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The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

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ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition.

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The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.

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BACKGROUND: We aimed to investigate the association between OA and treatment with dementia risk and structural brain abnormalities. METHODS: We recruited a total of 466,460 individuals from the UK Biobank to investigate the impact of OA on the incidence of dementia. Among the total population, there were 63,081 participants diagnosed with OA. We subsequently categorised the OA patients into medication and surgery groups based on treatment routes. Cox regression models explored the associations between OA/OA treatment and dementia risk, with the results represented as hazard ratios (HRs) and 95% confidence intervals (95% CI). Linear regression models assessed the associations of OA/OA therapy with alterations in cortical structure. RESULTS: During an average of 11.90 (± 1.01) years of follow-up, 5,627 individuals were diagnosed with all-cause dementia (ACD), including 2,438 AD (Alzheimer's disease), and 1,312 VaD (vascular dementia) cases. Results revealed that OA was associated with the elevated risk of ACD (HR: 1.116; 95% CI: 1.039-1.199) and AD (HR: 1.127; 95% CI: 1.013-1.254). OA therapy lowered the risk of dementia in both medication group (HR: 0.746; 95% CI: 0.652-0.854) and surgery group (HR: 0.841; 95% CI: 0.736-0.960). OA was negatively associated with cortical area, especially precentral, postcentral and temporal regions. CONCLUSIONS: Osteoarthritis increased the likelihood of developing dementia, and had an association with regional brain atrophy. OA treatment lowered the dementia risk. OA is a promising modifiable risk factor for dementia.

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INTRODUCTION: The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability. METHODS: Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. RESULTS: Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets. DISCUSSION: Our study contributes to the current body of evidence on the genetic etiology of ADRD. HIGHLIGHTS: Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.

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EGFR mutations are critical oncogenic drivers in lung adenocarcinoma (LUAD). However, the mechanisms by which they impact the tumor microenvironment (TME) and tumor immunity are unclear. Furthermore, the reasons underlying the poor response of EGFR-mutant (EGFR-MU) LUADs to immunotherapy with PD-1/PD-L1 inhibitors are unknown. Utilizing single-cell RNA (sc-RNA) and bulk RNA sequencing datasets, we conducted high-dimensional weighted gene coexpression network analysis to identify key genes and immune-related pathways contributing to the immunosuppressive TME. EGFR-MU cancer cells downregulated MHC class I genes to evade CD8+ cytotoxic T cells, expressed substantial levels of MHC class II molecules, and engaged with CD4+ regulatory T cells (Tregs). EGFR-MU tumors may recruit Tregs primarily through the CCL17/CCL22/CCR4 axis, leading to a Treg-enriched TME. High levels of MHC class II-positive cancer-associated fibroblasts and tumor endothelial cells were found within EGFR-MU tumors. Owing to the absence of costimulatory factors, they may inhibit rather than activate the tumor antigen-specific CD4+ T-cell response, contributing further to immune suppression. Multiplex immunohistochemistry analyses in a LUAD cohort confirmed increased expression of MHC class II molecules in cancer cells and fibroblasts in EGFR-MU tumors. Our research elucidates the highly immunosuppressive TME in EGFR-MU LUAD and suggests potential targets for effective immunotherapy.

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Aerogels are three-dimensional nanomaterials with low thermal conductivity, low density, high specific surface area, and high porosity. They have demonstrated remarkable performance advantages in thermal insulation, catalysis, and adsorption in recent years. However, their inherent brittleness and weak skeletal structure limit their applications. In order to improve the resilience and expand the capabilities of aerogels, it is essential to optimize their intrinsic properties. The chemical vapor deposition (CVD) method offers a number of advantages, including fine control, high selectivity, and the ability to modify the aerogel in both the outer surface and the inner layer. This approach allows for reinforcement of the gel skeleton while achieving functionalization. This paper reviews the research progress of aerogel modification by the CVD method with a focus on hydrophobic modification, structural improvement, antioxidant modification, catalytic modification, etc. In light of the current demand for aerogel applications and the difficulties encountered in modifying aerogels, this review proposes future research directions for aerogel modification by CVD.

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Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

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While cycloaddition reactions of bicyclobutanes (BCBs) have emerged as a potent method for synthesizing (hetero-)bicyclo[n.1.1]alkanes (usually n ≤ 3), their utilization in the synthesis of bicyclo[4.1.1]octane derivatives (BCOs) is still underdeveloped. Here, a palladium-catalyzed formal (4 + 3) reaction of BCBs with 1,4-O/C dipole precursors for the synthesis of oxa-BCOs is described. Unlike previous catalytic polar (3 + X) cycloadditions of BCBs, which are typically achieved through the activation of BCB substrates, the current reaction represents a novel strategy for realizing the cycloaddition of BCBs through the activation of the "X" cycloaddition partner. Moreover, the obtained functionalized oxa-BCOs products can be readily modified through various synthetic transformations.

