REDUCED CHLOROPLAST COVERAGE proteins are required for plastid proliferation and carotenoid accumulation in tomato.

Increasing the amount of cellular space allocated to plastids will lead to increases in the quality and yield of crop plants. However, mechanisms that allocate cellular space to plastids remain poorly understood. To test whether the tomato (Solanum lycopersicum L.) REDUCED CHLOROPLAST COVERAGE (SlREC) gene products serve as central components of the mechanism that allocates cellular space to plastids and contribute to the quality of tomato fruit, we knocked out the four-member SlREC gene family. We found that slrec mutants accumulated lower levels of chlorophyll in leaves and fruit, accumulated lower levels of carotenoids in flowers and fruits, allocated less cellular space to plastids in leaf mesophyll and fruit pericarp cells, and developed abnormal plastids in flowers and fruits. Fruit produced by slrec mutants initiated ripening later than wild type and produced abnormal levels of ethylene and ABA. Metabolome and transcriptome analyses of slrec mutant fruit indicated that the SlREC gene products markedly influence plastid-related gene expression, primary and specialized metabolism, and the response to biotic stress. Our findings and previous work with distinct species indicate that REC proteins help allocate cellular space to plastids in diverse species and cell types and, thus, play a central role in allocating cellular space to plastids. Moreover, the SlREC proteins are required for the high-level accumulation of chlorophyll and carotenoids in diverse organs, including fruit, promote the development of plastids, and influence fruit ripening by acting both upstream and downstream of ABA biosynthesis in a complex network.

scGAL: unmask tumor clonal substructure by jointly analyzing independent single-cell copy number and scRNA-seq data.

BACKGROUND: Accurately deciphering clonal copy number substructure can provide insights into the evolutionary mechanism of cancer, and clustering single-cell copy number profiles has become an effective means to unmask intra-tumor heterogeneity (ITH). However, copy numbers inferred from single-cell DNA sequencing (scDNA-seq) data are error-prone due to technically confounding factors such as amplification bias and allele-dropout, and this makes it difficult to precisely identify the ITH. RESULTS: We introduce a hybrid model called scGAL to infer clonal copy number substructure. It combines an autoencoder with a generative adversarial network to jointly analyze independent single-cell copy number profiles and gene expression data from same cell line. Under an adversarial learning framework, scGAL exploits complementary information from gene expression data to relieve the effects of noise in copy number data, and learns latent representations of scDNA-seq cells for accurate inference of the ITH. Evaluation results on three real cancer datasets suggest scGAL is able to accurately infer clonal architecture and surpasses other similar methods. In addition, assessment of scGAL on various simulated datasets demonstrates its high robustness against the changes of data size and distribution. scGAL can be accessed at: https://github.com/zhyu-lab/scgal . CONCLUSIONS: Joint analysis of independent single-cell copy number and gene expression data from a same cell line can effectively exploit complementary information from individual omics, and thus gives more refined indication of clonal copy number substructure.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and ß-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Mild Stereoselective Synthesis of Densely Substituted [3]Dendralenes via Ru-Catalyzed Intermolecular Dimerization of 1,1-Disubstituted Allenes.

Described here is a mild and stereoselective protocol for the synthesis of [3]dendralenes via the intermolecular dimerization of allenes. With the proper choice of a ruthenium catalyst, a range of unactivated 1,1-disubstituted allenes, without prefunctionalization in the allylic position, reacted efficiently to provide rapid access to densely substituted [3]dendralenes. An intermolecular C-C bond and three different types of C═C double bonds (di-, tri-, and tetrasubstituted) embedded in an acyclic structure were constructed with good to high E/Z stereocontrol. This is in contrast to the known catalytic protocols that focus on allenes with prefunctionalization at the allylic position and/or monosubstituted allenes, which would proceed by a different mechanism or require less stereocontrol. The silyl-substituted dendralene products are precursors of other useful dendralene molecules. Density functional theory (DFT) studies and control experiments supported a mechanism involving oxidative cyclometalation, ß-H elimination (the rate-determining step), and reductive elimination.

Experimentally Delineating the Catalytic Effect of a Single Water Molecule in the Photochemical Rearrangement of the Phenylperoxy Radical to the Oxepin-2(5H)-one-5-yl Radical.

