Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors.

Fluorine magnetic resonance imaging (19F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. We report innovative 19F-MRI agents based on supramolecular dendrimers self-assembled by an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron. Specifically, this amphiphilic dendrimer bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high fluorine nuclei mobility alongside good water solubility with favorable relaxation properties for use in 19F-MRI. Importantly, the self-assembling 19F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent DiR and the anticancer drug paclitaxel for multimodal 19F-MRI and NIRF imaging of and theranostics for pancreatic cancer, a deadly disease for which there remains no adequate early detection method or efficacious treatment. The 19F-MRI and multimodal 19F-MRI and NIRF imaging studies on human pancreatic cancer xenografts in mice confirmed the capability of both imaging modalities to specifically image the tumors and demonstrated the efficacy of the theranostic agent in cancer treatment, largely outperforming the clinical anticancer drug paclitaxel. Consequently, these dendrimer nanosystems constitute promising 19F-MRI agents for effective cancer management. This study offers a broad avenue to the construction of 19F-MRI agents and theranostics, exploiting self-assembling supramolecular dendrimer chemistry.

Electrifying HCOOH synthesis from CO2 building blocks over Cu-Bi nanorod arrays.

Precise electrochemical synthesis of commodity chemicals and fuels from CO2 building blocks provides a promising route to close the anthropogenic carbon cycle, in which renewable but intermittent electricity could be stored within the greenhouse gas molecules. Here, we report state-of-the-art CO2-to-HCOOH valorization performance over a multiscale optimized Cu-Bi cathodic architecture, delivering a formate Faradaic efficiency exceeding 95% within an aqueous electrolyzer, a C-basis HCOOH purity above 99.8% within a solid-state electrolyzer operated at 100 mA cm-2 for 200 h and an energy efficiency of 39.2%, as well as a tunable aqueous HCOOH concentration ranging from 2.7 to 92.1 wt%. Via a combined two-dimensional reaction phase diagram and finite element analysis, we highlight the role of local geometries of Cu and Bi in branching the adsorption strength for key intermediates like *COOH and *OCHO for CO2 reduction, while the crystal orbital Hamiltonian population analysis rationalizes the vital contribution from moderate binding strength of η2(O,O)-OCHO on Cu-doped Bi surface in promoting HCOOH electrosynthesis. The findings of this study not only shed light on the tuning knobs for precise CO2 valorization, but also provide a different research paradigm for advancing the activity and selectivity optimization in a broad range of electrosynthetic systems.

PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

The structure of the archaeal nuclease RecJ2 implicates its catalytic mechanism and inability to interact with GINS.

Bacterial RecJ exhibits 5'→3' exonuclease activity that is specific to ssDNA; however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins.

E3 ligase DECREASED GRAIN SIZE 1 promotes degradation of a G-protein subunit and positively regulates grain size in rice.

Grain size is one of the most important traits determining crop yield. However, the mechanism controlling grain size remains unclear. Here, we confirmed the E3 ligase activity of DECREASED GRAIN SIZE 1 (DGS1) in positive regulation of grain size in rice (Oryza sativa) suggested in a previous study. Rice G-protein subunit gamma 2 (RGG2), which negatively regulates grain size, was identified as an interacting protein of DGS1. Biochemical analysis suggested that DGS1 specifically interacts with canonical Gγ subunits (rice G-protein subunit gamma 1 [RGG1] and rice G-protein subunit gamma 2 [RGG2]) rather than non-canonical Gγ subunits (DENSE AND ERECT PANICLE 1 [DEP1], rice G-protein gamma subunit type C 2 [GCC2], GRAIN SIZE 3 [GS3]). We also identified the necessary domains for interaction between DGS1 and RGG2. As an E3 ligase, DGS1 ubiquitinated and degraded RGG2 via a proteasome pathway in several experiments. DGS1 also ubiquitinated RGG2 by its K140, K145 and S147 residues. Thus, this work identified a substrate of the E3 ligase DGS1 and elucidated the post transcriptional regulatory mechanism of the G-protein signalling pathway in the control of grain size.

Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.

Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle, renal senescence and fibrosis. We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels effectively restore PDH enzyme activity, improve mitochondrial function, mitigate cellular senescence and renal fibrosis. Mechanically, we found that mitochondrial copper could bind directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDH complex, thereby changing the interaction between the subunits of lipoylated DLAT, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Collectively, our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Taurine Alleviates Ferroptosis-Induced Metabolic Impairments in C2C12 Myoblasts by Stabilizing the Labile Iron Pool and Improving Redox Homeostasis.