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Agarwood is a valuable traditional medicine and fragrance. The production process is a typical injury-induced defense response. Currently, there are approximately 22 known species in the genus Aquilaria Lam., all of which can produce agarwood, whereas there are only two legal species of traditional Chinese medicinal agarwood, Aquilaria sinensis (Lour.) Spreng. and Aquilaria agallocha (Lour.) Roxb. The Taiwan herbal Pharmacopoeia of China stipulates that the medicinal agarwood species are A. sinensis and its relatives in the same genus. Moreover, there are five species of agarwood available for clinical medicinal use in Japan, including A. agallocha and A. sinensis, which are often confused with each other or used in a mixed way in the trade process. Therefore, accurate identification of traditional Chinese medicinal agarwood species is important to ensure the authenticity of traditional medicines and to guide the safety of clinical medication. In this study, 59 specific single-nucleotide polymorphism loci were screened and obtained from the chloroplast genomes of 12 species of the genus Aquilaria Lam. We established an identification method for traditional Chinese medicinal agarwood using mini-barcoding combined with high-resolution melting (HRM) and designed and validated 10 pairs of primers from the psbM-trnD, psbA, rps16, petN, ndhE-psaC, rps4, atpE, ycf1, rps15-trnN, and matK regions. The amplification products were all less than 200 bp, with a high success rate of amplification. The method was applied to successfully identify traditional Chinese medicinal agarwood species from commercial agarwood samples. Overall, the sensitivity of this method was sufficient to detect 1% of adulterants in medicinal agarwood products, proving that mini-barcoding HRM is a powerful and flexible tool. This method can be used as a fast and effective high-throughput method for authenticity testing of traditional Chinese medicinal agarwood and its raw materials containing agarwood-containing proprietary Chinese medicines and is recommended for industrial applications.

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BACKGROUND: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association. METHODS: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata. RESULTS: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential. LIMITATIONS: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations. CONCLUSIONS: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work.

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BACKGROUND: Heat stroke (HS) generated liver injury is a lethal emergency that occurs when the body is exposed to temperatures up to 40 °C for a few hours. PURPOSE: This study aimed to evaluate the therapeutic prospects of Catalpol (CA) from the blood-cooling herb Rehamanniae Radix on liver injury by HS. STUDY DESIGN AND METHODS: A murine HS model (41 ± 0.5 °C, 60 ± 5 % relative humidity) and two cell lines (lipopolysaccharide + 42 °C) were used to assess the protective effects of CA on physiological, pathological, and biochemical features in silico, in vivo, and in vitro. RESULTS: CA treatment significantly improved survival rates in vivo and cell viability in vitro over those of the untreated group. Additionally, CA treatment reduced core body temperature, enhanced survival time, and mitigated liver tissue damage. Furthermore, CA treatment also reduced the activities of AST and ALT enzymes in the serum samples of HS mice. Molecular docking analysis of the 28 overlapping targets between HS and CA revealed that CA has strong binding affinities for the top 15 targets. These targets are primarily involved in nine major signaling pathways, with the JAK-STAT pathway being highly associated with the other eight pathways. Our findings also indicate that CA treatment significantly downregulated the expression of proinflammatory cytokines both in vivo and in vitro while upregulating the expression of anti-inflammatory cytokines. Moreover, CA treatment reduced the levels of JAK2, phospho-STAT5, and phospho-STAT3 both in vivo and in vitro, which is consistent with its inhibition of the apoptotic markers p53, Bcl2, and Bax. CONCLUSIONS: Heat stroke-induced liver injury was inhibited by CA through the downregulation of JAK/STAT signaling.

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A novel Fe-MoOx nanozyme, engineered with enhanced peroxidase (POD)-like activity through strategic doping and the creation of oxygen vacancies, is introduced to catalyze the oxidation of TMB with high efficiency. Furthermore, Fe-MoOx is responsive to single electron transfer (SET) and hydrogen atom transfer (HAT) mechanisms related to antioxidants and can serve as a desirable nanozyme for total antioxidant capacity (TAC) determination. The TAC colorimetric platform can reach a low LOD of 0.512 µM in solution and 24.316 µM in the smartphone-mediated RGB hydrogel (AA as the standard). As proof of concept, the practical application in real samples was explored. The work paves a promising avenue to design diverse nanozymes for visual on-site inspection of food quality.

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BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.

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Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

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BACKGROUND: Deer-derived materials (antler, venison, fetus, penis, bone, tail, and others) are some of the most valuable traditional animal-based medicinal and food materials in China. In production, processing, and trade, the quality of deer products varies. The market is confusing, and counterfeit and shoddy products are common. There is an urgent need to establish an accurate identification method. RESULTS: Two pairs of primers suitable for identifying deer-derived medicinal materials were obtained by screening the cytochrome oxidase I (COI) sequences of 18 species from nine genera of the deer family. The two primers were used to identify the species and adulteration of 22 batches of commercially available deer-derived products with a mini-barcode combining high-resolution melting (HRM) technology and methodical investigation. Deer-derived materials (sika and red deer) were correctly identified by species using varying DNA amounts (1 to 500 ng). The two pairs of primers COI-1FR and COI-2FR yielded melting temperatures (Tm) of 80.55 to 81.00 °C and 82.00 to 82.50 °C for sika deer, and 81.00 to 82.00 °C and 81.40 to 82.00 °C for red deer. Twenty-two batches of commercially available samples were analyzed by HRM analysis and conventional amplification sequencing, and it was found that the species samples had an error rate of species labeling of 31.8%. Four batches of samples were identified as mixed (adulterated) in the HRM analysis. CONCLUSION: The combination of DNA mini-barcode with HRM analysis facilitated the accurate identification of species of deer-derived materials, especially the identification of samples in an adulterated mixed state. © 2024 Society of Chemical Industry.

