Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.

Alzheimer's disease (AD) has recently been associated with diverse cell states1-11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-ß proteinopathy while the other mediates the effect of amyloid-ß on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.

Chiral Binaphthol-Catalyzed Enantioselective Conjugate Addition of Alkenyl and Arylboronic Acids to α,ß-Unsaturated Cyclic N-Sulfonyl Ketimines.

The chiral binaphthol-catalyzed enantioselective conjugate addition of alkenylboronic acids and heteroarylboronic acids to cyclic N-sulfonyl ketimines is reported, providing the 1,4-addition products in high yields and moderate to excellent enantioselectivities (up to >99% ee). This mild, scalable catalytic system exhibits high efficiency and broad substrate scopes. Additionally, arylboronic acids were viable nucleophiles under more forcing conditions.

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-ß proteinopathy while the other mediated the effect of amyloid-ß in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

The Association between Physical Exercise during Pregnancy and Maternal and Neonatal Health Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: To explore the effect of exercise during pregnancy on the maternal and neonatal health outcomes. Methods: Eligible papers were systematically retrieved from PubMed, Embase, OVID, and ScienceDirect. Two researchers independently extracted the primary endpoints from the included literature. Random-effect model or fixed-effect model were utilized to generate and compute relative risk and mean difference, as appropriate. Publication bias was quantified and assessed using the funnel plot with Egger's test. Results: This study included 13 literatures with a total of 3047 pregnant women with gestational weeks more than 10 weeks. The incidence of vaginal delivery was significantly higher in the intervention group than that in the control group (28.7% vs 23.3%, P < 0.001). The differences of duration of the first stage and second stage of labor between the interventional group and control group were both statistically insignificant (mean difference: 27.92, 95% CI: - 70.60, 14.7, P = 0.20; mean difference: 0.63, 95% CI: - 4.47, 5.74, P = 0.81). In addition, there were no significant differences with regard to gestational age at delivery (mean difference = -0.23, 95% CI: - 1.29, 0.83, P = 0.67), Apgar score (mean difference = 0.06, 95% CI: - 0.13, 0.26, P = 0.53), and birth weight (mean difference = -23.78, 95% CI: - 60.66, 13.11, P = 0.21) between the 2 groups. Women in the intervention group were more likely to experience vaginal delivery than the control group (RR = 1.27, 95% CI: 1.04, 1.55, P = 0.01). Conclusions: Physical exercise during pregnancy could improve the incidence of natural labor.

Comparison of (poly)phenolic compounds and antioxidant properties of pomace extracts from kiwi and grape juice.

The aim of this study was to evaluate the phenolic profile of grape and kiwi juice pomace by HPLC-ESI-MS, and their correlation with antioxidant properties determined with DPPH, FRAP and OH scavenging assays. A total of 32 compounds have been identified including anthocyanins, flavonols, flavan-3-ols and phenolic acids. Significantly higher relative amounts of anthocyanin monoglucosides, flavan-3-ols (catechin, epicatechin, and procyanidin), and flavonols (quercetin and its derivatives) were found for grape pomace. Whereas kiwi pomace contained higher amounts of quinic acid, caffeic acid and its derivatives. Although grape pomace had higher total phenolic content (TPC), it showed lower OH scavenging capacity than kiwi pomace, but better DPPH scavenging activity and reducing power. This indicated that the antioxidant activities do not only rely on the TPC but also associate with their phenolic profiles. Overall the two pomaces could potentially be exploited as an inexpensive source of natural antioxidants for food production.

Comparison of Furans Formation and Volatile Aldehydes Profiles of Four Different Vegetable Oils During Thermal Oxidation.