Ferroptosis adversely affects the viability, differentiation, and metabolic integrity of C2C12 myoblasts, contributing to the decline in skeletal muscle health. The intricate mechanisms behind this process are not fully understood. In this study, we induced ferroptosis in myoblasts using targeted inducers and found a marked decrease in specific redox metabolites, particularly taurine. Taurine supplementation effectively reversed the deleterious effects of ferroptosis, significantly increased cellular glutathione levels, reduced MDA and ROS levels, and rejuvenated impaired myogenic differentiation. Furthermore, taurine downregulated HO-1 expression and decreased intracellular Fe2+ levels, thereby stabilizing the labile iron pool. Using NMR metabolomic analysis, we observed that taurine profoundly promoted glycerophospholipid metabolism, which is critical for cell membrane repair, and enhanced mitochondrial bioenergetics, thereby increasing the energy reserves essential for muscle satellite cell regeneration. These results suggest that taurine is a potent ferroptosis inhibitor that attenuates key drivers of this process, strengthens oxidative defenses, and improves redox homeostasis. This combined effect protects cells from ferroptosis-induced damage. This study highlights the potential of taurine as a valuable ferroptosis inhibitor that protects skeletal muscle from ferroptosis-induced damage and provides a basis for therapeutic strategies to rejuvenate and facilitate the regeneration of aging skeletal muscle.

Lactate-induced metabolic remodeling and myofiber type transitions via activation of the Ca2+-NFATC1 signaling pathway.

Lactate can serve as both an energy substrate and a signaling molecule, exerting diverse effects on skeletal muscle physiology. Due to the apparently positive effects, it would be interesting to consider it as a sports supplement. However, the mechanism behind these effects are yet to be comprehensively understood. In this study, we observed that lactate administration could improve the ability of antifatigue, and we further found that lactate upregulated the expression of myosin heavy chain (MYHC I) and MYHC IIa, while downregulating the expression of MYHC IIb. Besides, transcriptomics and metabolomics revealed significant changes in the metabolic profile of gastrocnemius muscle following lactate administration. Furthermore, lactate enhanced the activities of metabolic enzymes, including HK, LDHB, IDH, SDM, and MDH, and promoted the expression of lactate transport-related proteins MCT1 and CD147, thereby improving the transport and utilization of lactate in both vivo and vitro. More importantly, lactate administration increased cellular Ca2+ concentration and facilitated nuclear translocation of nuclear factor of activated T cells (NFATC1) in myotubes, whereas inhibition of NFATC1 significantly attenuated the effects of lactate treatment on NFATC1 nuclear translocation and MyHC expression. Our results elucidate the ability of lactate to induce metabolic remodeling in skeletal muscle and promote myofiber-type transitions by activating the Ca2+-NFATC1 signaling pathway. This study is useful in exploring the potential of lactate as a nutritional supplement for skeletal muscle adaptation and contributing to a mechanistic understanding of the central role of lactate in exercise physiology.

Atomic Design of Alkyne Semihydrogenation Catalysts via Active Learning.

Alkyne hydrogenation on palladium-based catalysts modified with silver is currently used in industry to eliminate trace amounts of alkynes in alkenes produced from steam cracking and alkane dehydrogenation processes. Intensive efforts have been devoted to designing an alternative catalyst for improvement, especially in terms of selectivity and catalyst cost, which is still far away from that as expected. Here, we describe an atomic design of a high-performance Ni-based intermetallic catalyst aided by active machine learning combined with density functional theory calculations. The engineered NiIn catalyst exhibits >97% selectivity to ethylene and propylene at the full conversion of acetylene and propyne at mild temperature, outperforming the reported Ni-based catalysts and even noble Pd-based ones. Detailed mechanistic studies using theoretical calculations and advanced characterizations elucidate that the atomic-level defined coordination environment of Ni sites and well-designed hybridization of Ni 3d with In 5p orbital determine the semihydrogenation pathway.

MRI versus Dual-Energy CT in Local-Regional Staging of Gastric Cancer.

