Comparative single-cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS-CoV-2 infection.

Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.

Emodin-8-O-ß-D-glucopyranoside-induced hepatotoxicity and gender differences in zebrafish as revealed by integration of metabolomics and transcriptomics.

BACKGROUND: Emodin-8-O-ß-D-glucopyranoside (Em8G) is an active ingredient of traditional Chinese medicine Rhei Radix et Rhizoma and Polygonum multiflorum Thunb.. And it caused hepatotoxicity, while the underlying mechanism was not clear yet. PURPOSE: We aimed to explore the detrimental effects of Em8G on the zebrafish liver through the metabolome and transcriptome integrated analysis. STUDY DESIGN AND METHODS: In this study, zebrafish larvae were used in acute toxicity tests to reveal the hepatotoxicity of Em8G. Adult zebrafish were then used to evaluate the gender differences in hepatotoxicity induced by Em8G. Integration of transcriptomic and metabolomic analysis was used further to explore the molecular mechanisms underlying gender differences in hepatotoxicity. RESULTS: Our results showed that under non-lethal concentration exposure conditions, hepatotoxicity was observed in Em8G-treated zebrafish larvae, including changes in liver transmittance, liver area, hepatocyte apoptosis and hepatocyte vacuolation. Male adult zebrafish displayed a higher Em8G-induced hepatotoxicity than female zebrafish, as demonstrated by the higher mortality and histopathological alterations. The results of transcriptomics combined with metabolomics showed that Em8G mainly affected carbohydrate metabolism (such as TCA cycle) in male zebrafish and amino acid metabolism (such as arginine and proline metabolism) in females, suggesting that the difference of energy metabolism disorder may be the potential mechanism of male and female liver toxicity induced by Em8G. CONCLUSIONS: This study provided the direct evidence for the hepatotoxicity of Em8G to zebrafish models in vivo, and brought a new insight into the molecular mechanisms of Em8G hepatotoxicity, which can guide the rational application of this phytotoxin. In addition, our findings revealed gender differences in the hepatotoxicity of Em8G to zebrafish, which is related to energy metabolism and provided a methodological reference for evaluating hepatotoxic drugs with gender differences.

Role of the circular RNA regulatory network in the pathogenesis of biliary atresia.

Circular RNAs (circRNAs) serve an essential role in the occurrence and development of cholangiocarcinoma, but the expression and function of circRNA in biliary atresia (BA) is not clear. In the present study, circRNA expression profiles were investigated in the liver tissues of patients with BA as well as in the choledochal cyst (CC) tissues of control patients using RNA sequencing. A total of 78 differentially expressed circRNAs (DECs) were identified between the BA and CC tissues. The expression levels of eight circRNAs (hsa_circ_0006137, hsa_circ_0079422, hsa_circ_0007375, hsa_circ_0005597, hsa_circ_0006961, hsa_circ_0081171, hsa_circ_0084665 and hsa_circ_0075828) in the liver tissues of the BA group and control group were measured using reverse transcription-quantitative polymerase chain reaction. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that the identified DECs are involved in a variety of biological processes, including apoptosis and metabolism. In addition, based on the GO and KEGG pathway enrichment analyses, it was revealed that target genes that can be affected by circRNAs regulatory network were enriched in the TGF-ß signaling pathway, EGFR tyrosine kinase inhibitor resistance pathway and transcription factor regulation pathway as well as other pathways that may be associated with the pathogenesis of BA. The present study revealed that circRNAs are potentially implicated in the pathogenesis of BA and could help to find promising targets and biomarkers for BA.

Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis.