Catalysis plays a pivotal role in both chemistry and biology, primarily attributed to its ability to stabilize transition states and lower activation free energies, thereby accelerating reaction rates. While computational studies have contributed valuable mechanistic insights, there remains a scarcity of experimental investigations into transition states. In this work, we embark on an experimental exploration of the catalytic energy lowering associated with transition states in the photorearrangement of the phenylperoxy radical-water complex to the oxepin-2(5H)-one-5-yl radical. Employing matrix isolation spectroscopy, density functional theory, and post-HF computations, we scrutinize the (photo)catalytic impact of a single water molecule on the rearrangement. Our computations indicate that the barrier heights for the water-assisted unimolecular isomerization steps are approximately 2-3 kcal mol-1 lower compared to the uncatalyzed steps. This decrease directly coincides with the energy difference in the required wavelength during the transformation (Δλ = λ546 nm - λ579 nm ≡ 52.4-49.4 = 3.0 kcal mol-1), allowing us to elucidate the differential transition state energy in the photochemical rearrangement of the phenylperoxy radical catalyzed by a single water molecule. Our work highlights the important role of water catalysis and has, among others, implications for understanding the mechanism of organic reactions under atmospheric conditions.

First-Principles Calculations of the Effect of γ-Alumina Surface Hydroxyl Structures on the Location and Dechlorination of a Platinum Precursor.

The interaction between Pt precursors and alumina support is an important step in synthesizing Pt/Al2O3 catalysts, while an in-depth understanding of the interaction is still lacking. Herein, density functional theory (DFT) calculations were performed to simulate the coordination of H2PtCl6 with different surface hydroxyl groups, revealing the influence of the γ-Al2O3 surface hydroxyl structure on the position of the Pt precursor and the removal of Cl ligands. After drying, the interaction mechanism between [PtCl6]2- and alumina support involves hydrogen bonds and van der Waals forces, which are the main driving forces for the structural transformation from [PtCl6]2- coordinated with the surface hydroxyl group into the PtClx(OH)y species (OH is the γ-Al2O3 surface group). HO-µ1-AlVI and H2O-µ1-AlVI on the (100) surface with electrophilicity facilitate hauling and activating the electron-rich [PtCl6]2-, but the nucleophilic (110) surface has a weaker interaction with [PtCl6]2-. Combining free energy and electronic property analysis, the stable structures on the (100) surface after drying treatment are PtCl4(OH)2 and PtCl3(OH)3, while only PtCl4(OH)2 structures can be formed on the (110) surface. This study can deepen our understanding of the interaction mechanism between Al-hydroxyl groups and Pt precursors, providing a theoretical reference for the precise placement of Pt active phases and the construction of metal-support interfaces.

Associations between Chinese visceral adiposity index and risks of all-cause and cause-specific mortality: A population-based cohort study.

AIM: To determine the associations between the Chinese visceral adiposity index (CVAI) and the risks of all-cause and cause-specific mortality. MATERIALS AND METHODS: A total of 3 916 214 Chinese adults were enrolled in a nationwide population cohort covering all 31 provinces of mainland China. The CVAI was calculated based on age, body mass index, waist circumference, and triglyceride and high-density lipoprotein cholesterol concentrations. We used a Cox proportional hazards regression model to determine the hazard ratios and 95% confidence intervals (CIs) for risk of mortality associated with different CVAI levels. RESULTS: The median follow-up duration was 3.8 years. A total of 86 158 deaths (34 867 cardiovascular disease [CVD] deaths, 29 884 cancer deaths, and 21 407 deaths due to other causes) were identified. In general, after adjusting for potential confounding factors, a U-shaped relationship between CVAI and all-cause mortality was observed by restricted cubic spline (RCS). Compared with participants in CVAI quartile 1, those in CVAI quartile 4 had a 23.0% (95% CI 20.0%-25.0%) lower risk of cancer death, but a 23.0% (95% CI 19.0-27.0) higher risk of CVD death. In subgroup analysis, a J-shaped and inverted U-shaped relationship for all-cause mortality and cancer mortality was observed in the group aged < 60 years. CONCLUSIONS: The CVAI, an accessible indicator reflecting visceral obesity among Chinese adults, has predictive value for all-cause, CVD, and cancer mortality risks. Moreover, the CVAI carries significance in the field of health economics and secondary prevention. In the future, it could be used for early screening purposes.

Astrocytic phagocytosis of myelin debris and reactive characteristics in vivo and in vitro.