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BACKGROUND: Chemokine ligand 14, which has a C-C motif (CCL14), mediates the immunological milieu around tumors. However, its role in the progression of lung adenocarcinoma (LUAD) is still unknown. Our objectives were to study the association between CCL14 and tumor-infiltrating immune cells (TIICs) as well as the predictive significance of CCL14 in LUAD. METHODS: The expression of CCL14 in LUAD was examined by using the Oncomine, The Cancer Genome Atlas (TCGA), The University of Alabama at Birmingham CANcer data analysis Portal (UALCAN), and Human Protein Atlas databases. To determine the prognostic significance of CCL14 in LUAD, researchers used the Kaplan‒Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA, version 2). We utilized TIMER and GEPIA2 to investigate the connection between CCL14 and TIICs. Gene set enrichment analysis (GSEA) was used to test for functional enrichment of genes. We used RT‒qPCR to measure CCL14 expression and Cell Counting Kit-8, Transwell, and wound healing assays to investigate the biological role of CCL14. RESULTS: The prognosis of patients with LUAD was worse when CCL14 expression was low. Statistical analysis revealed that CCL14 mRNA expression was significantly greater in lung epithelial cells than in LUAD cell lines in vitro. Enhancing CCL14 expression reduced cell migration, invasion, and proliferation. The results of the immune infiltration research showed that CCL14 and TIICs were positively correlated. Different immune infiltration patterns associated with CCL14 were also shown by TIIC markers. According to GSEA, histone deacetylases, G2/M checkpoints, and Notch signaling pathways were associated with low CCL14 expression. CONCLUSIONS: CCL14 is anticipated to emerge as a prognostic marker and therapeutic target for LUAD due to its role in regulating TIICs, suggesting that it may be an antioncogene.

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Natural gas hydrate (NGH) is a significant alternative energy resource in achieving carbon neutrality. The developmental trend and competitive landscape of NGH exploitation and production are crucial for policymakers in government, managers of enterprises, and researchers. This study introduces a novel framework for conducting an in-depth analysis of NGH, integrating patentometrics, technology evolution, and correlation relationships to monitor developmental trends and competitive landscape through patent analysis. The results indicate that China, the USA, and Japan have distinct technology advantages. Current technological developments in the NGH field focus primarily on extraction technologies, equipment, and processing systems. The co-opetition analysis among countries reveals that the most extensive international cooperation network is primarily in Europe and the USA, with national partnerships in Asia concentrated in China and Japan. Institutional cooperation remains limited, primarily within universities in China, while both the USA and Japan foster collaboration between enterprises. The competitive landscapes of key NGH-related technologies among countries and institutions are also examined. This study contributes not only to monitoring the developmental trend and competitive landscape in NGH but also to providing policy recommendations for government and enterprises regarding strategic management and collaborative innovation.

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Obtained from Aquilaria Lam. and Gyrinops Gaertn., agarwood is a prestigious perfume and medicinal material in the world. Its primary chemical constituents and indicators of agarwood's development are 2-(2-phenylethyl)chromones (PECs). However, how PECs affect its quality, accumulation, and transformation pattern is still unclear. The present study investigated this issue by monitoring resin filling in agarwood generated by the whole-tree agarwood-inducing technique over a span of a year, observing the ethanol extract concentration at different sampling times, and statistically examining PECs in agarwood from each sampling period. In agarwood, the resin accumulated over time, except during the 4th-6th month due to the creation of a barrier layer. The relative content of total PECs demonstrated an overall increase throughout the year but a decrease from the 4th month to the 6th month, and the relative content of 19 PECs that persisted throughout the year was positively correlated with the content of ethanol extracts. In addition, the process of chromone accumulation was accompanied by the production and transformation of different types of chromones, with flindersia type 2-(2-phenylethyl)chromones, epoxy-2-(2-phenylethyl)chromones, and diepoxy-2-(2-phenylethyl)chromones being the major chromone components; in addition, the content of 5,6,7,8-tetrahydro-2-(2-phenylethyl)chromones kept increasing after 6 months of agarwood formation. Three main trends were identified from 58 analogs of PECs, each with notable variation. The first type had the highest content at the beginning of resin formation. The second type had the highest content at 6 months and then started to decrease, and the third type had a slowly increasing content. As a whole, this study systematically investigated the accumulation of PECs during injury-induced agarwood production in A. sinensis, which is of scientific significance in resolving the transformation of PECs and revealing the secret of agarwood formation.