Metastasis is the main culprit of cancer-related death and account for the poor prognosis of hepatocellular carcinoma. Although platelets have been shown to accelerate tumor cell metastasis, the exact mechanism remained to be fully understood. Here, we found that high blood platelet counts and increased tumor tissue ADAM10 expression indicated the poor prognosis of HCC patients. Meanwhile, blood platelet count has positive correlation with tumor tissue ADAM10 expression. In vitro, we revealed that platelet increased ADAM10 expression in tumor cell through TLR4/NF-κB signaling pathway. ADAM10 catalyzed the shedding of CX3CL1 which bound to CX3CR1 receptor, followed by inducing epithelial to mesenchymal transition and activating RhoA signaling in cancer cells. Moreover, knockdown HCC cell TLR4 (Tlr4) or inhibition of ADAM10 prevented platelet-increased tumor cell migration, invasion and endothelial permeability. In vivo, we further verified in mice lung metastatic model that platelet accelerated tumor metastasis via cancer cell TLR4/ADAM10/CX3CL1 axis. Overall, our study provides new insights into the underlying mechanism of platelet-induced HCC metastasis. Therefore, targeting the TLR4/ADAM10/CX3CL1 axis in cancer cells hold promise for the inhibition of platelet-promoted lung metastasis of HCC.

Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications.

Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.

Lactobacillus-derived indole-3-lactic acid ameliorates colitis in cesarean-born offspring via activation of aryl hydrocarbon receptor.

Cesarean section (CS) delivery is known to disrupt the transmission of maternal microbiota to offspring, leading to an increased risk of inflammatory bowel disease (IBD). However, the underlying mechanisms remain poorly characterized. Here, we demonstrate that CS birth renders mice susceptible to dextran sulfate sodium (DSS)-induced colitis and impairs group 3 innate lymphoid cell (ILC3) development. Additionally, CS induces a sustained decrease in Lactobacillus abundance, which subsequently contributes to the colitis progression and ILC3 deficiency. Supplementation with a probiotic strain, L. acidophilus, or its metabolite, indole-3-lactic acid (ILA), can attenuate intestinal inflammation and restore ILC3 frequency and interleukin (IL)-22 level in CS offspring. Mechanistically, we indicate that ILA activates ILC3 through the aryl hydrocarbon receptor (AhR) signaling. Overall, our findings uncover a detrimental role of CS-induced gut dysbiosis in the pathogenesis of colitis and suggest L. acidophilus and ILA as potential targets to re-establish intestinal homeostasis in CS offspring.

Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption.

Osteoporosis has a profound influence on public health. First-line bisphosphonates often cause osteonecrosis of the jaw meanwhile inhibiting osteoclasts. Therefore, it is important to develop effective treatments. The results of this study showed that the increased level of NFATc1 m6A methylation caused by zoledronic acid (ZOL), with 4249A as the functional site, is highly correlated with the decreased bone resorption of osteoclasts. Upstream, METTL14 regulates osteoclast bone absorption through the methylation functional site of NFATc1. Downstream, YTHDF1 and YTHDF2 show antagonistic effects on the post-transcriptional regulation of NFATc1 after the m6A methylation level is elevated by METTL14. In this study, meRIP-Seq, luciferase reporter assays, meRIP and other methods were used to elucidate the NFATc1 regulatory mechanism of osteoclasts from the perspective of RNA methylation. In addition, EphA2 overexpression on exosomes is an effective biological method for targeted delivery of METTL14 into osteoclasts. Importantly, this study shows that METTL14 released by exosomes can increase the m6A methylation level of NFATc1 to inhibit osteoclasts, help postmenopausal osteoporosis patients preserve bone mass, and avoid triggering osteonecrosis of the jaw, thus becoming a new bioactive molecule for the treatment of osteoporosis.

Genome-wide identification and expression analysis of the GASA gene family in Chinese cabbage (Brassica rapa L. ssp. pekinensis).

BACKGROUND: The Gibberellic Acid-Stimulated Arabidopsis (GASA) gene family is widely involved in the regulation of plant growth, development, and stress response. However, information on the GASA gene family has not been reported in Chinese cabbage (Brassica rapa L. ssp. pekinensis). RESULTS: Here, we conducted genome-wide identification and analysis of the GASA genes in Chinese cabbage. In total, 15 GASA genes were identified in the Chinese cabbage genome, and the physicochemical property, subcellular location, and tertiary structure of the corresponding GASA proteins were elucidated. Phylogenetic analysis, conserved motif, and gene structure showed that the GASA proteins were divided into three well-conserved subfamilies. Synteny analysis proposed that the expansion of the GASA genes was influenced mainly by whole-genome duplication (WGD) and transposed duplication (TRD) and that duplication gene pairs were under negative selection. Cis-acting elements of the GASA promoters were involved in plant development, hormonal and stress responses. Expression profile analysis showed that the GASA genes were widely expressed in different tissues of Chinese cabbage, but their expression patterns appeared to diverse. The qRT-PCR analysis of nine GASA genes confirmed that they responded to salt stress, heat stress, and hormonal triggers. CONCLUSIONS: Overall, this study provides a theoretical basis for further exploring the important role of the GASA gene family in the functional genome of Chinese cabbage.

