Association between the AHA life's essential 8 and prediabetes/diabetes: a cross-sectional NHANES study.

Background and aims: The American Heart Association (AHA) recently introduced the Life's Essential 8 (LE8) to improve cardiovascular health (CVH). However, the association between LE8 and the risk of prediabetes or diabetes is not yet fully understood. Consequently, this study aims to assess the association between CVH, as evaluated by LE8, and the risk of prediabetes and diabetes. Methods and Results: This cross-sectional study encompassed 7,739 participants aged ≥20 years from the 2007-2018 National Health and Nutrition Examination Surveys (NHANES). The CVH of participants was evaluated using the LE8, combining four health behaviors and three health factors. Glucose metabolic status categories included normal glucose metabolism, prediabetes including isolated impaired fasting glucose, isolated impaired glucose tolerance, both IFG and IGT, and diabetes. The associations between CVH and prediabetes and diabetes were analyzed using logistic regression, linear regression, restricted cubic splines, and subgroup analyses. Among 7,739 participants, 1,949 had iIFG, 1,165 were diagnosed with iIGT, 799 were IFG+IGT, and 537 were diagnosed with diabetes. After multivariable adjustments, CVH scores were inversely associated with prediabetes and diabetes, with the most robust inverse association observed between IFG+IGT and CVH across all prediabetes subgroups. Of all CVH components not directly in the causal pathway, body mass index (BMI) had the most robust associations with prediabetes and diabetes. Subgroup analyses indicated that the negative correlation between CVH and prediabetes was stronger among those with university or higher education. Conclusion: CVH, as defined by LE8, showed a significant negative association with prediabetes and diabetes.

Bioenzymatic detoxification of mycotoxins.

Mycotoxins are secondary metabolites produced during the growth, storage, and transportation of crops contaminated by fungi and are physiologically toxic to humans and animals. Aflatoxin, zearalenone, deoxynivalenol, ochratoxin, patulin, and fumonisin are the most common mycotoxins and can cause liver and nervous system damage, immune system suppression, and produce carcinogenic effects in humans and animals that have consumed contaminated food. Physical, chemical, and biological methods are generally used to detoxify mycotoxins. Although physical methods, such as heat treatment, irradiation, and adsorption, are fast and simple, they have associated problems including incomplete detoxification, limited applicability, and cause changes in food characteristics (e.g., nutritive value, organoleptic properties, and palatability). Chemical detoxification methods, such as ammonification, ozonation, and peroxidation, pollute the environment and produce food safety risks. In contrast, bioenzymatic methods are advantageous as they achieve selective detoxification and are environmentally friendly and reusable; thus, these methods are the most promising options for the detoxification of mycotoxins. This paper reviews recent research progress on common mycotoxins and the enzymatic principles and mechanisms for their detoxification, analyzes the toxicity of the degradation products and describes the challenges faced by researchers in carrying out enzymatic detoxification. In addition, the application of enzymatic detoxification in food and feed is discussed and future directions for the development of enzymatic detoxification methods are proposed for future in-depth study of enzymatic detoxification methods.

Small vessel disease burden and prognosis of recent subcortical ischaemic stroke differ by parent artery atherosclerosis.