Background Preoperative local-regional tumor staging of gastric cancer (GC) is critical for appropriate treatment planning. The comparative accuracy of multiparametric MRI (mpMRI) versus dual-energy CT (DECT) for staging of GC is not known. Purpose To compare the diagnostic accuracy of personalized mpMRI with that of DECT for local-regional T and N staging in patients with GC receiving curative surgical intervention. Materials and Methods Patients with GC who underwent gastric mpMRI and DECT before gastrectomy with lymphadenectomy were eligible for this single-center prospective noninferiority study between November 2021 and September 2022. mpMRI comprised T2-weighted imaging, multiorientational zoomed diffusion-weighted imaging, and extradimensional volumetric interpolated breath-hold examination dynamic contrast-enhanced imaging. Dual-phase DECT images were reconstructed at 40 keV and standard 120 kVp-like images. Using gastrectomy specimens as the reference standard, the diagnostic accuracy of mpMRI and DECT for T and N staging was compared by six radiologists in a pairwise blinded manner. Interreader agreement was assessed using the weighted κ and Kendall W statistics. The McNemar test was used for head-to-head accuracy comparisons between DECT and mpMRI. Results This study included 202 participants (mean age, 62 years ± 11 [SD]; 145 male). The interreader agreement of the six readers for T and N staging of GC was excellent for both mpMRI (κ = 0.89 and 0.85, respectively) and DECT (κ = 0.86 and 0.84, respectively). Regardless of reader experience, higher accuracy was achieved with mpMRI than with DECT for both T (61%-77% vs 50%-64%; all P < .05) and N (54%-68% vs 51%-58%; P = .497-.005) staging, specifically T1 (83% vs 65%) and T4a (78% vs 68%) tumors and N1 (41% vs 24%) and N3 (64% vs 45%) nodules (all P < .05). Conclusion Personalized mpMRI was superior in T staging and noninferior or superior in N staging compared with DECT for patients with GC. Clinical trial registration no. NCT05508126 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Méndez and Martín-Garre in this issue.

Heteroatom-Doped Defects Anchoring Nano-Pt for High-Stability and Low-Humidity Proton Exchange Membrane Fuel Cell.

To meet the ever-increasing demand of proton exchange membrane fuel cell (PEMFC), it is necessary to carry out structure optimization for low-cost and high-stability oxygen reduction reaction (ORR) catalysts. Herein, a zeolitic imidazolate framework (ZIF)-derived carbon material with a mass of heteroatoms and defects is developed and serves as advanced support for nano-Pt-based ORR catalysts. This unique structure enhances the interaction between nano-Pt and support, leading to higher ORR intrinsic activity. During fuel cell applications, it demonstrates impressive water-retaining capacity and electrochemical stability. Under H2-O2 supply without cathode humidification, this catalyst achieves high mass activity of 0.475 A mgPt -1, with only 7.4% attenuation in maximum power density after 20 000 cycles of accelerated durability test, highlighting its remarkable potential for fuel cell applications. Physicochemical characterization and theoretical simulation reveal the crucial anchoring effect of heteroatom-doped defects to nano-Pt, providing valuable insights for further ORR catalyst design and PEMFC applications.

3D Dense Encapsulated Architecture of 2D Bi Nanosheets Enabling Potassium-Ion Storage with Superior Volumetric and Areal Capacities.

2D alloy-based anodes show promise in potassium-ion batteries (PIBs). Nevertheless, their low tap density and huge volume expansion cause insufficient volumetric capacity and cycling stability. Herein, a 3D highly dense encapsulated architecture of 2D-Bi nanosheets (HD-Bi@G) with conducive elastic networks and 3D compact encapsulation structure of 2D nano-sheets are developed. As expected, HD-Bi@G anode exhibits a considerable volumetric capacity of 1032.2 mAh cm-3, stable long-life span with 75% retention after 2000 cycles, superior rate capability of 271.0 mAh g-1 at 104 C, and high areal capacity of 7.94 mAh cm-2 (loading: 24.2 mg cm-2) in PIBs. The superior volumetric and areal performance mechanisms are revealed through systematic kinetic investigations, ex situ characterization techniques, and theorical calculation. The 3D high-conductivity elastic network with dense encapsulated 2D-Bi architecture effectively relieves the volume expansion and pulverization of Bi nanosheets, maintains internal 2D structure with fast kinetics, and overcome sluggish ionic/electronic diffusion obstacle of ultra-thick, dense electrodes. The uniquely encapsulated 2D-nanosheet structure greatly reduces K+ diffusion energy barrier and accelerates K+ diffusion kinetics. These findings validate a feasible approach to fabricate 3D dense encapsulated architectures of 2D-alloy nanosheets with conductive elastic networks, enabling the design of ultra-thick, dense electrodes for high-volumetric-energy-density energy storage.

Organic Electrolyte Additive: Dual Functions Toward Fast Sulfur Conversion and Stable Li Deposition for Advanced Li-S Batteries.