Longitudinal change trend of the TCR repertoire reveals the immune response intensity of the inactivated COVID-19 vaccine.

Evidence concerning the individual differences in neutralizing antibody responses after receiving the COVID-19 vaccine remains lacking. In this study, we collected the serum and Peripheral blood mononuclear cells(PBMC) of 16 subjects who had never suffered from COVID-19 before during the course of two vaccine doses. Microneutralization assay is used to determine the immune response intensity of vaccine subjects. we revealed the change trend of TCR diversity using T cell receptor (TCR) sequencing. Then, we analyzed the correlation between HLA class II allele frequencies and the intensity of immune response. Finally, we identified several CDR3 sequences related to the intensity of the immune response. We analyzed the differences in D50 (DD50) between different time points, and found that there were two patterns in the change trend of TCR diversity, and the increased diversity group has stronger immune response. The inactivated vaccine is different from the mRNA vaccine against the spike protein, resulting in differences in TCR repertoire response patterns and antibody responses, which are related to HLA-DRB1 * 09:01. The presence of specific CDR3 sequences in the increased diversity group, rather than gene usage of the VJ gene, determines the intensity and persistence of neutralizing antibody titers. Finally, We identified the different response patterns of the human TCR repertoire to inactivated vaccines. The pattern with increased diversity is more likely to appear strong and more lasting immune response.

Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization.

Neuropathic pain (NP) is a common pain disease that seriously affects the quality of life and physical and mental health of patients. Daphnetin is extracted from the Daphne giraldii Nitsche and has the structure of 7,8-dihydroxy coumarin. As a natural product, daphnetin displays a wide range of pharmacological activities, such as analgesia and anti-inflammatory activities, but whether it is able to improve NP through anti-inflammatory effects is unknown. Therefore, this paper intends to investigate the mechanism of daphnetin in improving NP rats affected by the intrathecal injection of tumor necrosis factor-α (TNF-α) from the perspective of anti-inflammation. Our results showed that daphnetin significantly improved hyperalgesia in NP rats. Daphnetin inhibited the activation and polarization of glial cells and neurons in the spinal cord of NP rats and reduced the expression of mRNA and protein of inflammatory factors and chemokine pairs in the spinal cord. Daphnetin inhibited the polarization of human microglia cell 3 (HMC3) cells and human glioma cells (U251) cells toward M1 microglia and A1 astrocytes, respectively, and induced the conversion of M1 microglia and A1 astrocytes to M2 microglia and A2 astrocytes, respectively. In conclusion, daphnetin ameliorates NP by inhibiting the expression of inflammatory factors and chemokines and the polarization of glial cells in the spinal cord of NP rats. This study provides a theoretical basis for the treatment of NP with daphnetin to expand the clinical application of daphnetin.

CircUTRN24/miR-483-3p/IGF-1 Regulates Autophagy Mediated Liver Fibrosis in Biliary Atresia.

