Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Iron-Catalyzed Primary Amination of C(sp3)-H Bonds.

Primary amines are privileged molecules in drug development. Yet, there is a noticeable scarcity of methods for directly introducing a primary amine group into the ubiquitous C(sp3)-H bonds within organic compounds. Here, we report an iron-based catalytic system that enables direct primary amination of C(sp3)-H bonds under aqueous conditions and air. Various types of C(sp3)-H bonds, including benzylic, allylic, and aliphatic ones, can be readily functionalized with high selectivity and efficiency. The broad utility of this method has been further verified by late-stage amination of 11 complex bioactive molecules. Mechanistic studies unveil a protonated iron-nitrene complex as the key intermediate for the C-H bond activation. This work extends the toolbox for direct C(sp3)-H functionalizations, opening up new opportunities for late-stage modifications of organic molecules.

Mesenchymal stem cells arouse myocardial NAD+ metabolism to alleviate microgravity-induced cardiac dysfunction.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

Construction of Hydration Layer for Proton Transport by Implanting the Hydrophilic Center Ag0 in Nickel Metal-Organic Frameworks.

The directional arrangement of H2O molecules can effectively regulate the ordered protons transfer to improve transport efficiency, which can be controlled by the interaction between materials and H2O. Herein, a strategy to build a stable hydration layer in metal-organic framework (MOF) platforms, in which hydrophilic centers that can manipulate H2O molecules are implanted into MOF cavities is presented. The rigid grid-Ni-MOF is selected as the supporting material due to the uniformly distributed cavities and rigid structures. The Ag0 possesses potential combination ability with the hydrophilic substances, so it is introduced into the MOF as hydration layer centers. Relying on the strong interaction between Ag0 and H2O, the H2O molecules can rearrange around Ag0 in the cavity, which is intuitively verified by DFT calculation and molecular dynamics simulation. The establishment of a hydration layer in Ag@Ni-MOF regulates the chemical properties of the material and gives the material excellent proton conduction performance, with a proton conductivity of 4.86 × 10-2 S cm-1.

Direct Solution Deposition of Large-Area Non-Solvated Fullerene Single-Crystal Films for High-Performance n-Type Field-Effect Transistors.

Fullerene (C60) crystals have attracted considerable attention in the field of optoelectronic devices owing to their excellent performance as n-type semiconductor material. However, a challenge still remains unbeaten as to the continuous crystallization of non-solvated C60 single-crystal films with high coverage and uniform alignment using low-cost solution techniques. Here, a facile bar coating method is used to prepare ribbon-shaped non-solvated C60 crystals with a large area (up to centimeters) and high coverage (>95%) by precisely controlling the crystallization process from specific solvents. Benefiting from the non-solvated crystalline structure, well-distributed thickness, uniform morphological alignment, and crystallographic orientation, organic field-effect transistors fabricated from the C60 single-crystal films exhibit a high average electron mobility of 2.28 cm2 V-1s-1, along with the coefficient of variance (CV) as small as 13.6%. This efficient manufacturing method will lay a strong foundation for C60 single-crystal films to fit into the future high-performance integrated optoelectronic application.

A Minimalist Iron Oxide Nanoprobe for the High-Resolution Depiction of Stroke by Susceptibility-Weighted Imaging.

The precise mapping of collateral circulation and ischemic penumbra is crucial for diagnosing and treating acute ischemic stroke (AIS). Unfortunately, there exists a significant shortage of high-sensitivity and high-resolution in vivo imaging techniques to fulfill this requirement. Herein, a contrast enhanced susceptibility-weighted imaging (CE-SWI) using the minimalist dextran-modified Fe3O4 nanoparticles (Fe3O4@Dextran NPs) are introduced for the highly sensitive and high-resolution AIS depiction under 9.4 T for the first time. The Fe3O4@Dextran NPs are synthesized via a simple one-pot coprecipitation method using commercial reagents under room temperature. It shows merits of small size (hydrodynamic size 25.8 nm), good solubility, high transverse relaxivity (r2) of 51.3 mM-1s-1 at 9.4 T, and superior biocompatibility. The Fe3O4@Dextran NPs-enhanced SWI can highlight the cerebral vessels readily with significantly improved contrast and ultrahigh resolution of 0.1 mm under 9.4 T MR scanner, enabling the clear spatial identification of collateral circulation in the middle cerebral artery occlusion (MCAO) rat model. Furthermore, Fe3O4@Dextran NPs-enhanced SWI facilitates the precise depiction of ischemia core, collaterals, and ischemic penumbra post AIS through matching analysis with other multimodal MR sequences. The proposed Fe3O4@Dextran NPs-enhanced SWI offers a high-sensitivity and high-resolution imaging tool for individualized characterization and personally precise theranostics of stroke patients.

BELL1 interacts with CRABS CLAW and INNER NO OUTER to regulate ovule and seed development in pomegranate.

