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Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family. Glucagon-like peptide-1 receptor (GLP-1R) plays an important role in glucose homeostasis and treatment of type 2 diabetes. Here authors report the peptide-free crystal structure of human GLP-1R in an inactive state which reveals a unique closed conformation of the extracellular domain.

Background Accumulating evidence has highlighted that lncRNA ABHD11-AS1 plays an essential role in tumorigenesis and is expected to become a new predictive biomarker and ideal target for cancer therapy, whereas some of their findings are conflicting due to the relatively small sample size of individual studies. Thus, this meta-analysis aimed to quantitatively ascertain the association of ABHD11-AS1 with diverse human malignancies. Methods Eight databases were comprehensively screened for relevant articles on January 1, 2024. The significance of ABHD11-AS1 in malignancies was determined by odds ratios (ORs) or hazard ratios (HRs) with corresponding 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were applied to verify the reliability and robustness of the pooled results. Simultaneously, the GEPIA2021 and UCSC Xena databases were applied to further strengthen the results. Results Fourteen clinical studies comprising eight kinds of malignancies and 1215 malignancy cases were enrolled into this meta-analysis. The pooled results showed that increased ABHD11-AS1 expression was remarkably associated with lymph node metastasis (OR = 2.73, 95%CI [1.97, 3.77], I 2  = 0%, p  < 0.00001), advanced tumor stage ( OR = 3.14, 95%CI [2.34, 4.21], I 2  = 39%, p  < 0.00001), and unfavorable overall survival (OS) (HR = 1.81, 95%CI [1.58, 2.06], I 2  = 0%, p  < 0.00001). Subgroup analyses and sensitivity analyses indicated that the pooled results were reliable and robust. Additionally, ABHD11-AS1 was significantly increased in eight kinds of malignancies according to the validation of the GEPIA2021 database. Meanwhile, the UCSC Xena databases further revealed that elevated ABHD11-AS1 expression was significantly associated with poor prognosis as assessed by progression free interval (PFI), disease free interval (DFI), disease specific survival (DSS), and OS. Conclusions Current evidence supports the association of elevated ABHD11-AS1 expression with poor prognosis. Thereby, ABHD11-AS1 may be considered as a promising biomarker to screen cancer and predict malignancy prognosis. Also, there is a necessity for larger-scale multicenter studies with uniform study protocols from different countries to further validate the conclusions.

In this study, we investigated CD70 as a promising target for renal cell carcinoma (RCC) therapy and developed a potent chimeric antigen receptor T (CAR-T) cells for potential clinical testing. CD70, found to be highly expressed in RCC tumors, was associated with decreased survival. We generated CAR-T cells expressing VHH sequence of various novel nanobodies from immunized alpaca and a single-chain variable fragment (scFv) derived from human antibody (41D12). In our in vitro experiments, anti-CD70 CAR-T cells effectively eliminated CD70-positive tumor cells while sparing CD70-negative cells. The nanobody-based CAR-T cells demonstrated significantly higher production of cytokines such as IL-2, IFN-γ and TNF-ɑ during co-culture, indicating their potential for enhanced functionality. In xenograft mouse model, these CAR-T cells exhibited remarkable anti-tumor activity, leading to the eradication of RCC tumor cells. Importantly, human T cell expansion after infusion was significantly higher in the VHH groups compared to the scFv CAR-T group. Upon re-challenging mice with RCC tumor cells, the VHH CAR-T treated group remained tumor-free, suggesting a robust and long-lasting anti-tumor response. These findings provide strong support for the potential of nanobody-based CD70 CAR-T cells as a promising therapeutic option for RCC. This warrants further development and consideration for future clinical trials and applications.

Cervical cancer's tumor microenvironment (TME) was composed of a diverse array of immune cells that significantly influence tumor progression and response to treatment. Recent advancements in multi-omics and single-cell sequencing had provided valuable insights into the cellular heterogeneity and immune landscape of the TME, revealing critical interactions that shape tumor behavior and therapy outcomes. This study used multi-omics and single-cell sequencing to explore the immune landscape, cellular heterogeneity, and drug sensitivity in cervical cancer, focused on tumor subtypes and their interactions with immune cells, and aimed to understand therapy responses. The research presented a thorough single-cell analysis of cervical cancer, identified distinct tumor epithelial cell (EPC) subtypes, and explored their roles in tumor progression, immune evasion, and therapeutic response. It underscored the potential of tumor EPCs as valuable biomarkers for prognosis and as targets for personalized treatment approaches. The immune landscape of cervical cancer and its interaction with tumor endothelial progenitor cells played crucial roles in determining the tumor's progression and response to therapy. The classification of tumor subtypes based on immune characteristics and drug sensitivity was critical for personalized treatment. The identification of as key biomarkers provided insight into tumor biology and potential therapeutic targets. Our findings emphasized the need for combining immune checkpoint modulation with precise drug sensitivity analysis to optimize treatment strategies, particularly in advanced cervical cancer.

