Catalytic Asymmetric Hydrogen Atom Transfer Based on a Chiral Hydrogen Atom Donor Generated from TBADT and Chiral BINOL.

Enantioselective radical reactions mediated by TBADT have seldom been seen due to the inherent challenges. Herein, we disclose a new chiral hydrogen atom transfer (HAT) reagent that was generated easily from 8H-BINOL, potassium carbonate, and TBADT under irradiation. The new complex 8H-BINOL/DTs could be used as a chiral H donor. A series of azaarenes could be converted into the corresponding chiral compounds via radical addition followed by enantioselective HAT.

Cells in the liver microenvironment regulate the process of liver metastasis.

The research of liver metastasis is a developing field. The ability of tumor cells to invade the liver depends on the complicated interactions between metastatic cells and local subpopulations in the liver (including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells, and immune-related cells). These interactions are mainly mediated by intercellular adhesion and the release of cytokines. Cell populations in the liver microenvironment can play a dual role in the progression of liver metastasis through different mechanisms. At the same time, we can see the participation of liver parenchymal cells and nonparenchymal cells in the process of liver metastasis of different tumors. Therefore, the purpose of this article is to summarize the relationship between cellular components of liver microenvironment and metastasis and emphasize the importance of different cells in the occurrence or potential regression of liver metastasis.

Dynamic Cytoophidia during Late-Stage Drosophila Oogenesis.

CTP synthase (CTPS) catalyzes the final step of de novo synthesis of CTP. CTPS was first discovered to form filamentous structures termed cytoophidia in Drosophila ovarian cells. Subsequent studies have shown that cytoophidia are widely present in cells of three life domains. In the Drosophila ovary model, our previous studies mainly focused on the early and middle stages, with less involvement in the later stages. In this work, we focus on the later stages of female germline cells in Drosophila. We use live-cell imaging to capture the continuous dynamics of cytoophidia in Stages 10-12. We notice the heterogeneity of cytoophidia in the two types of germline cells (nurse cells and oocytes), manifested in significant differences in morphology, distribution, and dynamics. Surprisingly, we also find that neighboring nurse cells in the same egg chamber exhibit multiple dynamic patterns of cytoophidia over time. Although the described dynamics may be influenced by the in vitro incubation conditions, our observation provides an initial understanding of the dynamics of cytoophidia during late-stage Drosophila oogenesis.

Impacts of physiological characteristics and human activities on the species distribution models of orchids taking the Hengduan Mountains as a case.

The biogeography research of orchids through species distribution models (SDMs), a vital tool in the biogeography field, is critical to understanding the fundamental geographic distribution patterns and identifying conservation priorities. The correspondence between species occurrence and environmental information is crucial to the model's performance. However, ecological preferences unique to different orchid species, such as their life forms, are often overlooked during the modeling process. This oversight can introduce bias and increase model uncertainty. Additionally, human activities, as an important potential predictor, have not been quantified in any orchid SDMs. Taking the Hengduan Mountains as an example, we preprocessed all orchid species' occurrences based on physiological characteristics. Choosing five spatial factors related to human activities to quantify the interference and enter into models as HI factor. Using different modeling methods (GLM, MaxEnt, and RF) and evaluation indices (AUC, TSS, and Kappa), diverse modeling strategies have been constructed in the study. A double-ranking method has been adopted to select the critical orchid distribution regions. The results showed that classification models based on physiological characteristics significantly improved the model's accuracy while adding the HI factor had the same effect but the absence of enough significance. Suitability maps indicated that highly heterogeneous mountainous areas were vital for the distribution of orchids in the Hengduan Mountains. Different distribution patterns and critical regions existed between various orchid life forms geographically - terrestrial orchids were dominant in the mountain, and mycoherterophical orchids were primarily located in the north, more influenced by vegetation and temperature. Critical regions of epiphytic orchids were in the south due to a greater dependence on precipitation and temperature. These studies are informative for understanding the orchids' geographic distribution patterns in the Hengduan Mountains, promoting conservation and providing references for similar research beyond orchids.

Synthesis of Sulfilimines via Selective S-C Bond Formation in Water.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

One-Pot Tandem Oxidative Bromination and Amination of Sulfenamide for the Synthesis of Sulfinamidines.

The sulfinamidines as aza analogues of sulfinamides received limited attention from both organic chemists and pharmaceutical chemists. Herein, we present a tandem oxidative/nucleophilic substitution approach for the synthesis of sulfinamidines in high yield (up to 98%). This cascade reaction method is enabled by N-bromosuccinimide (NBS) as an oxidant and diverse readily available amines as nucleophiles without any additives or catalysts. Notably, this method is highly time-economical, safe to operate, and easy to scale up and has excellent functional group compatibility.