BACKGROUND AND PURPOSE: Parent artery atherosclerosis is an important aetiology of recent subcortical ischaemic stroke (RSIS). However, comparisons of RSIS with different degrees of parent artery atherosclerosis are lacking. METHODS: Prospectively collected data from our multicentre cohort (all were tertiary centres) of the Stroke Imaging Package Study between 2015 and 2017 were retrospectively reviewed. The patients with RSIS defined as a single clinically relevant diffusion-weighted imaging positive lesion in the territory of lenticulostriate arteries were categorized into three subgroups: (1) normal middle cerebral artery (MCA) on magnetic resonance angiography and high-resolution magnetic resonance imaging (HR-MRI); (2) low-grade MCA atherosclerosis (normal or <50% stenosis on magnetic resonance angiography and with MCA plaques on HR-MRI); (3) steno-occlusive MCA atherosclerosis (stenosis ≥50% or occlusion). The primary outcome was 90-day functional dependence (modified Rankin Scale score >2). The clinical and imaging findings were compared between subgroups. RESULTS: A total of 239 patients (median age 60.0 [52.0-67.0] years, 72% male) were enrolled, including 140 with normal MCA, 64 with low-grade MCA atherosclerosis and 35 with steno-occlusive MCA atherosclerosis. Patients with steno-occlusive MCA atherosclerosis had the largest infarct volume. Low-grade MCA atherosclerosis was independently associated with cerebral microbleeding, more severe perivascular spaces in basal ganglia and higher total cerebral small vessel disease burden. Low-grade MCA atherosclerosis was an independent determinant of 90-day functional dependence (odds ratio 3.897; 95% confidence interval 1.309-11.604). CONCLUSIONS: Our study suggested RSIS with varying severity of parent artery atherosclerosis exhibits distinctive clinical and neuroimaging characteristics, with low-grade MCA atherosclerosis associating with higher cerebral small vessel disease burden and worse prognosis.

Integrating serum pharmacochemistry, network pharmacology and untargeted metabolomics strategies to reveal the material basis and mechanism of action of Feining keli in the treatment of chronic bronchitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Feining keli (FNKL) is herbal preparation mainly made from Senecio cannabifolius Less., In recent years, more and more studies have found that FNKL has excellent therapeutic effects on chronic bronchitis (CB). Nevertheless, its pharmacodynamic material basis and mechanism of action are still unknown. AIM OF THE STUDY: This study aimed to explore the pharmacodynamic material basis and mechanism of action of FNKL in treating CB. MATERIALS AND METHODS: The CB rat model was induced using nasal drops of lipopolysaccharide (LPS) in combination with smoking. Various assessments including behavioral and body mass examination, lung index measurement, enzyme linked immunosorbent assay (ELISA), as well as histological analyses using hematoxylin and eosin (H&E) and Masson staining were conducted to validate the reliability of the CB model. The serum components of FNKL in CB rats were identified using ultra-high-performance liquid chromatography Orbitrap Exploris mass spectrometer (UHPLC-OE-MS). Network pharmacology was used to predict the network of action of the active ingredients in FNKL based on these serum components. Signaling pathways were enriched and analyzed, and molecular docking was conducted for key targets. Molecular dynamics simulations were performed using GROMACS software. The mechanism was confirmed through a series of experiments including Western blot (WB), immunofluorescence (IF), and reverse transcription (RT)-PCR. Additionally, untargeted metabolomics was employed to identify biomarkers and relevant metabolic pathways associated with the treatment of CB with FNKL. RESULTS: In CB rats, FNKL improved body mass, lung index, and pathological damage of lung tissues. It also decreased interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), malonaldehyde (MDA) levels, and percentage of lung collagen fiber area. Furthermore, FNKL increased IL-10 and superoxide dismutase (SOD) levels, which helped alleviate bronchial inflammation in the lungs. A total of 70 FNKL chemical components were identified in CB rat serum. Through network pharmacology analysis, 5 targets, such as PI3K, AKT, NF-κB, HIF-1α, and MYD88, were identified as key targets of FNKL in the treatment of CB. Additionally, the key signaling pathways identified were PI3K/AKT pathway、NF-κB/MyD88 pathway、HIF-1α pathway. WB, IF, and RT-PCR experiments were conducted to confirm the findings. Molecular docking studies demonstrated successful docking of 16 potential active components with 5 key targets. Additionally, molecular dynamics simulations indicated the stability of quercetin-3-galactoside and HIF-1α. Metabolomics analysis revealed that FNKL primarily regulated pathways related to alpha-linolenic acid metabolism, primary bile acid biosynthesis, bile secretion, arachidonic acid metabolism, neuroactive ligand-receptor interaction, and folate biosynthesis. Furthermore, the expression levels of traumatic acid, traumatin, alpha linolenic acid, cholic acid, 2-arachidonoylglycerol, deoxycholic acid, 7,8-dihydroneopterin, and other metabolites were found to be regulated. CONCLUSION: FNKL exhibits positive therapeutic effects on CB, with quercetin-3-galactoside identified as a key active component. The mechanism of FNKL's therapeutic action on CB involves reducing inflammatory response, oxidative stress, and regulating metabolism, and its molecular mechanism was better elucidated in a holistic manner. This study serves as a reference for understanding the pharmacodynamic material basis and mechanism of action of FNKL in treating CB, and provides avenues for exploring the effects of compounded herbal medicines on CB.