Background Cervical cancer (CC) remains a significant global health challenge despite advancements in screening, HPV vaccination, and therapeutic strategies. Tumor heterogeneity, driven by epigenetic modifications, affects immune evasion, metastasis, and treatment response. Cancer-associated fibroblasts (CAFs) play a crucial role in CC progression and therapy resistance. Single-cell sequencing offers new insights but remains underutilized in CC research. This study integrates single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and deconvolution analysis to identify key genes and immunotherapy targets. By constructing a prognostic model and exploring the immune microenvironment, we aim to provide novel insights into CC pathogenesis and potential therapeutic strategies. Methods We utilized scRNA-seq, spatial transcriptomics, deconvolution analysis, and pseudotime trajectory mapping to delineate fibroblast subtypes within the tumor immune microenvironment (TIME) of CC. Functional annotations, differential gene expression profiling, cell–cell communication pathways, and transcription factor networks were systematically analyzed. A prognostic model based on bulk RNA-seq data was constructed and validated through survival analysis, with correlations to immune microenvironment characteristics. Functional experiments investigated the role of SDC1, a critical mediator of fibroblast-tumor crosstalk. Additionally, Fibroblast–tumor cell co-culture systems and functional assays were employed to investigate the paracrine role of SDC1. The CAF MYH11⁺ subpopulation was isolated via fluorescence-activated cell sorting (FACS). Multiplex immunofluorescence and immunohistochemical analyses were performed on both cultured cells and human cervical cancer tissue samples to characterize the spatial distribution and dynamic remodeling of MYH11 during stromal reorganization. Results Six distinct fibroblast subtypes were identified, including the C0 MYH11 + fibroblasts, which exhibited unique roles in stemness maintenance, metabolic activity, and immune regulation. Spatial and functional analyses revealed that the C0 subtype is central to tumor-fibroblast interactions, particularly through the MDK-SDC1 signaling axis. The prognostic model incorporating fibroblast-specific markers demonstrated robust predictive power for patient survival outcomes. Additionally, in vitro SDC1 knockdown significantly inhibited CC cell proliferation, migration, and invasion. Fibroblasts show spatially regulated heterogeneity, with activation markers enriched in the tumor zone and MYH11 highest in normal zones, indicating dynamic stromal remodeling. C0 MYH11 + CAF Promotes Tumor Cell Proliferation, Migration, and Inhibits Apoptosis via Soluble SDC1. Conclusion Our results illustrate, in some ways, the possible immunomodulatory and tumor supporting roles of CAFs in CC TIME and highlight the possibility that the MDK-SDC1 pathway is a promising therapeutic target. This study not only promotes a partially new understanding of temporal heterogeneity in CC, but also provides a possible reference base for the development of new biomarkers and immunotherapy approaches to improve clinical outcomes.

To evaluate the potential benefits of hyperbaric oxygen intervention on people with Alzheimer's disease (AD) based on the existing randomized controlled trials (RCTs). A systematic search was conducted in nine databases until November 17, 2023, for RCTs assessing the effect of hyperbaric oxygen intervention for AD. The primary outcomes included Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), activities of daily living (ADL), and adverse events. All results were shown in forest plots, and sensitivity analysis was adopted to further verify the robustness of the pooled results. A total of 11 RCTs recruiting 847 participants were included in this meta-analysis. Based on the pooled evidence, hyperbaric oxygen could remarkably ameliorate MMSE [MD = 3.08, 95%CI (2.56, 3.61),  < 0.00001], ADAS-Cog [MD = -4.53, 95%CI (-5.05, -4.00),  < 0.00001], ADL [MD = 10.12, 95%CI (4.46, 15.79),  = 0.0005], MDA levels [SMD = -2.83, 95%CI (-5.27, -0.38),  = 0.02], SOD levels [SMD = 2.12, 95%CI (1.10, 3.15),  < 0.0001], IL-1-β levels [SMD = -1.00, 95%CI (-1.48, -0.53),  < 0.0001], and TGF-β1 levels [MD = 4.87, 95%CI (3.98, 5.76),  < 0.00001] without adverse events [OR = 1.17, 95%CI (0.68, 2.03),  = 0.58] for people with AD. The pooled results were robust after checking by sensitivity analysis. These evidences suggest that hyperbaric oxygen is an effective and safe intervention for the treatment of AD. Further studies with more rigorous design will help to fully evaluate the clinical value of hyperbaric oxygen on cognition function in people with AD. https://www.crd.york.ac.uk, identifier CRD42023483726.