Synthesis of Chiral Sulfonimidoyl Chloride via Desymmetrizing Enantioselective Hydrolysis.

Direct construction of chiral S(VI) from prochiral S(II) is a formidable challenge due to the inevitable formation of stable chiral S(IV). Previous synthetic strategies rely on the conversion of chiral S(IV) or enantioselective desymmetrization of preformed symmetrical S(VI) substrates. Here, we report desymmetrizing enantioselective hydrolysis of in situ-generated symmetric aza-dichlorosulfonium from sulfenamides for the preparation of chiral sulfonimidoyl chlorides, which could be used as a general stable synthon for obtaining a series of chiral S(VI) derivatives.

Neuronal nitric oxide synthase/reactive oxygen species pathway is involved in apoptosis and pyroptosis in epilepsy.

Dysfunction of neuronal nitric oxide synthase contributes to neurotoxicity, which triggers cell death in various neuropathological diseases, including epilepsy. Studies have shown that inhibition of neuronal nitric oxide synthase activity increases the epilepsy threshold, that is, has an anticonvulsant effect. However, the exact role and potential mechanism of neuronal nitric oxide synthase in seizures are still unclear. In this study, we performed RNA sequencing, functional enrichment analysis, and weighted gene coexpression network analysis of the hippocampus of tremor rats, a rat model of genetic epilepsy. We found damaged hippocampal mitochondria and abnormal succinate dehydrogenase level and Na+-K+-ATPase activity. In addition, we used a pilocarpine-induced N2a cell model to mimic epileptic injury. After application of neuronal nitric oxide synthase inhibitor 7-nitroindazole, changes in malondialdehyde, lactate dehydrogenase and superoxide dismutase, which are associated with oxidative stress, were reversed, and the increase in reactive oxygen species level was reversed by 7-nitroindazole or reactive oxygen species inhibitor N-acetylcysteine. Application of 7-nitroindazole or N-acetylcysteine downregulated the expression of caspase-3 and cytochrome c and reversed the apoptosis of epileptic cells. Furthermore, 7-nitroindazole or N-acetylcysteine downregulated the abnormally high expression of NLRP3, gasdermin-D, interleukin-1ß and interleukin-18. This indicated that 7-nitroindazole and N-acetylcysteine each reversed epileptic cell death. Taken together, our findings suggest that the neuronal nitric oxide synthase/reactive oxygen species pathway is involved in pyroptosis of epileptic cells, and inhibiting neuronal nitric oxide synthase activity or its induced oxidative stress may play a neuroprotective role in epilepsy.

Chiral Primary Amine Catalyzed Enantioselective Tandem Reactions Based on Heyns Rearrangement: Synthesis of α-Tertiary Amino Ketones.

Herein, we disclose a new catalytic asymmetric tandem reaction based on the Heyns rearrangement for the synthesis of chiral α-amino ketones with readily available substrates. The rearrangement is different from the Heyns rearrangement in that the α-amino ketones were obtained without the shift of the carbonyl group. The key to success is using chiral primary amine as a catalyst by mimicking glucosamine-6-phosphate synthase in catalyzing the efficient Heyns rearrangement in organisms.

Chiral Phosphoric Acid Catalyzed Enantioselective Desymmetrization of 1,4-Dihydropyridines by C(sp3 )-H Bromination.

Described herein is the enantioselective synthesis of Hantzsch-type 1,4-dihydropyridines (DHPs), which are frequently contained in pharmaceuticals. Readily available symmetrical 1,4-DHPs were used as substrates, and the methyl group at the 2- or 6-position of the 1,4-DHP was selectively monobrominated by desymmetrizing enantioselective bromination. The inert C-H bond was converted into a versatile C-Br bond, which guaranteed the modification of the chiral 1,4-DHP derivatives with high efficiency. Furthermore, axially chiral 4-aryl pyridines were accessible by central-to-axial chirality conversion.

Compromised autophagy and mitophagy in brain ageing and Alzheimer's diseases.

Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.

Highly Regio- and Enantioselective Reductive Coupling of Alkynes and Aldehydes via Photoredox Cobalt Dual Catalysis.

A Co-catalyzed highly regio- and enantioselective reductive coupling of alkynes and aldehydes has been developed under visible light photoredox dual catalysis. A variety of enantioenriched allylic alcohols have been obtained by using unsymmetrical internal alkynes and commercially available catalyst, chiral ligand, and reagents. It is noteworthy that this approach has considerable advantages, such as excellent regio- (>95:5 for >40 examples), stereo- (up to >95:5 E/Z), and enantioselectivity (92-99% ee, >35 examples) control, mild reaction conditions, broad substrate scope, and good functional group compatibility, making it a great improvement to enantioselective alkyne-aldehyde reductive coupling reactions.