Regio- and enantioselective nickel-alkyl catalyzed hydroalkylation of alkynes.

The migratory insertion of metal-hydride into alkene has allowed regioselective access to organometallics, readily participating in subsequent functionalization as one conventional pathway of hydroalkylation, whereas analogous process with feedstock alkyne is drastically less explored. Among few examples, the regioselectivity of metal-hydride insertion is mostly governed by electronic bias of alkynes. To alter the regioselectivity and drastically expand the intermediate pools that we can access, one aspirational design is through alternative nickel-alkyl insertion, providing opposite regioselectivity induced by steric demand. Leveraging in situ formed nickel-alkyl species, we herein report the regio- and enantioselective hydroalkylation of alkynes with broad functional group tolerance, excellent regio- and enantioselectivity, enabling efficient route to diverse valuable chiral allylic amines motifs. Preliminary mechanistic studies indicate the aminoalkyl radical species can participate in metal-capture and lead to formation of nickel-alkyl, of which the migratory insertion is key to reverse regioselectivity observed in metal-hydride insertion.

Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection.

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.

Pharmacological induction of MHC-I expression in tumor cells revitalizes T cell anti-tumor immunity.

Antigen presentation by Major Histocompatibility Complex Class I (MHC-I) is crucial for T-cell-mediated killing, and aberrant surface MHC-I expression is tightly associated with immune evasion. To address MHC-I downregulation, we conducted a high-throughput flow cytometry screen, identifying bleomycin (BLM) as a potent inducer of cell surface MHC-I expression. BLM-induced MHC-I augmentation renders tumor cells more susceptible to T cells in co-culture assays and enhances anti-tumor responses in an adoptive cellular transfer mouse model. Mechanistically, BLM remodels the tumor immune microenvironment, inducing MHC-I expression in an ATM/ATR-NF-κB-dependent manner. Furthermore, BLM improves T-cell-dependent immunotherapeutic approaches, including bispecific antibodies therapy, immune checkpoint therapy (ICT), and autologous tumor-infiltrating lymphocytes (TILs) therapy. Importantly, low-dose BLM treatment in mouse models amplified the anti-tumor effect of immunotherapy without detectable pulmonary toxicity. In summary, our findings repurpose BLM as a potential inducer of MHC-I, enhancing its expression to improve the efficacy of T-cell-based immunotherapy.

Oxysophocarpine attenuates inflammatory osteolysis by modulating the NF-κb pathway and the reactive oxygen species-related Nrf2 signaling pathway.

BACKGROUND AND AIM: Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. EXPERIMENTAL PROCEDURE: This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. RESULTS: OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1ß, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. CONCLUSION: OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.

Rate control or rhythm control in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention.

Background: Restoring and maintaining sinus rhythm in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has been studied in clinical trials to reduce symptoms and improve quality of life. Limited data exist on the effectiveness of rate or rhythm control therapy in these patients. Methods: Consecutive patients with AF and ACS or referred for PCI were prospectively recruited in Fuwai Hospital during 2017-2020. The primary endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular mortality, myocardial infarction, ischemic stroke, non-central nervous system embolism and ischemia-driven revascularization. Kaplan-Meier curves and Cox regressions were performed to evaluate the association between rhythm/rate control and subsequent outcomes. For the primary endpoints, we used the Benjamini-Hochberg correction for multiple comparisons. Results: A total of 1499 patients with AF and ACS or undergoing PCI were included, with a median follow-up of 34.7 months. Compared to non-rate control, rate control strategy reduced the risk of subsequent MACCEs (adjusted HR, 0.320; 95 % CI 0.220-0.466; p <0.001; *p <0.002) and all-cause death (adjusted HR, 0.148; 95 % CI 0.093-0.236; p <0.001; *p <0.002). Similar trends were observed across all predefined subgroups (p <0.001). In the final multivariate model, rhythm control was not associated with a lower subsequent MACCEs but significantly improved all-cause mortality compared to non-rhythm control (adjusted HR, 0.546; 95 % CI 0.313-0.951; p =0.033; *p =0.044). Conclusions: In this real-world study, rate control strategy was associated with lower risk of MACCEs and all-cause death in AF and ACS or undergoing PCI. Besides, management with rhythm control strategy may improve all-cause mortality.

