644 at 2.8 Å. Diltiazem and verapamil traverse the central cavity of the pore domain, directly blocking ion permeation. Although nifedipine and Bay K 8644 occupy the same fenestration site at the interface of repeats III and IV, the coordination details support previous functional observations that Bay K 8644 is less favored in the inactivated state. These structures elucidate the modes of action of different Cav ligands and establish a framework for structure-guided drug discovery.
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•High-resolution cryo-EM structures of Cav1.1 bound to four prototypical ligands•Molecular determinants for the specificity between DHP and L-type Cav channels•Molecular basis for the stereo-selectivity of DHP antagonists and agonists•Molecular details of Cav channel blockade by diltiazem and verapamil
A view on how both agonists and antagonists interact with a voltage-gated calcium channel opens up avenues for understanding channel gating and new ligand design.
Fully understanding spatiotemporal patterns of electric power consumption (EPC) is one of the key questions related to sustainable socioeconomic and environmental development in countries along the ...Silk Road Economic Belt and the 21st-Century Maritime Silk Road (hereinafter referred to as the Belt and Road countries). However, studies about spatiotemporal patterns of EPC in the Belt and Road countries are still scarce due to the lack of reliable data. This study attempted to investigate spatiotemporal patterns of EPC in the Belt and Road countries from multiple perspectives. Firstly, the Defense Meteorological Satellite Program’s Operational Linescan System (DMSP-OLS) nighttime stable light data were used to estimate EPC from 1992 to 2013. Subsequently, the mathematical statistic method, standard deviational ellipse, rank size rule, and correlation analysis were employed to evaluate the EPC change in detail. The results reveal that the EPC growth mainly occurs in the developing countries, especially in China. The geographical distribution of EPC in the Belt and Road countries is oriented in the Northwest-Southeast direction between 1992 and 2013. Based on the rank size rule analysis, the slope values of q are −2.392 and −2.175 between 1992 and 2013, with an average R2 value of 0.664, indicating a clear clustering pattern of EPC. It is also proved that GDP is a more important impact factor to EPC than the population. Our findings can offer an effective way to understand spatiotemporal evolution characteristics of EPC in the Belt and Road countries, and provide references for regional socioeconomic development and cooperation.
•Spatiotemporal patterns of EPC are explored from multiple perspectives.•The EPC growth mainly occurs in the developing countries.•The geographical distribution of EPC is oriented in the Northwest-Southeast direction.•The size distribution of EPC has a clear clustering pattern.•GDP is a more important impact factor to EPC than the population.
The sedimentary and crustal thicknesses and Poisson's ratios of the NE Tibetan Plateau and its adjacent regions are estimated by the h–κ stacking and CCP image of receiver functions from the data of ...1,317 stations. The horizontal resolution of the obtained results is as high as 0.5° × 0.5°, which can be used for further high resolution model construction in the region. The crustal thicknesses from Airy's equilibrium are smaller than our results in the Sichuan Basin, Qilian tectonic belt, northern Alxa block and Qaidam Basin, which is consistent with the high densities in the mantle lithosphere and may indicate that the high-density lithosphere drags crust down overall. High Poisson's ratios and low velocity zones are found in the mid- and lower crust beneath eastern Qilian tectonic belt and the boundary areas of the Ordos block, indicating that partial melting may exist in these regions. Low Poisson's ratios and low-velocity anomalies are observed in the crust in the NE Tibetan Plateau, implying that the mafic lower crust is thinning or missing and that the mid- and lower crust does not exhibit melting or partial melting in the NE Tibetan Plateau, and weak flow layers are not likely to exist in this region.
•High resolution sedimentary and crustal thicknesses in the study region are obtained.•The top interface of the low-velocity zone in the mid- and lower crust are studied by the h–κ stacking of receiver functions.•The boundary areas of the Ordos block show high Poisson's ratios and low-velocity zones.•Low Poisson's ratios and low-velocity zones imply that the NE Tibetan Plateau has no weak flow layers.
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