Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.

GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.

Transport Channels of Air Pollutants Affecting the Southern Sichuan Basin Based on Gridded Dispersion Simulation.

Air pollutants suspended in the atmosphere have a large impact on air quality, climate, and human health. As one of the important populated and industrialized regions in China, the Sichuan Basin (SCB) has confronted severe air pollution in recent years. Previous studies have shown that regional transport played a significant role in the formation of regional pollution in the SCB, particularly in the southern basin. Using Yibin and Zigong as representative receptor cities, we further identified the transport channels affecting the southern basin by conducting gridded dispersion simulations. A total of seven channels were identified, including three for cyclonic transport, three through the mountainous areas between the Longquan Mountain and the Huaying Mountain, and one along the Yangtze River. Varying seasonal distributions of their occurrence frequencies were observed. Furthermore, observational evidence for several universal channels was presented during a typical transport case. The transport pathways identified in this study can guide the planning of regional distribution of emission sources and the measures for regional joint prevention and control of air pollution.

LncRNA GAS5 suppresses TGF-ß1-induced transformation of pulmonary pericytes into myofibroblasts by recruiting KDM5B and promoting H3K4me2/3 demethylation of the PDGFRα/ß promoter.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a condition that may cause persistent pulmonary damage. The transformation of pericytes into myofibroblasts has been recognized as a key player during IPF progression. This study aimed to investigate the functions of lncRNA growth arrest-specific transcript 5 (GAS5) in myofibroblast transformation during IPF progression. METHODS: We created a mouse model of pulmonary fibrosis (PF) via intratracheal administration of bleomycin. Pericytes were challenged with exogenous transforming growth factor-ß1 (TGF-ß1). To determine the expression of target molecules, we employed quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical and immunofluorescence staining. The pathological changes in the lungs were evaluated via H&E and Masson staining. Furthermore, the subcellular distribution of GAS5 was examined using FISH. Dual-luciferase reporter assay, ChIP, RNA pull-down, and RIP experiments were conducted to determine the molecular interaction. RESULTS: GAS5 expression decreased whereas PDGFRα/ß expression increased in the lungs of IPF patients and mice with bleomycin-induced PF. The in vitro overexpression of GAS5 or silencing of PDGFRα/ß inhibited the TGF-ß1-induced differentiation of pericytes to myofibroblasts, as evidenced by the upregulation of pericyte markers NG2 and desmin as well as downregulation of myofibroblast markers α-SMA and collagen I. Further mechanistic analysis revealed that GAS5 recruited KDM5B to promote H3K4me2/3 demethylation, thereby suppressing PDGFRα/ß expression. In addition, KDM5B overexpression inhibited pericyte-myofibroblast transformation and counteracted the promotional effect of GAS5 knockdown on pericyte-myofibroblast transformation. Lung fibrosis in mice was attenuated by GAS5 overexpression but promoted by GAS5 deficiency. CONCLUSION: GAS5 represses pericyte-myofibroblast transformation by inhibiting PDGFRα/ß expression via KDM5B-mediated H3K4me2/3 demethylation in IPF, identifying GAS5 as an intervention target for IPF.

Activin Receptor-Like Kinase 3 Directly Couples Gαq (Guanine Nucleotide-Binding Protein Subunit αq)/ Gαq (Guanine Nucleotide-Binding Protein Subunit α11) to Regulate Vascular Contractility.

BACKGROUND: Vascular smooth muscle cell (VSMC) contractility is critical for blood pressure regulation and vascular homeostasis. Identifying the key molecule that maintains VSMC contractility may provide a novel therapeutic target for vascular remodeling. ALK3 (activin receptor-like kinase 3) is a serine/threonine kinase receptor, and deletion of ALK3 causes embryonic lethality. However, little is known about the role of ALK3 in postnatal arterial function and homeostasis. METHODS: We conducted in vivo studies in a tamoxifen-induced postnatal VSMC-specific ALK3 deletion mice suitable for analysis of blood pressure and vascular contractility. Additionally, the role of ALK3 on VSMC was determined using Western blot, collagen-based contraction assay and traction force microscopy. Furthermore, interactome analysis were performed to identify the ALK3-associated proteins and bioluminescence resonance energy transfer assay was used to characterize Gαq activation. RESULTS: ALK3 deficiency in VSMC led to spontaneous hypotension and impaired response to angiotensin II in mice. In vivo and in vitro data revealed that ALK3 deficiency impaired contraction force generation by VSMCs, repressed the expression of contractile proteins, and inhibited the phosphorylation of myosin light chain. Mechanistically, Smad1/5/8 signaling mediated the ALK3-modulated contractile protein expressions but not myosin light chain phosphorylation. Furthermore, interactome analysis revealed that ALK3 directly interacted with and activated Gαq (guanine nucleotide-binding protein subunit αq)/Gα11 (guanine nucleotide-binding protein subunit α11), thereby stimulating myosin light chain phosphorylation and VSMC contraction. CONCLUSIONS: Our study revealed that in addition to canonical Smad1/5/8 signaling, ALK3 modulates VSMC contractility through direct interaction with Gαq/Gα11, and therefore, might serve as a potential target for modulating aortic wall homeostasis.

