Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

Longitudinal study of multidimensional factors influencing maternal and offspring health outcomes: a study protocol.

BACKGROUND: Reducing preventable adverse maternal and offspring outcomes is a global priority. The causes of adverse maternal and fetal outcomes are complex with multidimensional influencing factors. In addition, the Covid-19 epidemic has had a significant psychological and physical impact on people. China is now stepping into the post-epidemic era. We are curious about the psychological and physical situation of maternity in China at this stage. Therefore, we plan to initiate a prospective longitudinal study to investigate the multidimensional influences and mechanisms that affect maternal and offspring health. METHOD: We will recruit eligible pregnant women at Renmin Hospital of Hubei Province, China. The expected sample size is 1490. We will assess socio-demographics, Covid-19 related information, social capital, sleep, mental health and medical records, including clinical examination and biochemical tests. Eligible pregnant women will be enrolled in the study with less than 14 weeks of gestation. Participants will receive a total of nine follow-up visits between mid-pregnancy and one year postpartum. The offspring will be followed up at birth, 6 weeks, 3 months, 6 months and one year. In addition, a qualitative study will be conducted to understand the underlying causes that affect maternal and offspring health outcomes. DISCUSSION: This is the first longitudinal study of maternity in Wuhan, Hubei Province which integrates physical, psychological and social capital dimensions. Wuhan is the first city to be affected by Covid-19 in China. As China moves into the post-epidemic era, this study will provide us with a better understanding of the long-term impact of the epidemic on maternal and offspring health outcomes. We will implement a range of rigorous measures to enhance participants' retention rate and ensure the quality of data. The study will provide empirical results for maternal health in the post-epidemic era.

Mid-Term Outcomes of Cemented or Uncemented Total Hip Arthroplasty for Failed Proximal Femoral Nail Antirotation Following Intertrochanteric Femur Fractures: A Retrospective Observational Study.

Introduction: The aim of this retrospective study was to assess the clinical outcomes of cemented or uncemented total hip arthroplasty (CTHA or UTHA) following prior failed proximal femoral nail antirotation (PFNA) fixation in patients with intertrochanteric femur fractures (IFFs). Materials and methods: Data from 244 patients with IFFs who experienced a conversion of PFNA to CTHA (n = 120) or to UTHA (n = 124) due to screw cut-out, mal/nonunion, or osteonecrosis during 2008-2018 were retrospectively analyzed. Follow-up occurred 1, 3, 6, and 12 months postoperatively and yearly thereafter. The primary outcome was the incidence of orthopedic complications; the secondary outcome was the Harris hip score (HHS). Results: The median follow-up was 60 months (range, 50-67 months). The incidences of orthopedic complications were 10% in the PFNA to CTHA group and 19.3% in the PFNA to UTHA group (P = .040). Significant differences were also observed regarding the incidence of prosthesis revision (1.7% for PFNA to CTHA vs 7.2% for PFNA to UTHA, P = .036). From the three years after conversion surgery to the final follow-up, significant differences were detected in HHS between groups (each P < .05). At the final follow-up, a statistically significant difference was detected in the HHS (79.54±18.85 for PFNA to CTHA vs. 75.26±18.27 for PFNA to UTHA, P = .014). Conclusion: The results of the study may demonstrate a significant statistical advantage with respect to the orthopedic complication rate and HHS in favor of CTHA compared to UTHA in patients with failed PFNA.

Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.

Nanostructured Iron Fluoride Derived from Fe-Based Metal-Organic Framework for Lithium Ion Battery Cathodes.

A comprehensive strategy for the morphological control of octahedral and spindle Fe-based metal-organic frameworks (Fe-MOFs) via microwave-assisted adjustment is proposed in this research. Afterward, in situ copyrolysis under N2 atmosphere contributes to the fabrication of two shape-maintained FeF3·0.33H2O nanostructures (named O-FeF3·0.33H2O and S-FeF3·0.33H2O, respectively) with confined hierarchical porosity and graphitized carbon skeleton. The lithium storage performances for the MOF-derived octahedral O-FeF3·0.33H2O and spindle S-FeF3·0.33H2O composites are investigated, and the prospective lithium storage mechanism is discussed. As a result, the main product of the porous O-FeF3·0.33H2O structure is found to be a promising cathode material for lithium ion batteries owing to its advantageous electrochemical capability. Even after being cycled over 1000 times at 2 C (1 C = 237 mAh g-1), the capacity attenuation rate of the as-prepared O-FeF3·0.33H2O electrode is as low as 0.039% per cycle. The combination of proper octahedral morphology and highly graphitized carbon modification can not only enhance the conductivity of the cathode but also promote the diffusion of Li+ effectively. The remarkable performance of octahedral O-FeF3·0.33H2O can be confirmed by the Li-ion diffusion coefficient (DLi+) calculation analysis and kinetics analysis of lithium storage behavior.

Method for Synthesis of Zeolitic Imidazolate Framework-Derived LiCoO2/CNTs@AlF3 with Enhanced Lithium Storage Capacity.

Metal-organic framework-derived lithium cobaltate nanoparticles were fabricated by annealing of the ZIF-67 precursor with Li2CO3 under air, followed by homogeneous AlF3 coating and carbon nanotubes (CNTs) wrapping. The as-prepared AlF3-coated LiCoO2/CNTs electrode can act as a potential cathode for enhanced lithium storage at both room temperature and an elevated temperature of 50 °C.

Four new Zn(ii) and Cd(ii) coordination polymers using two amide-like aromatic multi-carboxylate ligands: synthesis, structures and lithium-selenium batteries application.

Four new coordination polymers, {[Zn(3-PBI)(H2O)]·2DMF} n (1), [Cd(3-PBI)(DMF)] n (2), {[Zn4(µ4-O)(4-PBI)3]·3DMF} n (3), {[Cd4(4-PBI)4(H2O)6]·13H2O} n (4), have been constructed from two isomeric flexible multi-carboxylate ligands, 3-H2PBI = 5-(3-(pyridin-3-yl)benzamido)isophthalic acid and 4-H2PBI = 5-(3-(pyridin-4-yl)benzamido)isophthalic acid. Structural analysis reveals that compound 1 is a one-dimensional (1D) ladder-like chain assembled by Zn(ii) ions and 3-PBI2- ligands, which further extend into a 3D supramolecular structure through π⋯π stacking and interlayer (O-H⋯O) hydrogen bonding interactions. In compound 2, Cd2+ metal ions are connected by carboxylate groups to form [Cd2(COO)4] secondary building units (SBUs). The whole framework possesses a quadrilateral channel and constitutes a unique 3D (3,6)-connected rutile net with the Schläfli symbol of (42·610·83)(4·62)2. As for 3, Zn(ii) ions are bridged by one µ4-O and six carboxylate groups to form a tetranuclear [Zn4(µ4-O)(COO)6] cluster, resulting in a rare (3,9)-connected 3D network. Compound 4 has an appealing 2D layered architecture involving two distinct topologies in the crystal structure, stacking in an unusual ABBABB mode (where A represents (4·82) topology and B denotes kgd topology). Moreover, compound 2 is prepared as a support for active selenium through a melt-diffusion method. The obtained Cd-CP/Se electrode can be tested for lithium-selenium batteries and shows an initial capacity of 514 mA h g-1 and a reversible capacity of 200 mA h g-1 at 1C after 500 cycles. The good storage performance of Cd-CP/Se demonstrates it to be a prospective cathode material for lithium-selenium batteries.