People with amnestic mild cognitive impairment (aMCI) carry a substantial risk of developing dementia compared to non-amnestic MCI (naMCI). Several previous studies proved the remarkable effectiveness of acupuncture for MCI, but they didn't distinguish between aMCI and naMCI. We conducted this meta-analysis to systematically assess the evidence of the efficacy of acupuncture in this unique population with aMCI. We comprehensively searched nine databases on January 09, 2024, to identify relevant articles estimating the effects of acupuncture for aMCI, and then assessed the risk of bias of the included trials utilizing the RoB 2.0 tool which included the domain of randomization process, deviation from intended interventions, missing outcome data, measurement of the outcome, selection of the reported outcome, and overall bias. The results of this meta-analysis were exhibited with forest plots. Sensitivity analyses were conducted to determine the robustness of the pooled results, and publication bias was estimated by Egger's and Begg's tests. Besides, we also performed subgroup analysis to determine whether there was a difference in therapeutic effects between four weeks and eight weeks of treatment duration. The certainty of the evidence was graded using GRADEpro GDT. A total of 15 randomized controlled trials (RCTs) involving 908 people with aMCI were included in this study. According to the meta-analysis, acupuncture treatment provided a remarkable improvement in cognitive function as assessed by Mini-Mental State Examination (MD = 1.09, 95 %CI [0.86, 1.31], p < 0.00001), Montreal Cognitive Assessment (MD = 0.93, 95 %CI [0.80, 1.07], p < 0.00001), Alzheimer's Disease Assessment Scale-Cognitive (MD = 1.00, 95 %CI [-1.23, −0.77], p < 0.00001), and P300 latency (MD = −15.40, 95 %CI [-23.68, −7.12], p = 0.0003). Subgroup analysis showed evidence that the efficacy of four weeks of acupuncture treatment was consistent with that of eight weeks. Sensitivity analyses, Egger's and Begg's tests suggested the pooled results were robust and reliable. The overall quality of the evidence, as appraised by the GRADE criteria, was very low or low for all outcomes. The evidence from 15 RCTs demonstrated that acupuncture interventions are effective in ameliorating cognitive function in people with aMCI. There is a need for larger-scale multicenter RCTs using standardised training protocols and more rigorous designs to confirm the conclusions further. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42023460470. •To our knowledge, this is the newest meta-analysis to assess the clinical value of acupuncture for aMCI.•Acupuncture interventions are effective in ameliorating cognitive function in people with aMCI.•There is a need for larger-scale RCTs using standardised training protocols and rigorous designs to confirm the conclusions.

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen–deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors. The crystal structure of the full-length human glucagon receptor reveals the essential role of the 12-residue ‘stalk’ segment and an extracellular loop in the regulation of ligand binding and receptor activation. Full-length class B GPCR structures The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) belong to the class B G-protein-coupled receptor family and have opposing physiological roles in glucose homeostasis and insulin release. As such, they are important in regulating metabolism and appetite and offer significant treatment possibilities for type 2 diabetes. However, as yet, no full-length structures of these receptors have been solved. Three papers in this issue of Nature report the structure of GLP-1R. Ray Stevens and colleagues describe the crystal structure of the human GLP-1R transmembrane domain in an inactive state in complex with negative allosteric modulators. Fiona Marshall and colleagues describe the active-state full-length receptor in complex with truncated peptide agonists, which have potent activity in mice on oral administration. Georgios Skiniotis, Brian Kobilka and colleagues describe the cryo-electron microscopy structure of an unmodified GLP-1R in complex with its endogenous peptide ligand, GLP-1, and the heterotrimeric G protein. Finally, in a fourth paper in this week's issue of Nature , Beili Wu and colleagues report the crystal structure of the full-length GCGR in an inactive conformation. Taken together, these studies provide key insights into the activation and signalling mechanisms of class B receptors and provide therapeutic opportunities for targeting this receptor family.

Rare-earth barium copper oxide (REBCO) high-temperature superconductors, owing to their ability to maintain high critical current density (Jc) under liquid-nitrogen-temperature and high-magnetic-field conditions, are widely regarded as one of the most promising material systems among all superconductors. This review systematically summarizes fabrication strategies for REBCO coated conductors, with a focus on pulsed laser deposition (PLD) for achieving high-quality epitaxial growth with precise composition control. To enhance in-field performance, strategies for introducing artificial pinning centers (APCs) are examined, including rare-earth element doping, substrate surface decoration, and nanoscale secondary phase incorporation. The mechanisms of vortex pinning from different dimensional defects and their synergistic effects are compared. Finally, we suggest potential future directions aimed at further enhancing the superconducting properties.

Background Non-suicidal self-injury (NSSI) and suicide attempts (SAs) by adolescent patients with depression have become serious public health problems. There is still insufficient research evidence on the effects of NSSI and SAs on neurocognitive functioning in adolescents. Cognitive function alterations may be associated with SAs and self-injury. NSSI and SAs have different influencing factors. Methods Participants were recruited from outpatient clinics and included 142 adolescent patients with depression (12–18 years old). This cohort included the SAs group (n = 52), NSSI group (n = 65), and depression without SAs/NSSI control group (n = 25). All participants underwent a clinical interview and neuropsychological assessment for group comparisons, and post-hoc tests were performed. Finally, partial correlation analysis was used to explore factors related to changes in cognitive function. Results The SAs group performed significantly worse than the control group in executive function and working memory. The depression score was directly proportional to the executive function of the SAs group, whereas cognitive functioning in the NSSI group was associated with borderline traits and rumination. Conclusions These findings suggest that impairment of executive function and working memory may be a common pattern in adolescent depressed patients with SAs. However, borderline traits and rumination may be indicative of NSSI but not SAs.