BACKGROUND INFORMATION: Persistent myelin debris can inhibit axonal regeneration, thereby hindering remyelination. Effective removal of myelin debris is essential to eliminate the interference of myelin debris in oligodendrocyte progenitor cell (OPC) activation, recruitment to demyelinating sites and/or differentiation into mature oligodendrocytes (OLs). In addition to microglia, it has been reported that astrocytic phagocytosis of myelin debris is a feature of early demyelination. RESULTS: In the present study, astrocytes effectively phagocytized myelin debris in vitro and in vivo. On the 5th day after injecting myelin debris into the brain, astrocytes were enriched in the area injected with myelin debris compared with microglia, and their ability to engulf myelin debris was stronger than that of microglia. When exposed to myelin debris, astrocytes phagocytizing myelin debris triggered self-apoptosis, accompanied by the activation of NF-κB, down-regulation of Nrf2, and the increase of ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF). However, the activation of astrocytic NF-κB did not influence the inflammatory cytokines IL-1ß, IL-6, and TNF-α, and the anti-inflammatory factor IL-10. The proliferation of astrocytes and mobilization of OPCs in the subventricular zone were elevated on the 5th day after intracerebral injection of myelin debris. CONCLUSIONS: The results suggested that myelin phagocytosis of astrocytes should help improve the microenvironment and promote myelin regeneration by increasing CNTF and bFGF within the central nervous system. SIGNIFICANCE: However, the molecular interaction of astrocytes acting as phagocytes remains to be further explored. Therefore, an improvement of astrocytes to phagocytize myelin debris may be a promising treatment measure to prevent demyelination and promote remyelination in MS and other diseases with prominent myelin injury.

Bibliometric Analysis of Stem Cells in Ischemic Stroke (2001-2022): Trends, Hotspots and Prospects.

Background: Ischemic stroke is a common cerebrovascular accident with a high risk of neurological deficits. Stem cell therapy has progressively attracted the interest of scientists and clinicians due to the benefits of promoting neural regeneration and regulating the microenvironment surrounding the lesion after ischemic stroke. Our study aimed to evaluate the development trends and research hotspots in the field of stem cells and ischemic stroke. Materials and methods: Publications related to stem cells and ischemic stroke were retrieved from the Web of Science from 2001 to 2022. Data analysis and mapping were performed using VOSviewer, Citespace and ImageGP. Results: In total, 1932 papers were included in the analysis. Publications have steadily increased over the past 22 years. China has contributed the maximum number of publications, whereas the USA ranked first in the total number of citations and was considered the center of the international collaboration network. University of South Florida, Henry Ford Hospital, and Oakland University were the most influential institutions. Stroke, Brain Research, and Neural Regeneration Research were the most productive journals. The research in this field was primarily focused on the effects of stem cells on neurogenesis, inflammation, and angiogenesis following ischemic stroke, as well as their therapeutic potential for the disease. In addition, neural stem cells and mesenchymal stem cells are the most commonly utilized stem cells. The topics related to miRNA, extracellular vesicles, exosomes, mesenchymal stem cells, neuroinflammation, and autophagy are current research hotspots. Conclusion: Our bibliometric study provides a novel perspective on the research trends in the field of stem cells and ischemic stroke. The outcome of this study may benefit scientists to identify research hotspots and development directions, thereby advancing the application of stem cell-based therapy for ischemic stroke.

Exosomal MicroRNAs modulate the cognitive function in fasudil treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aß) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aß plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aß plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments.

Icariin ameliorates the cuprizone-induced demyelination associated with antioxidation and anti-inflammation.