Pomegranate (Punica granatum) flowers are classified as bisexual flowers and functional male flowers. Functional male flowers have sterile pistils that show abnormal ovule development. In previous studies, we identified INNER NO OUTER (INO), CRABS CLAW (CRC), and BELL1 (BEL1), which were specifically expressed in bisexual and functional male flowers. However, the functions of ovule identity genes and the mechanism underlying ovule sterility in pomegranate remain unknown. Here, we found that the integument primordia formed and then ceased developing in the ovules of functional male flowers with a vertical diameter of 8.1-13.0 mm. Megaspore mother cells were observed in bisexual flowers when the vertical diameters of flowers were 10.1-13.0 mm, but not in functional male flowers. We analyzed the expression patterns of ovule-related genes in pomegranate ovule sterility and found that PgCRC mRNA was highly expressed at a critical stage of ovule development in bisexual flowers. Ectopic expression of PgCRC and PgINO was sufficient to increase seed number in transgenic lines. PgCRC partially complemented the Arabidopsis (Arabidopsis thaliana) crc mutant, and PgINO successfully rescued the seeds set in the Arabidopsis ino mutant. The results of yeast two-hybrid assays, bimolecular fluorescence complementation assays, and genetic data analyses showed that PgCRC and PgINO directly interact with PgBEL1. Our results also showed that PgCRC and PgINO could not interact directly with MADS-box proteins and that PgBEL1 interacted with SEPALLATA proteins. We report the function of PgCRC and PgINO in ovule and seed development and show that PgCRC and PgINO interact with PgBEL1. Thus, our results provide understanding of the genetic regulatory networks underlying ovule development in pomegranate.

Consideration of hormonal changes for orthodontic treatment during pregnancy and lactation - a review.

Hormonal changes in pregnant and lactating women significantly affect bone metabolism and overall stress levels, positioning them as a unique group within the orthodontic population. Fluctuations in estrogen, progesterone, prolactin, and other hormones are closely linked to bone remodeling and the periodontal tissue's response to inflammation caused by dental plaque. Hormones such as thyrotropin, leptin, and melatonin also play crucial roles in pregnancy and bone remodeling, with potential implications for orthodontic tooth movement. Additionally, adverse personal behaviors and changes in dietary habits worsen periodontal conditions and complicate periodontal maintenance during orthodontic treatment. Notably, applying orthodontic force during pregnancy and lactation may trigger stress responses in the endocrine system, altering hormone levels. However, these changes do not appear to adversely affect the mother or fetus. This review comprehensively examines the interaction between hormone levels and orthodontic tooth movement in pregnant and lactating women, offering insights to guide clinical practice.

TmcA functions as a lysine 2-hydroxyisobutyryltransferase to regulate transcription.

Protein lysine 2-hydroxyisobutyrylation (Khib) has recently been shown to play a critical role in the regulation of cellular processes. However, the mechanism and functional consequence of Khib in prokaryotes remain unclear. Here we report that TmcA, an RNA acetyltransferase, functions as a lysine 2-hydroxyisobutyryltransferase in the regulation of transcription. We show that TmcA can effectively catalyze Khib both in vitro and intracellularly, and that R502 is a key site for the Khib catalytic activity of TmcA. Using quantitative proteomics, we identified 467 endogenous candidates targeted by TmcA for Khib in Escherichia coli. Interestingly, we demonstrate that TmcA can specifically modulate the DNA-binding activity of H-NS, a nucleoid-associated protein, by catalysis of Khib at K121. Furthermore, this TmcA-targeted Khib regulates transcription of acid-resistance genes and enhances E. coli survival under acid stress. Our study reveals transcription regulation mediated by TmcA-catalyzed Khib for bacterial acid resistance.

Investigation of Tribological Behavior and Lubrication Mechanisms of Zinc Oxide under Poly α-olefin Lubrication Enhanced by the Electric Field.

The electric field induces complex effects on the tribological properties of zinc oxide (ZnO) under lubricated conditions, particularly at the nanoscale, where the friction process and mechanism remain unclear. In this paper, the tribological behaviors of ZnO under the lubrication of poly α-olefins (PAO) were investigated by molecular dynamics (MD) simulations with reactive force field (ReaxFF). The results reveal a significant enhancement in the tribological performances of ZnO with the application of the electric field, resulting in a 58.6% reduction in the coefficient of friction (COF) from 0.193 at 0 V/Å to 0.080 at 0.1 V/Å. This improvement can be attributed to the weakening of interfacial interaction, evidenced by a reduction in the number of C-O covalent bonds under the influence of the electric field, along with the formation of an adsorption film due to applied load and shear effects. Notably, the effect of the electric field and applied load extends the impact of interface slip on the tribological performance of ZnO. Overall, this study provides a comprehensive understanding of the impact of the electric field on reducing the friction of ZnO-based structured models, shedding light on explaining their tribological properties and lubrication mechanisms.