Impacts of video communication on psychological well-being and cosmetic surgery acceptance.

Video communication via platforms such as Zoom has been routinely used as a communication tool during the COVID-19 pandemic. Scientific evidence has suggested that constant video communication can have detrimental consequences such as "Zoom fatigue", inhibiting collaboration, and new information exchange. The current study focuses on the effects of using video communication technology on self-esteem, affect, and image perception under the framework of objective self-awareness (OSA). We implemented a survey among a large sample of video communication users. The results revealed a nuanced picture of OSA with video communication: merely seeing self-video and the time of using video communication won't activate OSA. However, being a listener and a part of the audience in video communication activated OSA. In turn, OSA significantly increased the attention paid to oneself, leading to critical self-evaluation, negative affect, and a greater level of cosmetic surgery acceptance. Moreover, OSA reduced the level of self-esteem. Theoretical and practical implications are discussed.

Vehicle exhausts contribute high near-UV absorption through carbonaceous aerosol during winter in a fast-growing city of Sichuan Basin, China.

Carbonaceous aerosols pose significant climatic impact, however, their sources and respective contribution to light absorption vary and remain poorly understood. In this work, filter-based PM2.5 samples were collected in winter of 2021 at three urban sites in Yibin, a fast-growing city in the south of Sichuan Basin, China. The composition characteristics of PM2.5, light absorption and source of carbonaceous aerosol were analyzed. The city-wide average concentration of PM2.5 was 87.4 ± 31.0 µg/m3 in winter. Carbonaceous aerosol was the most abundant species, accounting for 42.5% of the total PM2.5. Source apportionment results showed that vehicular emission was the main source of PM2.5 during winter, contributing 34.6% to PM2.5. The light absorption of black carbon (BC) and brown carbon (BrC) were derived from a simplified two-component model. We apportioned the light absorption of carbonaceous aerosols to BC and BrC using the Least Squares Linear Regression with optimal angstrom absorption exponent of BC (AAEBC). The average absorption of BC and BrC at 405 nm were 51.6 ± 21.5 Mm-1 and 17.7 ± 8.0 Mm-1, respectively, with mean AAEBC = 0.82 ± 0.02. The contribution of BrC to the absorption of carbonaceous reached 26.1% at 405 nm. Based on the PM2.5 source apportionment and the mass absorption cross-section (MAC) value of BrC at 405 nm, vehicle emission was found to be the dominant source of BrC in winter, contributing up to 56.4%. Therefore, vehicle emissions mitigation should be the primary and an effective way to improve atmospheric visibility in this fast-developing city.

Deep unsupervised endoscopic image enhancement based on multi-image fusion.

BACKGROUND AND OBJECTIVE: A deep unsupervised endoscopic image enhancement method is proposed based on multi-image fusion to achieve high quality endoscope images from poorly illuminated, low contrast and color deviated images through an unsupervised mapping and deep learning network without the need for ground truth. METHODS: Firstly, three image enhancement methods are used to process original endoscopic images to obtain three derived images, which are then transformed into HSI color space. Secondly, a deep unsupervised multi-image fusion network (DerivedFuse) is proposed to extract and fuse features of the derived images accurately by utilizing a new no-reference quality metric as loss function. I-channel images of the three derived images are inputted into the DerivedFuse network to enhance the intensity component of the original image. Finally, a saturation adjustment function is proposed to adaptive adjusting the saturation component of HSI color space to enrich the color information of the original input image. RESULTS: Three evaluation metrics: Entropy, Contrast Improvement Index (CII) and Average Gradient (AG) are used to evaluate the performance of the proposed method. The results are compared with that of fourteen state-of-the-art algorithms. Experiments on endoscopic image enhancement show that the Entropy value of our method is 3.27% higher than the optimal entropy value of comparison algorithms. The CII of our proposed method is 6.19% higher than that of comparison algorithms. The AG of our method is 7.83% higher than the optimal AG of comparison algorithms. CONCLUSIONS: The proposed deep unsupervised multi-image fusion method can obtain image information details, enhance endoscopic images with high contrast, rich and natural color information, visual and image quality. Sixteen doctors and medical students have given their assessments on the proposed method for assisting clinical diagnoses.