Fine mapping and functional validation of the maize nicosulfuron-resistance gene CYP81A9.

Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.

Efficacy and safety of the disposable eyelid warming masks in the treatment of dry eye disease due to Meibomian gland dysfunction.

BACKGROUND: Warm compresses are the routine treatment for Meibomian gland dysfunction (MGD) in daily life, but in order to achieve satisfactory efficacy, the treatment needs to be sustained over a long time, which can have an impact on the patient compliance. A more convenient warm compresses will help improve the patient compliance. Therefore, the purpose of the study is to investigate the efficacy and safety of the disposable eyelid warming masks for treatment of dry eye disease (DED) due to MGD. METHODS: This was a randomized, controlled, non-masked, two-center clinical trial. One hundred and forty-four patients were treated by the masks or the hot towel twice daily for 12 weeks. Patients were evaluated at baseline, 4-week and 12-week visits for subjective symptoms, objective signs and safety assessments, including ocular symptom scores, ocular surface disease index (OSDI), tear break-up time (BUT), corneal fluorescein staining (CFS), Schirmer I test (SIT), meibum quality, meibum expressibility, and adverse events (AEs). RESULTS: A totle of 134 patients were followed in the study. The mean age of the masks group (14 males and 52 females) and the hot towel group (20 males and 48 females) was 43.7 ± 13.5 years and 39.5 ± 13.9 years, respectively. At 4-week visit, there were significant statistical differences in ocular symptom scores, OSDI and CFS between two groups (P < 0.05). Except for SIT, the treatment group showed a greater improvement in subjective symptoms and objective signs than the control group at 12-week visit. (P < 0.05). In addition, 40 AEs occurred in 27 patients (37.5%) in the treatment group, and 34 AEs occurred in 21 patients (29.17%) in the control group. No serious AEs were reported. CONCLUSIONS: The masks had a good efficacy and safety in the treatment of DED due to MGD, and might offer an attractive treatment option for some patients. TRIAL REGISTRATION: The study was registered at Chinese Clinical Trial Registry (ChiCTR1900025443) on August 26, 2019.

Study on diagnostic-sensitive markers of primary immune thrombocytopaenia in children based on plasma proteomics.

To use proteomic techniques to identify sensitive diagnostic biomarkers for paediatric immune thrombocytopenia (ITP). We selected children in ITP and control groups, using a four-dimensional data-independent acquisition approach (4D-DIA) to analyse its protein expression. The significantly differentially expressed proteins were selected for enzyme-linked immunosorbent assay (ELISA) validation in a cohort comprising 50 samples (13 healthy controls, 15 secondary thrombocytopenia controls and 22 children with ITP). Receiver operating characteristics (ROC) were generated to diagnose ITP and to assess the diagnostic effectiveness of this approach. Compared with the control group, 55 differentially expressed proteins (43 increased and 12 decreased) were determined in the ITP group. Matrix metalloproteinases-9 (MMP-9) and thrombospondin-1 (THBS1) were significantly expressed and selected for ELISA. The verification outcomes aligned with the findings from the proteomic examinations. In contrast to the control cohort, the ITP subjects exhibited markedly elevated plasma MMP-9 levels and reduced plasma THBS1 concentrations. Additionally, the ROC curves indicated the diagnostic value of these biomarkers. In conclusion, proteomics facilitates identifying the sensitive biomarkers for ITP diagnosis. We have preliminarily selected two differentially expressed proteins, MMP-9 and THBS1, whose potential role as biomarkers for diagnosing ITP requires further research.