The treatment of immunomodulation in multiple sclerosis (MS) can alleviate the severity and relapses. However, it cannot improve the neurological disability of patients due to a lack of myelin protection and regeneration. Therefore, remyelinating therapies may be one of the feasible strategies that can prevent axonal degeneration and restore neurological disability. Natural product icariin (ICA) is a flavonol compound extracted from epimedium flavonoids, which has neuroprotective effects in several models of neurological diseases. Here, we attempt to explore whether ICA has the potential to treat demyelination and its possible mechanisms of action using lipopolysaccharide-treated BV2 microglia, primary microglia, bone marrow-derived macrophages, and cuprizone-induced demyelination model. The indicators of oxidative stress and inflammatory response were evaluated using commercial kits. The results showed that ICA significantly reduced the levels of oxidative intermediates nitric oxide, hydrogen peroxide, malondialdehyde, and inflammatory cytokines TNF-α, IL-1ß, and increased the levels of antioxidants superoxide dismutase, catalase, glutathione peroxidase, and anti-inflammatory cytokines IL-10 and TGF-ß in vitro cell experiments. In vivo demyelination model, ICA significantly alleviated the behavioral abnormalities and enhanced the integrated optical density/mm2 of Black Gold II and myelin basic protein myelin staining, accompanied by the inhibition of oxidative stress/inflammatory response. Immunohistochemical staining showed that ICA significantly induced the expression of nuclear factor erythroid derived 2/heme oxygenase-1 (Nrf2/HO-1) and inhibited the expression of toll-like receptor 4/ nuclear factor kappa B (TLR4/NF-κB), which are two key signaling pathways in antioxidant and anti-inflammatory processes. Our results strongly suggest that ICA may be used as a potential agent to treat demyelination via regulating Nrf2/HO-1-mediated antioxidative stress and TLR4/NF-κB-mediated inflammatory responses.

[Tetramethylpyrazine regulates angiogenesis of endothelial cells in cerebral ischemic stroke injury via SIRT1/VEGFA signaling pathway].

This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P<0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P<0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P<0.05, P<0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P<0.05, P<0.01, P<0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.

Ir-Catalyzed Regioselective Dihydroboration of Thioalkynes toward Gem-Diboryl Thioethers.

While 1,1-diboryl (gem-diboryl) compounds are valuable synthetic building blocks, currently, related studies have mainly focused on those 1,1-diboryl alkanes without a hetero functional group in the α-position. gem-Diboryl compounds with an α-hetero substituent, though highly versatile, have been limitedly accessible and thus rarely utilized. Herein, we have developed the first α-dihydroboration of heteroalkynes leading to the efficient construction of gem-diboryl, hetero-, and tetra-substituted carbon centers. This straightforward, practical, mild, and atom-economic reaction is an attractive complement to the conventional multistep synthetic strategy relying on deprotonation of gem-diborylmethane by a strong base. Specifically, [Ir(cod)(OMe)]2 was found to be uniquely effective for this process of thioalkynes, leading to excellent α-regioselectivity when delivering the two boryl groups, which is remarkable in view of the many competitive paths including monohydroboration, 1,2-dihydroboration, dehydrodiboration, triboration, tetraboration, etc. Control experiments combined with DFT calculations suggested that this process involves two sequential hydroboration events. The second hydroboration requires a higher energy barrier due to severe steric repulsion in generating the highly congested α-sulfenyl gem-diboryl carbon center, a structural motif that was almost unknown before.

Time-Varying Effect of Physical Activity on Mortality Among Myocardial Infarction Survivors: A Nationwide Population-Based Cohort Study.

Background: Physical activity (PA) is an important component of secondary prevention after myocardial infarction (MI). The mortality risk of MI survivors varies at different post-MI periods, yet the time-varying effect of total PA is unclear. We aimed to investigate the association between different volumes and patterns of total PA and mortality at different post-MI periods. Methods: Using data from the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project, we divided the screened MI survivors into within-1-year and beyond-1-year groups based on the duration between their baseline interview and MI onset. Total PA was divided into insufficient ( < 3000 metabolic equivalent of task [MET] minutes/week) and sufficient PA. Sufficient PA was further categorized as moderate and high (3000-4500 and > 4500 MET minutes/week) volumes; leisure ( ≥ 50%) and non-leisure ( > 50%) patterns. Data on mortality were derived from the National Mortality Surveillance System and Vital Registration of the Chinese Center for Disease Control and Prevention. Cox proportional hazard models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline regression analyses were performed to examine the dose-response association between PA and mortality. Results: During the follow-up (median 3.7 years) of the 20,653 post-MI patients, 751 patients died. In the within-1-year group, moderate (HR: 0.59, 95% CI: 0.40 to 0.88) and high (0.63, 0.45 to 0.88) volumes and both patterns (leisure: 0.52, 0.29 to 0.94; non-leisure: 0.64, 0.46 to 0.88) of PA were all associated with significantly lower risk of mortality, compared with insufficient PA. In the beyond-1-year group, the association was observed in high volume (0.69, 0.56 to 0.86) and both patterns (leisure: 0.64, 0.48 to 0.87; non-leisure: 0.79, 0.65 to 0.97). A non-linear relationship between PA and mortality was found in the within-1-year group (p for non-linearity < 0.001), while a linear relationship was demonstrated in the beyond-1-year group (p for non-linearity = 0.107). Conclusions: Sufficient total PA was associated with mortality risk reduction after MI, either leisure or non-leisure pattern. Different dose-response associations between PA and mortality were found at different post-MI periods. These results could promote individualized and scientifically derived secondary prevention strategies for MI.