Biliary atresia (BA) is a rare neonatal cholestatic disease that presents with a marked bile duct reaction and rapid fibrotic development. Our earlier research has shown that circUTRN24 is highly elevated in BA, but the exact molecular mechanism is still unknown. This study attempted to investigate whether circUTRN24 induces BA liver fibrosis through regulation of autophagy and to elucidate its molecular mechanism. Using TGF-ß-treated hepatic stellate cells (HSC) LX-2, we created a liver fibrosis model. qRT-PCR was used to analyze the expression of circUTRN24, miR-483-3p, and IGF-1. Western blot analysis was used to assess the expression of IGF-1, HSC activation-related proteins, and autophagy-related proteins. The TGF-ß-induced LX-2 cell fibrosis model was then supplemented with circUTRN24 siRNA, miR-483-3p mimics, and the autophagy activator Rapamycin, and functional rescue tests were carried out to investigate the role of circUTRN24, miR-483-3p, and autophagy in BA liver fibrosis. Using a luciferase reporter assay, a direct interaction between miR-483-3p and circUTRN24 or IGF-1 was discovered. With the increase of TGF-ß treatment concentration, circUTRN24 expression also gradually increased, as did HSC activation and autophagy-related protein. si-circUTRN24 significantly decreased circUTRN24 expression and inhibited HSC activation and autophagy, which was reversed by Rapamycin. Through bioinformatics prediction and validation, we found circUTRN24 might act through miR-483-3p targeting IGF-1 in the autophagy-related mTOR pathway. Furthermore, miR-483-3p mimics significantly increased miR-483-3p expression and inhibited HSC activation and autophagy, which were reversed by Rapamycin. Functional rescue experiments showed that si-circUTRN24 inhibited circUTRN24 and IGF-1 expressions and promoted miR-483-3p expression, while the miR-483-3p inhibitor abolished these effects. These findings imply that circUTRN24/miR-483-3p/IGF-1 axis mediated LX-2 cell fibrosis by regulating autophagy.

Parthenolide targets NLRP3 to treat inflammasome-related diseases.

Natural products have attracted extensive attention from researchers in medical fields due to their abundant biological activities. Parthenolide (PTL) is a sesquiterpene lactone originally purified from herb Feverfew (Tanacetum parthenium), recent studies have showed its potential activities of anti-cancer and anti-inflammatory. Acting as the most studied inflammasome, NLRP3 inflammasome played an important role in human diseases including type-2 diabetes (T2D), Alzheimer's disease (AD) and cryopyrin-associated periodic syndromes (CAPS). In this article, we show that PTL specially inhibits the activation of NLRP3 inflammation by block the upstream signal and prevent the assembly of NLRP3 inflammasome complex. Furthermore, we showed the treatment of PTL significantly attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation and dextran sulfate sodium (DSS)-induced colitis in mice models. Thus, our results demonstrate that PTL alleviates inflammation by targeting NLRP3 inflammasome, which indicate that PTL acting as a promising natural product for the treatment of NLRP3 inflammasome-related diseases.

Identification of hsa-miR-619-5p and hsa-miR-4454 in plasma-derived exosomes as a potential biomarker for lung adenocarcinoma.

Introduction: Lung cancer has long been at the forefront of all cancers in terms of incidence and mortality. Lung adenocarcinoma is the most common type of lung cancer, accounting for 40% of all lung cancer types. Exosomes can act as biomarkers of tumors and thus play an important role. Methods: In this article, high-throughput sequencing of miRNAs in plasma exosomes from lung adenocarcinoma patients and healthy individuals was performed to obtain 87 upregulated miRNAs, which were then combined with data from the GSE137140 database uploaded by others for screening. The database included 1566 preoperative lung cancer patients, 180 postoperative patients, and 1774 non-cancerous controls. We overlapped the miRNAs upregulated in the serum of lung cancer patients in the database relative to those of non-cancer controls and post-operative patients with the upregulated miRNAs obtained from our next-generation sequencing to obtain nine miRNAs. Two miRNAs that were not reported as tumor markers in lung cancer, hsa-miR-4454 and hsa-miR-619-5p, were selected from them and then validated by qRT-PCR, and further analysis of miRNAs was performed using bioinformatics. Results: Real-time quantitative PCR showed that the expression levels of hsa-miR-4454 and hsa-miR-619-5p in plasma exosomes of patients with lung adenocarcinoma were significantly up-regulated. The AUC values of hsa-miR-619-5p and hsa-miR-4454 were 0.906 and 0.975, respectively, both greater than 0.5, showing good performance. The target genes of miRNAs were screened by bioinformatics methods, and the regulatory network between miRNAs and lncRNAs and mRNAs was studied. Discussion: Our work demonstrated that hsa-miR-4454 and hsa-miR-619-5p have the potential to be used as biomarkers for the early diagnosis of lung adenocarcinoma.

C:N:P stoichiometric characteristics of mosses in Picea crassifolia forest in Helan Mountains, Ningxia, China.