Advances in Extracellular-Vesicles-Based Diagnostic and Therapeutic Approaches for Ocular Diseases.

Extracellular vesicles (EVs) are nanoscale membrane vesicles of various sizes that can be secreted by most cells. EVs contain a diverse array of cargo, including RNAs, lipids, proteins, and other molecules with functions of intercellular communication, immune modulation, and regulation of physiological and pathological processes. The biofluids in the eye, including tears, aqueous humor, and vitreous humor, are important sources for EV-based diagnosis of ocular disease. Because the molecular cargos may reflect the biology of their parental cells, EVs in these biofluids, as well as in the blood, have been recognized as promising candidates as biomarkers for early diagnosis of ocular disease. Moreover, EVs have also been used as therapeutics and targeted drug delivery nanocarriers in many ocular disorders because of their low immunogenicity and superior biocompatibility in nature. In this review, we provide an overview of the recent advances in the field of EV-based studies on the diagnosis and therapeutics of ocular disease. We summarized the origins of EVs applied in ocular disease, assessed different methods for EV isolation from ocular biofluid samples, highlighted bioengineering strategies of EVs as drug delivery systems, introduced the latest applications in the diagnosis and treatment of ocular disease, and presented their potential in the current clinical trials. Finally, we briefly discussed the challenges of EV-based studies in ocular disease and some issues of concern for better focusing on clinical translational studies of EVs in the future.

Massive acceleration of SN2 reaction using the oriented external electric field.

Nucleophilic substitution is one of the most fundamental chemical reactions, and the pursuit of high reaction rates of the reaction is one of the ultimate goals in catalytic and organic chemistry. The reaction barrier of the nucleophilic substitution originates from the highly polar nature of the transition state that can be stabilized under the electric field created by the solvent environment. However, the intensity of the induced solvent-electric field is relatively small due to the random orientation of solvent molecules, which hinders the catalytic effects and restricts the reaction rates. This work shows that oriented external electric fields applied within a confined nanogap between two nanoscopic tips could accelerate the Menshutkin reaction by more than four orders of magnitude (over 39 000 times). The theoretical calculations reveal that the electric field inside the nanogap reduces the energy barrier to increase the reaction rate. Our work suggests the great potential of electrostatic catalysis for green synthesis in the future.

Oleanane-type triterpenoids from Sabia limoniacea and their anti-inflammatory activities.

Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.

Chirality and Curvature on Protein Adsorption and Osteogenesis.

Here we designed enantiomeric lipid-mimetic glutamic acid derivatives (L/D-UG) and investigated their self-assembled chiral nanostructures and performance with the protein adsorption as well as the osteogenesis. It was found that L or D-UG can self-assemble into vesicle bilayers and two-dimensional (2D) nanocrystals via a kinetic and thermodynamic control, respectively. These chiral vesicles and 2D crystals showed differentiated adsorption of proteins by their curvature and chirality. Specifically, fibronectin constituted by L-amino acids adsorbed preferentially on L-UG 2D crystal in a semi-random pattern and L-2D nanocrystal show as the most effective structures to promote bone regeneration. The controlled vesicle and 2D crystal assemblies with different chirality and curvature helps to clarify their determine roles in protein adsorption and osteogenesis.

An Engineered Imine Reductase for Highly Diastereo- and Enantioselective Synthesis of ß-Branched Amines with Contiguous Stereocenters.

ß-Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo- and enantioselective biocatalytic approach for preparing a broad range of ß-branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution-asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild-type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9% ee, >99:1 dr, and >99% conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74% yield, >99.9% ee, and 98:2 dr at a challenging substrate loading of 110 g L-1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution-asymmetric reductive amination reaction system.

Clean air policy reduces the atherogenic lipid profile levels: Results from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) Study.