Binocular measurement method for the continuous casting slab model based on the improved BRISK algorithm.

Due to the low accuracy of the traditional image feature matching algorithm in binocular vision measurement, a binocular measurement method for the continuous casting slab model based on the improved binary robust invariant scalable keypoints (BRISK) algorithm is proposed. First, the feature points of the image are detected. After that, local area sampling and sub-area division are carried out with the feature points as the center, sub-areas with low offset values are removed, and the main direction is obtained by using the centroid of the remaining sub-areas. Then, the gray difference threshold is used to replace the traditional gray value intensity comparison to generate descriptors. Finally, the Hamming distance is used to match the feature points, and the three-dimensional coordinates of the matching points are calculated to complete the measurement. Through comparative experiments, the lowest relative error of the improved algorithm in this paper reaches 0.4723%, which meets the requirement of measurement accuracy.

Activation of PTH1R alleviates epididymitis and orchitis through Gq and ß-arrestin-1 pathways.

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration-approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and ß-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq± and Arrb1-/- mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.

G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT1 receptor) - a prototypical class A GPCR-activation. Our findings suggest a synergistic transition mechanism for AT1 receptor activation. A key intermediate state is identified in the activation pathway, which possesses a cryptic binding site within the intracellular region of the receptor. Mutation of this cryptic site prevents activation of the downstream G protein signaling and ß-arrestin-mediated pathways by the endogenous AngII octapeptide agonist, suggesting an allosteric regulatory mechanism. Together, these findings provide a deeper understanding of AT1 receptor activation at an atomic level and suggest avenues for the design of allosteric AT1 receptor modulators with a broad range of applications in GPCR biology, biophysics, and medicinal chemistry.

Intra-abdominal hypertension and increased acute kidney injury risk: a systematic review and meta-analysis.

OBJECTIVE: The present meta-analysis aimed to determine the relationship between intra-abdominal hypertension (IAH) and an increased prevalence of acute kidney injury (AKI) and identify the associated risk factors in various patient populations, regardless of whether they were admitted to an intensive care unit. METHODS: We used three databases for the following search terms: "IAH," "abdominal compartment syndrome," "AKI," "acute kidney failure," and others. The articles retrieved were compared to identify appropriate studies published until 7 May 2020. The main outcome was AKI. RESULTS: Six studies with 344 individuals were included. The patients were divided into two main groups: the IAH and non-IAH groups. Compared with patients without IAH, patients with IAH had a higher risk of AKI (odds ratio = 2.57, 95% confidence interval: 1.55-4.26). In the subgroup and meta-regression analyses, body mass index, age, the presence or absence of burns, and cardiac surgery did not affect the risk of AKI. CONCLUSION: IAH was associated with AKI risk, and this association was not influenced by age, body mass index, the presence or absence of burns, or cardiac surgery.

A novel Ce0.8Fe0.1Zr0.1O2 solid solution with high catalytic activity for hydrogen storage in MgH2.

The effect of the solid solution Ce0.8Fe0.1Zr0.1O2, successfully prepared by a hydrothermal synthesis method, on the hydrogen sorption properties of MgH2 is systemically investigated. The Ce0.8Fe0.1Zr0.1O2-modified MgH2 composite exhibits remarkable hydrogen kinetics properties and thermodynamics behavior compared to those of as-milled MgH2, with a reduction in the initial desorption temperature of approximately 82 K. With respect to the hydrogen kinetics, the Ce0.8Fe0.1Zr0.1O2-added sample could uptake approximately 5.3 wt% H2 at 473 K in 2500 s, whereas only 1.5 wt% hydrogen could be absorbed by pristine MgH2 in the same conditions. Furthermore, about 4.5 wt% of hydrogen could be desorbed by Ce0.8Fe0.1Zr0.1O2-doped MgH2 composite at 623 K, which was 2 wt% higher than the as-milled MgH2 sample over the same period of time. The decomposition apparent activation energy for MgH2-Ce0.8Fe0.1Zr0.1O2 is reduced to 84.3 kJ mol-1, which is about 77 kJ mol-1 lower than that of pristine MgH2. It is believed that the notable improvement in the hydrogen sorption kinetics is due to the in situ-formed active species of CeH2.51 and MgO as well as the abundant oxygen vacancies, which play a vital role in catalyzing the hydrogen sorption performance of MgH2.

