Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex.

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available1-3. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)4-6, a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-Go complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W6.53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the Go protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.

An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Reduced plasma coagulation factor XIII in patients with acute leukemia in remission during consolidation chemotherapy cycles.

Acute leukemia (AL) is a malignancy from hematologic stem cells (HSC). Consolidation with intensive chemotherapy is required after induced remission and repeatedly causes treatment-related bleeding that is usually attributed to chemotherapy-induced thrombocytopenia (CIT). However, our previous study demonstrated that severe deficiency of plasma coagulation factor XIII (pFXIII) also participated in the bleeding of CIT in AL. However, the relationship between pFXIII deficiency and consolidation chemotherapy was unknown. Here, we observed the concentration of pFXIII in patients with AL before and after consolidation chemotherapy and reevaluated the correlation to bleeding in myelosuppression. Thus, we found that the concentration of pFXIII before chemotherapy in all patients was markedly lower than in the control data and was further decreased by chemotherapy, related to bleeding in myelosuppression. These findings indicated that chemotherapy-induced pFXIII deficiency should be of concern and explored in depth.

Adsorption and Detection of Iodine Species by a Thorium-Based Metal-Organic Framework.

Actinide-bearing metal-organic frameworks (MOFs) encompass intriguing structures and properties, but the radioactivity of actinide cripples their applications. Herein, we have constructed a new thorium-based MOF (Th-BDAT) as a bifunctional platform for the adsorption and detection of radioiodine, a more radioactive fission product that can readily spread through the atmosphere in its molecular form or via solution as anionic species. The iodine capture within the framework of Th-BDAT from both the vapor phase and the cyclohexane solution has been verified, showing that Th-BDAT features maximum I2 adsorption capacities (Qmax) of 959 and 1046 mg/g, respectively. Notably, the Qmax of Th-BDAT toward I2 from cyclohexane solution ranks among the highest value for Th-MOFs reported to date. Furthermore, incorporating highly extended and π-electron-rich BDAT4- ligands renders Th-BDAT as a luminescent chemosensor whose emission can be selectively quenched by iodate with a detection limit of 1.367 µM. Our findings thus foreshadow promising directions that might unlock the full potential of actinide-based MOFs from the point of view of practical application.

[PROSI Mutation With Clinical Heterogeneity in Protein S Deficiency:Report of One Case].

Reduced protein S activity is one of the high-risk factors for venous thromboembolism.Hereditary protein S deficiency is an autosomal dominant disorder caused by mutations in the PROS1 gene.We reported a female patient with a mutation of c.292 G>T in exon 3 of the PROS1 gene,which was identified by sequencing.The genealogical analysis revealed that the mutation probably originated from the patient's mother.After searching against the PROS1 gene mutation database and the relevant literature,we confirmed that this mutation was reported for the first time internationally.

Hydrolytically Stable Zr-Based Metal-Organic Framework as a Highly Sensitive and Selective Luminescent Sensor of Radionuclides.

Effective detections of radionuclides including uranium and its predominant fission products, for example, iodine, are highly desired owing to their radiotoxicity and potential threat to human health. However, traditional analytical techniques of radionuclides are instrument-demanding, and chemosensors targeted for sensitization of radionuclides remain limited. In this regard, we report a sensitive and selective sensor of UO22+ and I- based on the unique quenching behavior of a luminescent Zr-based metal-organic framework, Zr6O4(OH)4(OH)6(H2O)6(TCPE)1.5·(H2O)24(C3H7NO)9 (Zr-TCPE). Immobilization of the luminescent tetrakis(4-carboxyphenyl)ethylene (TCPE4-) linkers by Zr6 nodes enhances the photoluminescence quantum yield of Zr-TCPE, which facilitates the effective sensing of radionuclides in a "turn-off" manner. Moreover, Zr-TCPE can sensitively and selectively recognize UO22+ and I- ions with the lowest limits of detection of 0.67 and 0.87 µg/kg, respectively, of which the former one is much lower than the permissible value (30 µg/L) defined by the U.S. EPA. In addition, Zr-TCPE features excellent hydrolytic stability and can withstand pH conditions ranging from 3 to 11. To facilitate real-world applications, we have further fabricated polyvinylidene fluoride-integrating Zr-TCPE as luminescence-based sensor membranes for on-site sensing of UO22+ and I-.