To explore the stoichiometric characteristics of C, N and P and adaptive mechanism of mosses in mountain forest ecosystems, we set up 15 plots along the altitude gradient in Picea crassifolia forest in Helan Mountains, Ningxia. We analyzed the C:N:P stoichiometry of moss aboveground tissues and its relationship with environmental factors. The results showed the mean values of C, N and P concentration in moss aboveground tissues were 336.67, 20.31 and 0.66 mg·g-1, respectively. The mean value of aboveground tissue N:P was 33.4, indicating that the growth of mosses was limited by P. The C concentration in the aboveground tissues of mosses was positively correlated with soil total nitrogen concentration and negatively correlated with soil total phosphorus concentration. The N concentration in aboveground tissues of mosses was significantly negatively correlated with soil organic carbon and soil total nitrogen concentrations. Results of redundancy analysis showed that the interpretation rate of environmental factors on the stoichiometry was 48.5%, with canopy closure, soil total nitrogen and soil total phosphorus as the main factors. Canopy closure was the main environmental factor affecting the growth of mosses in P. crassifolia forest in Helan Mountains. High canopy closure facilitated the growth of mosses.

Prefrontal Cortex Hemodynamics and Functional Connectivity Changes during Performance Working Memory Tasks in Older Adults with Sleep Disorders.

OBJECTIVE: Older adults with sleep disorders (SDs) show impaired working memory abilities, and working memory processes are closely related to the prefrontal cortex (PFC). However, the neural mechanism of working memory impairment in older adults with SD remains unclear. This study aimed to investigate changes in PFC function among older adults with SD when carrying out the N-back task by functional near-infrared spectroscopy (fNIRS). METHOD: A total of 37 older adults with SDs were enrolled in this study and matched with 37 healthy older adults by gender, age, and years of education. Changes in PFC function were observed by fNIRS when carrying out the N-back task. RESULTS: The accuracy on the 0-back and 2-back tasks in the SD group was significantly lower than that in the healthy controls (HC) group. The oxygenated hemoglobin (oxy-Hb) concentration of channel 8 which located in the dorsolateral prefrontal cortex (DLPFC) was significantly reduced in the SD group during the 2-back task, and the channel-to-channel connectivity between the PFC subregions was significantly decreased. CONCLUSIONS: These results suggest that patients with sleep disorders have a weak performance of working memory; indeed, the activation and functional connectivity in the prefrontal subregions were reduced in this study. This may provide new evidence for working memory impairment and brain function changes in elderly SDs.

The biomarkers related to immune infiltration to predict distant metastasis in breast cancer patients.

Background: The development of distant metastasis (DM) results in poor prognosis of breast cancer (BC) patients, however, it is difficult to predict the risk of distant metastasis. Methods: Differentially expressed genes (DEGs) were screened out using GSE184717 and GSE183947. GSE20685 were randomly assigned to the training and the internal validation cohort. A signature was developed according to the results of univariate and multivariate Cox regression analysis, which was validated by using internal and external (GSE6532) validation cohort. Gene set enrichment analysis (GSEA) was used for functional analysis. Finally, a nomogram was constructed and calibration curves and concordance index (C-index) were compiled to determine predictive and discriminatory capacity. The clinical benefit of this nomogram was revealed by decision curve analysis (DCA). Finally, we explored the relationships between candidate genes and immune cell infiltration, and the possible mechanism. Results: A signature containing CD74 and TSPAN7 was developed according to the results of univariate and multivariate Cox regression analysis, which was validated by using internal and external (GSE6532) validation cohort. Mechanistically, the signature reflect the overall level of immune infiltration in tissues, especially myeloid immune cells. The expression of CD74 and TSPAN7 is heterogeneous, and the overexpression is positively correlated with the infiltration of myeloid immune cells. CD74 is mainly derived from myeloid immune cells and do not affect the proportion of CD8+T cells. Low expression levels of TSPAN7 is mainly caused by methylation modification in BC cells. This signature could act as an independent predictive factor in patients with BC (p = 0.01, HR = 0.63), and it has been validated in internal (p = 0.023, HR = 0.58) and external (p = 0.0065, HR = 0.67) cohort. Finally, we constructed an individualized prediction nomogram based on our signature. The model showed good discrimination in training, internal and external cohort, with a C-index of 0.742, 0.801, 0.695 respectively, and good calibration. DCA demonstrated that the prediction nomogram was clinically useful. Conclusion: A new immune infiltration related signature developed for predicting metastatic risk will improve the treatment and management of BC patients.