Loneliness Assuaged: Eye-Tracking an Audience Watching Barrage Videos.

Researchers usually theorize media exposure based on assumptions of legacy media. However, a new interactive video viewing format, in this case barrage video where viewers' comments are overlaid over visual content, challenges past perspectives. This study proposes an activation and match satisfaction model to study viewing behaviors of lonely people and to challenge previous claims. It presents a protocol to examine the mechanism of how loners use barrage videos by combining eye tracking and self-report measures. Eye tracking documents the audience's conscious and subconscious watching behaviors in real time and allows for inference of the amount of allocated cognitive resources in response to rational and emotional content. The self-report gauges the amount of satisfaction obtained. Overall, results from the measures supported an activation and match satisfaction model regarding loners and their barrage video viewing behaviors. Implications are discussed.

Improved hydrogen storage properties of MgH2 by nickel@nitrogen-doped carbon spheres.

Magnesium hydride is considered to be one of the most desirable hydrogen storage materials due to its high weight capacity (7.6 wt% H2) and low price. However, its relatively high operating temperatures and slow dynamics have always hampered its commercial applications. In this paper, nano-nickel particle coated nitrogen-doped carbon spheres (Ni@NCS) were synthesized by a chemical reduction method and then introduced into Mg to form an MgH2-Ni@NCS composite via hydriding combustion and subsequent high-energy ball milling processes. The results showed that the MgH2-Ni@NCS composite possessed high hydrogen storage capacity and fast absorbing/desorbing kinetics, absorbing 5.7 wt% H2 and desorbing 4.3 wt% H2 within 8 min at 623 K. Moreover, the capacity shows negligible degradation after 10 cycles, indicating that the MgH2-Ni@NCS composite has good cycling stability. Even at relatively low temperature (373 K), the MgH2-Ni@NCS composite still absorbed 4.2 wt% H2 within 60 min compared to 0.9 wt% H2 for milled MgH2. The improvement in hydrogen storage properties is ascribed to the in situ formed Mg2NiH4 induced dehydrogenation of MgH2 and effective prevention of the agglomeration of magnesium during the hydriding/dehydriding reaction by the carbon material.

Overexpression of MEF2D contributes to oncogenic malignancy and chemotherapeutic resistance in ovarian carcinoma.

The transcription factor MEF2 promotes survival in various cell types and a number of studies indicate that abnormal regulation of MEF2 is linked to oncogenicity in several carcinomas. We have found that MEF2D, a member of the MEF2 family, is upregulated in Ovarian Cancer (OC). Immunohistochemistry analysis of tumor sections of 402 OC patients revealed that MEF2D is significantly elevated at the protein level. We have also found that the expression level of MEF2D is associated with cisplatin-resistance and poor prognosis by a retrospective analysis. Furthermore, Downregulation of MEF2D by siRNA reduces proliferation and invasiveness of OC cells SKOV3 and OVCAR3, induces apoptosis in vitro, and abolishes OVCAR3 tumorigenicity in xenograft model. Mechanistic study via ChIP analysis identified two of MEF2D-targeted genes, HPSE and IKBKE, which are associated with tumor invasion and chemotherapy-resistance, in accord with MEF2D expression in OC. Remarkably, knock-down of MEF2D invariably lead to the downregulation of IKBKE and reversed cisplatin (DDP)-resistance in cisplatin-resistant cells SKOV3-DDP. Our results suggest that MEF2D promotes malignant biological behaviors and cisplatin-resistance in OC and establish MEF2D as a new therapeutic target in OC treatment.

Clicking Health Risk Messages on Social Media: Moderated Mediation Paths Through Perceived Threat, Perceived Efficacy, and Fear Arousal.