The evolution of volatile aldehydes and the conversion of oxygenated ityß-unsaturated aldehydes (OαßUAs) into furans were compared in four vegetable oils (soybean oil, olive oil [OVO], peanut oil [PO], and perilla oil [PAO]) thermally oxidized at temperatures of 150, 180, and 210 °C for 10 hr/day over a 3-day period. Results showed that 2 alkyl furans and 23 volatile aldehydes including 4 toxic OdßUAs were detected by GC-MS. The original fatty acid compositions of the oils played a key role in the type and concentration of those volatile compounds. 4-Hydroxy-2-hexenal (HHE) and ethyl furan were only detected in PAO with a high content of linolenic acid, while the greatest level of pentyl furan was detected in PO with abundant linoleic acid. Greater amounts of 4-hydroxy-(E)-2-nonenal (HNE) and 4-oxo-(E)-2-nonenal (ONE) were formed in the OVO with abundant oleic acid. The close relativity of HHE and ethyl furan was also demonstrated. With principal component analysis, these vegetable oils could be discriminated based on their fatty acids and volatile compounds. The loading plot confirmed that HHE and ethyl furan were derived from the linolenic acid oxidation and degradation. PRACTICAL APPLICATION: The chemometric results showed that the formation of the volatile components during heating in different vegetable oils has close correlation with the original fatty acids composition of vegetable oils. Our research has also confirmed the presence of toxic OɑßUAs in oils after heating. Considering that they are proven to generate lots of degenerative diseases, further studies are needed to establish the risk level of using certain oils in frying and seek effective methods to inhibit their formation.

Prediction of fatty acid composition in camellia oil by 1H NMR combined with PLS regression.

A rapid method for the determination of fatty acid (FA) composition in camellia oils was developed based on the 1H NMR technique combined with partial least squares (PLS) method. Outliers detection, LVs optimization and data pre-processing selection were explored during the model building process. The results showed the optimal models for predicting the content of C18:1, C18:2, C18:3, saturated, unsaturated, monounsaturated and polyunsaturated FA were achieved by Pareto scaling (Par) pretreatment, with correlation coefficient (R2) above 0.99, the root mean square error of estimation and prediction (RMSEE, RMSEP) lower than 0.954 and 0.947, respectively. Mean-centering (Ctr) was more suitable for the model of C16:0 and C18:0 with the best performance indicators (R2 ≥ 0.945, RMSEE ≤ 0.377, RMSEP ≤ 0.212). This study indicated that 1H NMR has the potential to be applied as a rapid and routine method for the analysis of FA composition in camellia oils.

miR-431 inhibits adipogenic differentiation of human bone marrow-derived mesenchymal stem cells via targeting insulin receptor substance 2.

BACKGROUND: An understanding of the mechanism underlying adipogenic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) will provide new therapeutic approaches for many diseases, including osteoporosis. This study aimed to investigate the role of miR-431 in adipogenic differentiation of hMSCs. METHODS: hMSCs were induced for adipogenic differentiation and miR-431 was detected by polymerase chain reaction (PCR). hMSCs were transfected by miR-431 or small interfering RNA (siRNA) for insulin receptor substance 2 (IRS2). The expression of IRS2 was detected by PCR and Western blot analysis. The targeting of the 3'-untranslated region (UTR) of IRS2 by miR-431 was examined by luciferase assay. RESULTS: miR-431 expression was decreased during adipogenesis of hMSCs. Overexpression of miR-431 inhibited adipogenic differentiation, accompanied by the downregulation of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), two key regulators of adipogenesis. Moreover, miR-431 decreased both protein and mRNA levels of IRS2. The expression of IRS2 was increased during adipogenic differentiation of hMSCs in conjunction with decreased levels of miR-431, and knockdown of IRS2 in hMSCs inhibited adipogenic differentiation. Luciferase assay confirmed that miR-431 targeted the 3'-UTR of IRS2 in hMSCs. CONCLUSIONS: This is the first study to show that miR-431 inhibits adipogenic differentiation of hMSCs via targeting IRS2.

Chemistry and biology of deoxy-myo-inositol phosphates: stereospecificity of substrate interactions within an archaeal and a bacterial IMPase.

Six enantiomerically pure myo-inositol-monophosphates, including four deoxygenated analogues, have been synthesized by employing catalytic asymmetric phosphorylation methodology. These compounds were then evaluated as substrates for the direct interrogation of the stereospecificity of enzyme-substrate interactions with two inositol-monophosphatases (IMPases), one of which (from Archaeoglobus fulgidus) is characterized by an X-ray crystal structure with its substrate (d-I-1P) bound. The kinetic results lead to the finding that certain hydroxyl group contacts are actually destabilizing, while others have little effect. These new probes also allow a prediction of the active site binding mode of the substrate for the Escherichia coli IMPase for which no crystal structure exists.