Correlation between serum carnosinase concentration and renal damage in diabetic nephropathy patients.

Diabetic nephropathy (DN) is one of the major complications of diabetes and contributes significantly towards end-stage renal disease. Previous studies have identified the gene encoding carnosinase (CN-1) as a predisposing factor for DN. Despite this fact, the relationship of the level of serum CN-1 and the progression of DN remains uninvestigated. Thus, the proposed study focused on clarifying the relationship among serum CN-1, indicators of renal function and tissue injury, and the progression of DN. A total of 14 patients with minimal changes disease (MCD) and 37 patients with DN were enrolled in the study. Additionally, 20 healthy volunteers were recruited as control. Further, DN patients were classified according to urinary albumin excretion rate into two groups: DN with microalbuminuria (n = 11) and DN with macroalbuminuria (n = 26). Clinical indicators including urinary protein components, serum carnosine concentration, serum CN-1 concentration and activity, and renal biopsy tissue injury indexes were included for analyzation. The serum CN-1 concentration and activity were observed to be the highest, but the serum carnosine concentration was the lowest in DN macroalbuminuria group. Moreover, within DN group, the concentration of serum CN-1 was positively correlated with uric acid (UA, r = 0.376, p = 0.026) and serum creatinine (SCr, r = 0.399, p = 0.018) and negatively correlated with serum albumin (Alb, r = - 0.348, p = 0.041) and estimated glomerular filtration rate (eGRF, r = - 0.432, p = 0.010). Furthermore, the concentration of serum CN-1 was discovered to be positively correlated with indicators including 24-h urinary protein-creatinine ratio (24 h-U-PRO/CRE, r = 0.528, p = 0.001), urinary albumin-to-creatinine ratio (Alb/CRE, r = 0.671, p = 0.000), urinary transferrin (TRF, r = 0.658, p = 0.000), retinol-binding protein (RBP, r = 0.523, p = 0.001), N-acetyl-glycosaminidase (NAG, r = 0.381, p = 0.024), immunoglobulin G (IgG, r = 0.522, p = 0.001), cystatin C (Cys-C, r = 0.539, p = 0.001), beta-2-microglobulin (ß2-MG, r = 0.437, p = 0.009), and alpha-1-macroglobulin (α1-MG, r = 0.480, p = 0.004). Besides, in DN with macroalbuminuria group, serum CN-1 also showed a positive correlation with indicators of fibrosis, oxidative stress, and renal tubular injury. Taken together, our data suggested that the level of CN-1 was increased as clinical DN progressed. Thus, the level of serum CN-1 might be an important character during the occurrence and progression of DN. Our study will contribute significantly to future studies focused on dissecting the underlying mechanism of DN.

Clinical features of asthma with comorbid bronchiectasis: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to systematically estimate the prevalence of comorbid bronchiectasis in patients with asthma and to summarize its clinical impact. METHODS: Embase, PubMed, and Cochrane Library electronic databases were searched to identify relevant studies published from inception until March 2020. STUDY SELECTION: Studies were included if bronchiectasis was identified by high-resolution computed tomography. Outcomes included the prevalence of bronchiectasis and its association with demographic characteristics and indicators of asthma severity, including results of lung function tests and the number of exacerbations. RESULTS: Five observational studies with 839 patients were included. Overall, the mean prevalence of bronchiectasis in patients with asthma was 36.6% (307/839). Patients with comorbid bronchiectasis had lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (MD: -2.71; 95% CI: -3.72 to -1.69) and more frequent exacerbations (MD: 0.68; 95% CI: 0.03 to 1.33) than those with asthma alone, and there was no significant difference of sex, duration of asthma and serum levels of immunoglobulin(Ig)Es between asthmatic patients with or without bronchiectasis. CONCLUSION: The presence of bronchiectasis in patients with asthma was associated with greater asthma severity. There are important therapeutic implications of identifying bronchiectasis in asthmatic patients.

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN.

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To clarify the spatial variability of soil water content at field scale, a reasonable sampling method was established to support precision irrigation in the field. Soil samples were collected from Caoxinzhuang experimental area in Yangling District, Shaanxi Province at seven different dates. The spatial variation of soil water content in different soil layers of 0-60 cm were analyzed with classical statistics and geostatistics methods. The results showed that spatial distribution of soil water content in field scale was weak and moderate. When soil water content was within the range of 11.7%-20.1%, soil water content was negatively correlated with spatial variability. Sampling interval signifi-cantly affected the calculation accuracy of the spatial variability of soil water content. The coefficient of variation of soil water content between the east-west direction spacing of 27 m and the north-south direction spacing of 9 m was about 3.3% higher than the east-west direction spacing of 9 m and the north-south direction spacing of 18 m. With increasing sampling density, the contour change of soil water content distribution increased, and the number of grids with the least spatial variability of soil water content at the field scale was 21 points. When the sampling spacing was 18 m in the east-west direction, 9 m in the north-south direction, soil water content at field scale had a high spatial distribution correlation with soil water content in the middle position being 3%-5% higher than the surrounding. Our results provided reference for reasonable sampling of soil water content in the Guanzhong Plain and could guide the precision irrigation in agriculture.