This study drew on appraisal theory to examine how fear appeal messages and individual coping styles combined to drive users' intention to click (ITC) health risk messages on social media. A 2 × 2 × 2 mixed-design experiment was conducted, with threat and efficacy as between subject factors and message as the within subject factor. The results suggested that: (1) threat and efficacy message influenced ITC via the mediating effect of perceived threat, and perceived efficacy; (2) fear arousal was positively related to intention to click; (3) blunting style used by the participant suppressed fear arousal's ability to mobilize ITC; and (4) monitoring style had a positive main effect on ITC. Theoretical and practical implications are discussed.

Mechanistic effect of the human GJB6 gene and its mutations in HaCaT cell proliferation and apoptosis.

We constructed lentiviral vectors containing the human wild-type GJB6 gene and the mutant variants A88V and G11R. The three proteins were stably expressed by the Tet-on system in the HaCaT cell line and used to study the functional effect of the variants. The CCK-8 assay and flow cytometric analyses were used to determine the levels of cell proliferation and apoptosis. Western blot analyses were performed to analyze the relevant clinical indicators of hidrotic ectodermal dysplasia and markers of apoptosis in transfected HaCaT cells. The CCK8 assay and the flow cytometry results showed a significant increase (P<0.05) in the apoptosis of HaCaT cells expressing the A88V and G11R mutants. In addition, we demonstrated that the A88V and G11R mutants induced the apoptosis of transfected HaCaT cells via the activation of caspase-3, -8, -9, and PARA. No change was observed in the activity of BAX compared with the control. This study provides further clarification on the mechanisms underlying the effect of the mutant variants A88V and G11R of the GJB6 gene on the induction of HaCaT cell apoptosis.

The use of anti-ulcer agents and the risk of chronic kidney disease: a meta-analysis.

PURPOSE: We conducted a meta-analysis to explore the association between the use of different anti-ulcer agents and the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), and decline in glomerular filtration rate (GFR) in various study populations. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant entries up to July 1, 2017. The primary outcomes of the meta-analysis were risk ratios (RRs) of CKD, ESRD, and decline in GFR. We also investigated the heterogeneity of the meta-analysis by subgroup analysis and meta-regression analysis. RESULTS: A total of 662,624 individuals were enrolled in five trials. Compared with non-PPI users, PPI users had a higher trend of CKD (RR = 1.16, 95% CI 1.07-1.25, P < 0.001), especially ESRD (RR = 1.81, 95% CI 1.59-2.06, P < 0.001). There was an elevated risk of adverse renal outcome among participants receiving PPI and not H2RA (CKD: RR = 1.28, 95% CI 1.24-1.33, P < 0.001; ESRD: RR = 1.39, 95% CI 1.17-1.64, P < 0.001; GFR: RR = 1.31, 95% CI 1.26-1.36, P < 0.001). However, H2RA users were not associated with CKD when compared with non-H2RA users (RR = 1.02, 95% CI 0.83-1.25, P = 0.855). In subgroup analysis, the average age of individuals and drug dosage had no influence on the risk of CKD, while duration of PPI exposure from 31 to 720 days is a potential factor in progression to ESRD (P < 0.001). CONCLUSIONS: Chronic PPI use, but not H2RAs, is associated with deterioration in kidney function.

Mechanistic effect of the human GJB6 gene and its mutations in HaCaT cell proliferation and apoptosis

We constructed lentiviral vectors containing the human wild-type GJB6 gene and the mutant variants A88V and G11R. The three proteins were stably expressed by the Tet-on system in the HaCaT cell line and used to study the functional effect of the variants. The CCK-8 assay and flow cytometric analyses were used to determine the levels of cell proliferation and apoptosis. Western blot analyses were performed to analyze the relevant clinical indicators of hidrotic ectodermal dysplasia and markers of apoptosis in transfected HaCaT cells. The CCK8 assay and the flow cytometry results showed a significant increase (P<0.05) in the apoptosis of HaCaT cells expressing the A88V and G11R mutants. In addition, we demonstrated that the A88V and G11R mutants induced the apoptosis of transfected HaCaT cells via the activation of caspase-3, -8, -9, and PARA. No change was observed in the activity of BAX compared with the control. This study provides further clarification on the mechanisms underlying the effect of the mutant variants A88V and G11R of the GJB6 gene on the induction of HaCaT cell apoptosis.