Lithium-sulfur (Li-S) battery is of great potential for the next generation energy storage device due to the high specific capacity energy density. However, the sluggish kinetics of S redox and the dendrite Li growth are the main challenges to hinder its commercial application. Herein, an organic electrolyte additive, i.e., benzyl chloride (BzCl), is applied as the remedy to address the two issues. In detail, BzCl can split into Bz· radical to react with the polysulfides, forming a Bz-S-Bz intermediate, which changes the conversion path of S and improves the kinetics by accelerating the S splitting. Meanwhile, a tight and robust solid electrolyte interphase (SEI) rich in inorganic ingredients namely LiCl, LiF, and Li2O, is formed on the surface of Li metal, accelerating the ion conductivity and blocking the decomposition of the solvent and lithium polysulfides. Therefore, the Li-S battery with BzCl as the additive remains high capacity of 693.2 mAh g-1 after 220 cycles at 0.5 C with a low decay rate of 0.11%. This work provides a novel strategy to boost the electrochemical performances in both cathode and anode and gives a guide on the electrolyte design toward high-performance Li-S batteries.

Landscape of clinical drug development of ADCs used for the pharmacotherapy of cancers: an overview of clinical trial registry data from 2002 to 2022.

BACKGROUND: To provide reference for clinical development of ADCs in the industry, we analyzed the landscape and characteristics of clinical trials about antibody-drug conjugates (ADCs). METHOD: Clinical trials to study ADCs used for the pharmacotherapy of cancers initiated by the sponsor were searched in the Cite line Pharma Intelligence (Trialtrove database), and the landscape and characteristics of these clinical trials were analyzed from multiple perspectives, such as the number, phases, status, indications, and targets of the clinical trials. RESULT: As of December 31, 2022, a total of 431 clinical trials have been initiated to study ADCs used for the pharmacotherapy of cancers, and the number of the last 10 years was 5.5 times as large as the first 11 years. These clinical trials involved 47 indications, including breast cancer, lymphoma (lymphoma, non-Hodgkin's and lymphoma, Hodgkin's), unspecified solid tumor, bladder cancer and lung cancer (lung, non-small cell cancer and lung, small cell cancer). As for each of these five indications, 50 + clinical trials have been carried out, accounting for as high as 48.50% (454/936). ADCs involve 38 targets, which are relatively concentrated. Among them, ERBB2 (HER2) and TNFRSF8 (CD30) involve in 100 + registered clinical trials, and TNFRSF17 (BCMA), NECTIN4 and CD19 in 10 + trials. The clinical trials for these five targets account for 79.02% (354/448) of the total number. Up to 93.97% (405/431) of these clinical trials explored the correlation between biomarkers and efficacy. Up to 45.91% (292/636) of Lots (lines of treatment) applied in the clinical trials were the second line. Until December 31, 2022, 54.52% (235/431) of the clinical trials have been completed or terminated. CONCLUSION: ADCs are a hotspot of research and development in oncology clinical trials, but the indications, targets, phases, and Lot that have been registered are seemingly relatively concentrated at present. This study provides a comprehensive analysis which can assist researchers/developer quickly grasp relevant knowledge to assess a product and also providing new clues and ideas for future research.

Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

The biochemical characterization of a TatD nuclease from Thermus thermophilus.

Nucleases play pivotal roles in DNA repair and apoptosis. Moreover, they have various applications in biotechnology and industry. Among nucleases, TatD has been characterized as an exonuclease with various biological functions in different organisms. Here, we biochemically characterized the potential TatD nuclease from Thermus thermophilus. The tatD gene from T. thermophilus was cloned, then the recombinant TatD nuclease was expressed and purified. Our results revealed that the TthTatD nuclease could degrade both single-stranded and double-stranded DNA, and its activity is dependent on the divalent metal ions Mg2+ and Mn2+. Remarkably, the activity of TthTatD nuclease is highest at 37 °C and decreases with increasing temperature. TthTatD is not a thermostable enzyme, even though it is from a thermophilic bacterium. Based on the sequence similarity and molecular docking of the DNA substrate into the modeled TthTatD structure, several key conserved residues were identified and their roles were confirmed by analyzing the enzymatic activities of the site-directed mutants. The residues E86 and H149 play key roles in binding metal ions, residues R124/K126 and K211/R212 had a critical role in binding DNA substrate. Our results confirm the enzymatic properties of TthTatD and provide a primary basis for its possible application in biotechnology.

T2* cartilage mapping in early axial spondyloarthritis: diagnostic accuracy and correlation with clinical characteristics, sacroiliitis MRI scorings, and diffusion metrics.