Progress and Perspective of Ceramic/Polymer Composite Solid Electrolytes for Lithium Batteries.

Solid composite electrolytes (SCEs) that combine the advantages of solid polymer electrolytes (SPEs) and inorganic ceramic electrolytes (ICEs) present acceptable ionic conductivity, high mechanical strength, and favorable interfacial contact with electrodes, which greatly improve the electrochemical performance of all-solid-state batteries compared to single SPEs and ICEs. However, there are many challenges to overcome before the practical application of SCEs, including the low ionic conductivity less than 10-3 S cm-1 at ambient temperature, poor interfacial stability, and high interfacial resistance, which greatly restrict the room temperature performance. Herein, the advances of SCEs applied in all-solid-state lithium batteries are presented, including the Li ion migration mechanism of SCEs, the strategies to enhance the ionic conductivity of SCEs by various morphologies of ICEs, and construction methods of the low resistance and stable interfaces of SCEs with both cathode and anode. Finally, some typical applications of SCEs in lithium batteries are summarized and future development directions are prospected. This work presents how it is quite significant to further enhance the ionic conductivity of SCEs by developing the novel SPEs with the special morphology of ICEs for advanced all-solid-state lithium batteries.

An organocatalytic asymmetric Friedel-Crafts reaction of 2-substituted indoles with aldehydes: enantioselective synthesis of α-hydroxyl ketones by low loading of chiral phosphoric acid.

Hydroxyl alkylation of indoles by Friedel-Crafts reaction with a carbonyl compound is a useful strategy. However, the reaction was restricted to ketones due to the easy formation of a bisindole byproduct. Therefore, hydroxyl alkylation of an aldehyde with indole is confronted with great challenges. Here, we report an efficient strategy for asymmetric hydroxyl alkylation of 2-substituted indoles with aldehydes under 0.1 mol% chiral phosphoric acid. A series of α-hydroxyl ketones were obtained in high yields (up to 99%) and good enantioselectivities (up to 97%).

Fast separation of water-soluble vitamins by hydrophilic interaction liquid chromatography based on submicrometer flow-through silica microspheres.

In the present study, submicrometer flow-through silica microspheres (Sub-FTSiO2) was for the first time obtained via a suspension polymerization method coupled with sol-gel transition and phase separation. The Sub-FTSiO2 was characteristic of rich mesopores, penetrable macropores and small particle size, which would be beneficial to fast mass transfer, low column backpressure and high column efficiency. It was directly used as the hydrophilic interaction liquid chromatographic (HILIC) stationary phase, and the fast separation of seven water-soluble vitamins in 2.2 min was realized. The proposed method was successfully applied to the determination of water-soluble vitamins in two functional beverages on the market. The prepared Sub-FTSiO2 was well demonstrated for fast HILIC, and would be potential as the stationary phase matrix for fast liquid chromatography in diverse separation modes.

pH-Sensitive nanoparticles as smart carriers for selective intracellular drug delivery to tumor.

Herein, a smart pH-sensitive nanoparticle (DGL-PEG-Tat-KK-DMA-DOX) was prepared to achieve the selective intracellular drug delivery. In this nanoparticle, a PEG-grafted cell penetrating peptide (PEG-Tat-KK) was designed and acted as the cell penetrating segment. By introducing the pH-sensitive amide bonds between the peptide and blocking agent (2,3-dimethylmaleic anhydride, DMA), the controllable moiety (PEG-Tat-KK-DMA) endowed the nanoparticle with a charge-switchable shell and temporarily blocked penetrating function, thus improving the specific internalization. Besides, dendrigraft poly-L-lysine (DGL) used as the skeleton can greatly improve the drug loading because of the highly dendritic framework. Under the stimuli of acidic pH, this nanoparticle exhibited a remarkable charge-switchable property. The drug release showed an expected behavior with little release in the neutral pH media but relatively fast release in the acidic media. The in vitro experiments revealed that the cellular uptake and cytotoxicity were significantly enhanced after the pH was decreased. In vivo biodistribution and antitumor research indicated that the nanoparticle had noteworthy specificity and antitumor efficacy with a tumor inhibition rate of 79.7%. These results verified this nanoparticle could efficiently improve the selective intracellular delivery and possessed a great potential in tumor treatment.