Evidence of the associations between long-term exposure to PM2.5 and O3 and human blood lipid concentrations is abundant yet inconclusive. Whether clean air policies could improve lipid profiles remains unclear. In total, 2979312 participants from a Chinese nationwide prospective study were included. For cross-sectional analyses, linear mixed-effects models were utilized to assess the associations of pollutants with lipid profiles (TC, LDL-C, TG, HDL-C). For longitudinal analyses, a quasi-experimental design and difference-in-differences models were employed to investigate the impact of China's Clean Air Act. In the cross-sectional analyses, each IQR increase in PM2.5 was associated with 2.49 % (95 % CI: 2.36 %, 2.62 %), 2.51 % (95 % CI: 2.26 %, 2.75 %), 3.94 % (95 % CI: 3.65 %, 4.23 %), and 1.54 % (95 % CI: 1.38 %, 1.70 %) increases in TC, LDL-C, TG, and HDL-C, respectively. For each IQR increase in O3, TC, LDL-C, TG, and HDL-C changed by 1.06 % (95 % CI: 0.95 %, 1.17 %), 1.21 % (95 % CI: 1.01 %, 1.42 %), 1.78 % (95 % CI: 1.54 %, 2.02 %), and -0.63 % (95 % CI: -0.76 %, -0.49 %), respectively. Longitudinal analyses showed that the intervention group experienced greater TC, LDL-C, and HDL-C reductions (1.77 %, 4.26 %, and 7.70 %, respectively). Our findings suggest that clean air policies could improve lipid metabolism and should be implemented in countries with heavy air pollution burdens.

Lighting Up Bispyrene-Functionalized Chiral Molecular Muscles with Switchable Circularly Polarized Excimer Emissions.

Aiming at the further extension of the application scope of traditional molecular muscles, a novel bispyrene-functionalized chiral molecular [c2]daisy chain was designed and synthesized. Taking advantage of the unique dimeric interlocked structure of molecular [c2]daisy chain, the resultant chiral molecular muscle emits strong circularly polarized luminescence (CPL) attributed to the pyrene excimer with a high dissymmetry factor (glum) value of 0.010. More importantly, along with the solvent- or anion- induced motions of the chiral molecular muscle, the precise regulation of the pyrene stacking within its skeleton results in the switching towards either "inversed" state with sign inversion and larger glum values or "down" state with maintained handedness and smaller glum values, making it a novel multistate CPL switch. As the first example of chiral molecular muscle-based CPL switch, this proof-of-concept study not only successfully widens the application scopes of molecular muscles, but also provides a promising platform for the construction of novel smart chiral luminescent materials for practical applications.

Tracing the evolving dynamics and research hotspots of spinal cord injury and surgical decompression from 1975 to 2024: a bibliometric analysis.

Background: Exploration of the benefits and timing of surgical decompression in spinal cord injury (SCI) has been a research hotspot. However, despite the higher volume and increasing emphasis on quality there remains no bibliometric view on SCI and surgical decompression. In this study, we aimed to perform bibliometric analysis to reveal the core countries, affiliations, journals, authors, and developmental trends in SCI and surgical decompression across the past 50 years. Methods: Articles and reviews were retrieved from web of science core collection between 1975 and 2024. The bibliometrix package in R was used for data analysis and visualizing. Results: A total of 8,688 documents were investigated, indicating an ascending trend in annual publications. The USA and China played as the leaders in scientific productivity. The University of Toronto led in institutional productions. Core authors, such as Michael G. Fehlings, showed high productivity, and occasional authors showed widespread interests. Core journals like Spine and Spinal Cord served as beacons in this field. The interaction of core authors and international collaboration accentuated the cross-disciplinary feature of the field. Prominent documents emphasized the clinical significance of early decompression in 24 h post SCI. Conclusion: Based on comprehensive bibliometric analysis and literature review, we identified the hotspots and future directions of this field: (1) further investigation into the molecular and cellular mechanisms to provide pre-clinical evidence for biological effects of early surgical decompression in SCI animal models; (2) further evaluation and validation of the optimal time window of surgical decompression based on large cohort, considering the inherent heterogeneity of subpopulations in complicated immune responses post SCI; (3) further exploration on the benefits of early decompression on the neurological, functional, and clinical outcomes in acute SCI; (4) evaluation of the optimal surgical methods and related outcomes; (5) applications of artificial intelligence-based technologies in spinal surgical decompression.