Experiment and Computational Study on Pd-Catalyzed Methoxyiminoacyl-Directed γ-Alkoxylation of Alkylamides.

The direct alkoxylation of amides has been accomplished via methoxyiminoacyl (MIA)-mediated Pd-catalyzed C-H functionalization. A diverse array of alkylamide substrates is amenable to this protocol, providing γ-C(sp3)-alkoxylation of alkylamide derivatives with good to high efficiency. Two aspects of the research were completed to explore the reaction mechanism. On the one hand, the result of the kinetic isotopic effect experiment and control experiment indicated that reductive elimination is a rate-limiting step. On the other hand, density functional theory calculations demonstrated that a concerted Sn2 reductive elimination mechanism pathway is prior. Finally, the MIA group could be efficiently hydrogenated and protected in a one-pot procedure, which provides a short synthetic route to γ-methoxy amino acid derivatives.

Drug-induced microglial phagocytosis in multiple sclerosis and experimental autoimmune encephalomyelitis and the underlying mechanisms.

Microglia are resident macrophages of the central nervous system (CNS). It plays a significant role in immune surveillance under physiological conditions. On stimulation by pathogens, microglia change their phenotypes, phagocytize toxic molecules, secrete pro-inflammatory/anti-inflammatory factors, promotes tissue repair, and maintain the homeostasis in CNS. Accumulation of myelin debris in multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE) inhibits remyelination by decreasing the phagocytosis by microglia and prevent the recovery of MS/EAE. Drug induced microglia phagocytosis could be a novel therapeutic intervention for the treatment of MS/EAE. But the abnormal phagocytosis of neurons and synapses by activated microglia will lead to neuronal damage and degeneration. It indicates that the phagocytosis of microglia has many beneficial and harmful effects in central neurodegenerative diseases. Therefore, simply promoting or inhibiting the phagocytic activity of microglia may not achieve ideal therapeutic results. However, limited reports are available to elucidate the microglia mediated phagocytosis and its underlying molecular mechanisms. On this basis, the present review describes microglia-mediated phagocytosis, drug-induced microglia phagocytosis, molecular mechanism, and novel approach for MS/EAE treatment.

Median effective dose (ED50) of esketamine combined with propofol for children to inhibit response of gastroscope insertion.

BACKGROUND: Propofol is the most commonly used drug for procedural sedation during gastroscopy. However, independent use of propofol can lead to increased dosage and additional side effects. Esketamine was found to be exceptional in combination with propofol for painless gastroscopy. No studies have calculated the median effective dose (ED50) of esketamine combined with propofol in pediatric painless gastroscopy. Here, we designed a research to study the ED50 of esketamine combined with propofol using the Dixon and Massey up-and-down sequential method for inhibiting the response of gastroscope insertion. METHODS: Children who met the inclusion and exclusion criteria were included in this study. Propofol and esketamine were used as anesthetics for painless gastroscopy in children. To explore the ED50, the initial propofol dose was set at 3 mg/kg in all children. The first child was given an esketamine dose of 0.1 mg/kg, followed by 30 s of slow bolus injection propofol. If anesthesia induction failed (coughing or body movement of children during gastroscope insertion), the esketamine dose was elevated in the next child, with a interval difference of 0.05 mg/kg. Otherwise, if the anesthesia induction was successful, the next dosage was reduced by 0.05 mg/kg. The study was stopped if nine crossover inflection points were reached. The ED50 of esketamine was calculated using probit regression, and the blood pressure, pulse oxygen saturation, heart rate, recovery time, and side effects were recorded in all children. RESULTS: A total of 26 children were included in this study. The ED50 of esketamine combined with 3 mg/kg propofol was 0.143 mg/kg (95% CI 0.047-0.398 mg/kg). The total consumption of propofol was 16.04 ± 5.37 mg. The recovery time was 16.38 ± 8.70 min. Adverse effects recorded were delayed awakening in two cases and increased oral secretions of another child during the examination inducing cough and hypoxemia (86% was the lowest). DISCUSSION: The ED50 of esketamine was 0.143 mg/kg when combined with 3 mg/kg propofol for successful sedation in pediatric gastroscope insertion. This sub-anaesthetic dose of esketamine was safe and efficacious with few complications in pediatric painless gastroscopy. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ; registration number: ChiCTR2100052830 on 06/11/2021).