PURPOSE: To determine the performance of T2* cartilage mapping in diagnosing and assessing disease activity in early axial spondyloarthritis (axSpA), and to investigate the interaction of cartilage damage with clinical characteristics, sacroiliitis MRI scorings, and diffusion metrics. MATERIALS AND METHODS: This prospective study included 83 axSpA patients and 37 no-axSpA patients. Clinical characteristics, the Assessment of SpondyloArthritis International Society-defined active sacroiliitis on MRI, and T2* SIJs values were recorded. In axSpA, disease activity was evaluated using the ankylosing spondylitis disease activity score-C-reactive protein; active sacroiliitis was evaluated using Spondyloarthritis Research Consortium of Canada, intravoxel incoherent motion, and diffusion kurtosis imaging; chronic sacroiliitis was assessed using composite structural damage score (CSDS) and structural score fat. Mann-Whitney U-test, Kruskal-Wallis test with false discovery rate (FDR), ROC curve, and linear regression were used for statistical analysis. RESULTS: AxSpA patients had significantly higher T2*SIJs values than no-axSpA patients. (22.86 ± 2.42 ms vs 20.36 ± 1.30 ms, p < 0.001). The combination of T2*SIJs values and active sacroiliitis on MRI had the highest AUC for identifying axSpA. T2*SIJs values were significantly different between the inactive and very high, moderate and very high, high and very high, as well as inactive and high disease activity groups (all pFDR < 0.05). Dk (ß = 0.48) and CSDS (ß = 0.48) were independently associated with T2*SIJs values. CONCLUSION: T2* values may be a promising biomarker for diagnosing and differentiating disease activity in early axSpA. Both acute and chronic sacroiliitis influence cartilage properties. CLINICAL RELEVANCE STATEMENT: Sacroiliac joint cartilage abnormalities can be quantified with T2* relaxation time and allow better characterization of early axSpA. KEY POINTS: T2* mapping may have value in evaluating axSpA. The combination of T2* values and active sacroiliitis on MRI enhances diagnostic performance for axSpA. Abnormalities measured with T2* values correlate with disease activity, acute sacroiliitis, and degree of structural damage.

Aluminum Molecular Ring Meets Deep Eutectic Solvents: Adaptive Assembly and Optical Behavior.

Different from the previous neutral reaction solvent system, this work explores the synthesis of Al-oxo rings in ionic environments. Deep eutectic solvents (DESs) formed by quaternary ammonium salts hydrogen bond acceptor (HBA) and phenols hydrogen bond donor (HBD) further reduce the melting point of the reaction system and provide an ionic environment. Further, the quaternary ammonium salt was chosen as the HBA because it contains a halogen anion that matches the size of the central cavity of the molecular ring. Based on this thought, five Al8 ion pair cocrystals were synthesized via "DES thermal". The general formula is Q+ ⊂ {Cl@[Al8(BD)8(µ2-OH)4L12]} (AlOC-180-AlOC-185, Q+ = tetrabutylammonium, tetrapropylammonium, 1-butyl-3-methylimidazole; HBD = phenol, p-chlorophenol, p-fluorophenol; HL = benzoic acid, 1-naphthoic acid, 1-pyrenecarboxylic acid, anthracene-9-carboxylic acid). Structural studies reveal that the phenol-coordinated Al molecular ring and the quaternary ammonium ion pair form the cocrystal compounds. The halogen anions in the DES component are confined in the center of the molecular ring, and the quaternary ammonium cations are located in the organic shell. Such an adaptive cocrystal binding pattern is particularly evident in the structures coordinated with low-symmetry ligands such as naphthoic acid and pyrene acid. Finally, the optical behavior of these cocrystal compounds is understood from the analysis of crystal structure and theoretical calculation.

Promoting Sustainable Development Goals by Optimizing City-Level Solar Photovoltaic Deployment in China.

Solar photovoltaic (PV) installations, which enable carbon neutrality, are expected to surge in the coming decades. This growth will support sustainable development goals (SDGs) via reductions in power-generation-related environmental emissions and water consumption while generating new jobs. However, where and to what extent PVs should be utilized to support SDGs must be thoroughly addressed. Here, we use multiple PV deployment scenarios to compare the benefits of PVs and related SDGs progress in 366 prefectural-level cities in China. We developed an assessment framework that integrates a PV allocation model, an electricity system optimization model, and a benefit assessment approach. We identify vast differences in PV distribution and electricity transmission and elucidate trade-offs and synergies among the SDGs under various PV implementation scenarios. The water conservation-oriented scenario yields substantial carbon reduction, air pollutant mitigation, and water saving cobenefits, leading to the greatest SDGs improvements. Prioritizing employment creation enhances job-relevant SDGs but inhibits environmental resource benefits. SDGs in less developed cities present greater progress across all scenarios. This study highlights the need to consider spatial heterogeneity and the potential trade-offs between different SDGs and regions when designing energy transition strategies.