Effects of ionic valence on aggregation kinetics of colloidal particles with and without a mixing flow.

HYPOTHESIS: The classical Schulze-Hardy rule states that the critical coagulation concentration (CCC) of colloidal particles is inversely proportional to the counter-ionic valence at powers ranging from 2 to 6. However, the inverse Schulze-Hardy rule has recently been proposed, suggesting that the CCC can also be inversely proportional to the co-ionic valence. Previous studies on these rules did not consider the effect of flow on aggregation kinetics and the CCC. This study aims to investigate the effect of multivalent counter-ions and co-ions on aggregation kinetics and the CCCs in systems with and without a mixing flow. EXPERIMENTS: We measured the aggregation rate coefficients of polystyrene sulfate latex particles as a function of the salt concentration with different ionic species. Furthermore, we analyzed these measurements using theoretical models based on hydrodynamic pair-diffusion in a random flow and trajectory analysis in two steady flows. The analysis was conducted using zeta potentials determined through electrophoretic measurements. FINDINGS: Although the trajectory analysis underestimates the CCCs, the hydrodynamic pair-diffusion model can capture the shift of critical coagulation concentrations in the mixing flow to higher values than those in Brownian aggregation and also shows a better agreement with the experimental results. This result suggests that combining random flow and Brownian diffusion is crucial for developing a consistent framework for predicting both Brownian aggregation and aggregation in a mixing flow.

Bioinspired Total Synthesis of Complex Nucleoside Antibiotics A201A, A201D and A201E.

Herein, bioinspired total syntheses of A201A, A201D, and A201E based on a previously reported biosynthetic pathway are presented. The challenging 1,2-cis-furanoside, a core structure of the A201 family, was obtained by remote 2-quinolinecarbonyl-assisted glycosylation. We accomplished the total synthesis of A201A and A201E based on the critical 1,2-cis-furanoside moiety through late-stage glycosylation without any interference from basic dimethyl adenosine. We also confirmed the absolute configuration of A201E by total synthesis. This modular synthesis strategy enables efficient preparation of A201 family antibiotics, allowing the study of their structure-activity relationships and mode of action. This study satisfies the increasing demand for developing novel antibiotics inspired by the A201 family.

Copper-Catalyzed Difluoroalkylation Reaction.

This review describes recent advances in copper-catalyzed difluoroalkylation reactions. The RCF2 radical is generally proposed in the mechanism of these reactions. At present, various types of copper-catalyzed difluoroalkylation reactions have been realized. According to their characteristics, we classify these difluoroalkylation reactions into three types.

Effects of exercise interventions on executive function in old adults with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.

AIMS: To assess the effect of exercise interventions on subdomains of executive function (EF) in older adults with mild cognitive impairment (MCI). METHODS: Nine electronic databases were comprehensively searched from their inception to February 2021. Randomized controlled trials examining the effect of exercise training on EF in MCI were included. RESULTS: Twenty-four eligible articles involving 2278 participants were identified. The results showed that exercise interventions had positive benefits on working memory, switching and inhibition in MCI. Subgroup analysis based on exercise prescriptions revealed that both aerobatic exercise and mind-body exercise had similar positive effect size on working memory. However, only mind-body exercise had significant effect on switching. Exercise training with moderate frequency (3-4 times/week) had larger effect size than low frequency (1-2 times/week) and only moderate frequency had positive benefits on switching. Both short (4-12 weeks), medium (13-24 weeks) and long (more than 24 weeks) exercise duration significantly ameliorate working memory and switching, however with short duration having slight larger effect sizes than medium and long. CONCLUSION: Exercise significantly improves three subdomains of EF in MCI, especially mind-body exercise. Exercise training sticking to at least 4 weeks with 3-4 times a week tends to have larger effect size.