AHI estimation of OSAHS patients based on snoring classification and fusion model.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a chronic and common sleep-breathing disease that could negatively influence lives of patients and cause serious concomitant diseases. Polysomnography(PSG) is the gold standard for diagnosing OSAHS, but it is expensive and requires overnight hospitalization. Snoring is a typical symptom of OSAHS. This study proposes an effective OSAHS screening method based on snoring sound analysis. Snores were labeled as OSAHS related snoring sounds and simple snoring sounds according to real-time PSG records. Three models were used, including acoustic features combined with XGBoost, Mel-spectrum combined with convolution neural network (CNN), and Mel-spectrum combined with residual neural network (ResNet). Further, the three models were fused by soft voting to detect these two types of snoring sounds. The subject's apnea-hypopnea index (AHI) was estimated according to these recognized snoring sounds. The accuracy and recall of the proposed fusion model achieved 83.44% and 85.27% respectively, and the predicted AHI has a Pearson correlation coefficient of 0.913 (R2 = 0.834, p < 0.001) with PSG. The results demonstrate the validity of predicting AHI based on analysis of snoring sound and show great potential for monitoring OSAHS at home.

Ru-Catalyzed Hydroboration of Ynones Leads to a Nontraditional Mode of Reactivity.

Although hydroboration of simple ketones and alkynes have been well-established, little is known about the unique hydroboration reactivity for ynones, a family of important building blocks. Herein we report a new reaction mode of ynones leading to structurally novel and synthetically useful but previously inaccessible products, vinyl α-hydroxylboronates, under mild ruthenium-catalyzed hydroboration conditions. This reaction features high efficiency, a broad scope, and complete chemo-, regio-, and stereoselectivity, in spite of many possible competitive pathways. Both control experiments and detailed DFT studies suggested a two-step mechanism, involving initial rate-determining conjugate addition of hydroborane to form the key boryl allenolate intermediate followed by a fast second hydroboration of the enolate motif of the allenolate. Notably, direct 1,4-addition of hydroborane to carbonyl-conjugated alkynes also represents a new mode of reactivity. Despite the overwhelming complexity of this process, which involves selectivity control in almost every step, a thorough and detailed computation on a large set of possible transition states explained the unusual reactivity and intrinsic origin of selectivity.

Higher systolic blood pressure is specifically associated with better islet beta-cell function in T2DM patients with high glycemic level.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) usually have higher blood viscosity attributed to high blood glucose that can decrease blood supply to the pancreas. A mild increase in blood pressure (BP) has been reported as a potential compensatory response that can maintain blood perfusion in the islet. However, how BP influences beta-cell function in T2DM subjects remains inconsistent. This study aimed to examine the relationship between BP and beta-cell function in patients with T2DM under different HbA1c levels. METHODS: This is a cross-sectional study of 615 T2DM patients, whose clinical data were extracted from hospital medical records. Beta-cell function was assessed by insulin secretion-sensitivity index-2 (ISSI2). Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between systolic BP (SBP) and ISSI2. Mediation analysis was performed to determine whether higher SBP could reduce blood glucose by enhancing beta-cell function. RESULTS: After adjustment of potential confounders, in participants with HbA1c ≥ 10%, the SBP between 140 to150 mmHg had the highest log ISSI2 (b = 0.227, 95% CI 0.053-0.402), an association specific to participants with < 1 year duration of diabetes. RCS analyses demonstrated an inverted U-shaped association between SBP and ISSI2 with the SBP at 144 mmHg corresponding to the best beta-cell function. This higher SBP was "paradoxically" associated with lower 2 h postprandial blood glucose (PBG) when SBP < 150 mmHg that was almost exclusively mediated by ISSI2 (mediating effect = - 0.043, 95%CI - 0.067 to - 0.018; mediating effect percentage = 94.7%, P < 0.01). SBP was however not associated with improvement in ISSI2 or 2 h PBG in participants with HbA1c < 10%. CONCLUSIONS: In early stage of diabetes, a slightly elevated SBP (140-150 mmHg) was transiently associated with better beta-cell function in T2DM patients with HbA1c ≥ 10% but not in those with HbA1c < 10%.