The multifunctional adaptor protein HIP-55 couples Smad7 to accelerate TGF-ß type I receptor degradation.

Transforming growth factor ß (TGF-ß) is a multifunctional polypeptide that plays critical roles in regulating a broad range of cellular functions and physiological processes. TGF-ß signalling dysfunction contributes to many disorders, such as cardiovascular diseases, cancer and immunological diseases. The homoeostasis of negative feedback regulation is critical for signal robustness, duration and specificity, which precisely control physiological and pathophysiological processes. However, the underlying mechanism by which the negative regulation of TGF-ß signalling is integrated and coordinated is still unclear. Here, we reveal that haematopoietic progenitor kinase-interacting protein of 55 kDa (HIP-55) was upregulated upon TGF-ß stimulation, while the loss of HIP-55 caused TGF-ß signalling overactivation and the abnormal accumulation of downstream extracellular matrix (ECM) genes. HIP-55 interacts with Smad7 and competes with Smad7/Axin complex formation to inhibit the Axin-mediated degradation of Smad7. HIP-55 further couples Smad7 to TßRI but not TßRII, driving TßRI degradation. Altogether, our findings demonstrate a new mechanism by which the effector and negative feedback functions of HIP-55 are coupled and may provide novel strategies for the treatment of TGF-ß signalling-related human diseases.

Higenamine as a Potential Pharmacologic Stress Agent in the Detection of Coronary Artery Disease.

Myocardial perfusion imaging (MPI) is valuable for the diagnosis, prognosis, and management of coronary artery disease (CAD). The most commonly used pharmacologic stress agents at present are vasodilators and adrenergic agents. However, these agents have contraindications and may cause adverse effects in some patients. Thus, other stress agents feasible for more patients are required. Higenamine (HG) is a ß-adrenergic receptor agonist currently approved for clinical trials as a stress agent for myocardial infarction. It also has a promising value in MPI for the detection of CAD in preclinical and clinical studies. This review summarizes the application of HG on MPI, including its mechanism of action, stress protocol, efficacy, and safety.

A Water-Soluble Highly Oxidizing Cobalt Molecular Catalyst Designed for Bioinspired Water Oxidation.

Herein, we present a stable water-soluble cobalt complex supported by a dianionic 2,2'-([2,2'-bipyridine]-6,6'-diyl)bis(propan-2-ol) ligand scaffold, which is a rare example of a high-oxidation species, as demonstrated by structural, spectroscopic and theoretical data. Electron paramagnetic resonance (EPR) spectroscopy and magnetic susceptibility measurements revealed that the CoIV center of the mononuclear complex in the solid state resides in the high spin state (sextet, S=5/2). The complex can effectively catalyze water oxidation via a single-site water nucleophilic attack pathway with an overpotential of only 360 mV in a phosphate buffer with a pH of 6. The key intermediate toward water oxidation was speculated based on theoretical calculations and was identified by in situ spectroelectrochemical experiments. The results are important regarding the accessibility of high-oxidation state metal species in synthetic models for achieving robust and reactive oxidation catalysis.

Unveiling the Unique Roles of Metal Coordination and Modulator in the Polymorphism Control of Metal-Organic Frameworks.

Polymorphism control of metal-organic frameworks is highly desired for elucidating structure-property relationships, but remains an empirical process and is usually done in a trial-and-error approach. We adopted the rarely used actinide cation Th4+ and a ditopic linker to construct a series of thorium-organic frameworks (TOFs) with a range of polymorphs. The extraordinary coordination versatility of Th4+ cations and clusters, coupled with synthetic modulation, gives five distinct phases, wherein the highest degree of interpenetration (threefold) and porosity (75.9 %) of TOFs have been achieved. Notably, the O atom on the capping site of the nine-coordinated Th4+ cation can function as a bridging unit to interconnect neighboring secondary building units (SBUs), affording topologies that are undocumented for other tetravalent-metal-containing MOFs. Furthermore, for the first time HCOOH has been demonstrated as a bridging unit of SBUs to further induce structural complexity. The resulting TOFs exhibit considerably different adsorption behaviors toward organic dyes, thus suggesting that TOFs represent an exceptional and promising platform for structure-property relationship study.