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Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP–AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS–IFN–MEF2C axis to improve resilience against AD-related pathological insults.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

Purpose The aim of this study is to measure the trajectory of healthy ageing among Chinese middle-aged and older population, and explore the disparity of the trajectory, as well as contributing factors, between urban and rural areas in China. Methods A total of 9402 respondents aged 45 years and older interviewed in four waves (2011, 2013, 2015 and 2018) were selected from the China Health and Retirement Longitudinal Study. Healthy ageing score was calculated through item response theory. A latent growth mixture model (LGMM) was applied to distinguish the trajectory of healthy aging. A multinomial logistics regression model (MLRM) was used to explore the relationship between urban-rural areas and healthy aging trajectories, and further to explore associated factors in rural and urban areas separately. Results The healthy ageing score was lower in rural areas than urban areas in each survey wave. Five classes (“continuing-low”, “continuing-middle”, “continuing-middle-to-high”, “significantly-declining”, “continuing-high”) were grouped through LGMM. The MLRM results showed that urban living was significantly associated with a higher likelihood of being healthy (for [continuing-low/continuing-high]: β = − 1.17, RRR = 0.31, P P Conclusion Healthy ageing is a prominent objective in the development of a country, and rural-urban disparities are an essential obstacle to overcome, with the rural population more likely to develop a low level of healthy ageing trajectory. Prevention and standardized management of chronic diseases should be enhanced, and social participation should be encouraged to promote healthy ageing. The policy inclination and resource investment should be enhanced to reduce disparity in healthy ageing between urban and rural areas in China.

This study was designed to investigate the anti-inflammatory effects of volatile oil of Platycladus orientalis (L.) Franco leaves (VOPF) and the underlying molecular mechanisms by using the non-infectious inflammation rat models and infectious inflammation mouse models. Ear swelling and intraperitoneal capillary permeability in mice, and carrageenan-induced toe swelling and cotton ball-induced granuloma in rats were used to reveal anti-inflammatory effects of VOPF. Moreover, the lipopolysaccharide (LPS)-induced mouse model of acute lung injury was used to explore the anti-inflammatory mechanism of VOPF. The results showed that VOPF could significantly inhibit auricular swelling, intraperitoneal capillary permeability in mice, and reduce granuloma swelling and paw swelling in rats. Furthermore, it significantly alleviated the pathological damage of the lung tissue. In addition, VOPF could reduce the contents of IL-1β and TNF-α and increase the content of IL-10 in the serum. It had little effect on the expression of p65 but reduced the phosphorylation level of p65 and IκB in NF-κB pathway. In conclusion, VOPF has anti-inflammatory effects and the mechanisms involve the down-regulation of the phosphorylation levels of p65 and IκB and blockage of the NF-κB signaling pathway.

Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

Neurodegenerative diseases cause progressive loss of cognitive and/or motor function and pose major challenges for societies with rapidly aging populations. Human genetics studies have shown that disease-causing rare mutations and risk-associated common alleles overlap in different neurodegenerative disorders. Here we review the intricate genotype-phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies. Shared pathological mechanisms include defective protein quality-control and degradation pathways, dysfunctional mitochondrial homeostasis, stress granules, and maladaptive innate immune responses. Research efforts have started to bear fruit, as shown by recent treatment successes and an encouraging therapeutic outlook.

Aiming at the serious deformation problem of the roadway supported along gob-side by stowing with high-water-content packing on the engineering background of No. 1200 working face, the technologies of supporting beside the roadway by stowing with high-water-content packing and relieving pressure by roof-cutting along gob-side entry are applied in different sections respectively. Based on the engineering geological conditions of the working face, the roof-cutting parameter is calculated and some technologies have been put into use in the project: high constant resistance and large deformation (CRLD) cable supporting technology; bilateral cumulative tensile explosion technology; gangue blocking supporting technology. Arm-shortening beam resulting from roof-cutting cuts down the cantilever beam length of roadway roof. CRLD cable supporting can effectively improve the mechanical properties of roof strata. The roof collapses smoothly within the height of cutting seam along the gob-side entry, filling the gob with gangue quickly. The point where the gob roof touches the collapsed gangue moves toward the remained roadway side and the subsiding and rotary deformation problem of gangue-formed wall gets under control and the subsiding level is reduced. Compared with the original backfilling body, the collapsed gangue weakens the level of stress concentration. Meanwhile, the subsiding of minor roofs and the roof strengthening can dramatically reduce the bottom heave. Engineering practice has proved that in such mining geological conditions, the method of releasing pressure by roof-cutting along gob-side entry can effectively decrease the deformation of the retained roadways, greatly reduce the workload, enhance productivity and guarantee the remarkable benefit of retaining roadway economy.

CoPd nanocatalysts were synthesized by a successive reduction using poly(vinylpyrrolidone) as stabilizer. The structure, morphology, and composition of CoPd nanocatalysts were characterized by transmission electron microscopy (TEM), high-resolution TEM, X-ray powder diffraction (XRD), energy dispersive X-ray spectroscopy (EDS), and inductively coupled plasma mass spectrometry (ICP-MS). The CoPd nanocatalysts showed electrocatalytic performance for methanol oxidation in alkaline medium. The electrocatalytic performance was weakened after dealloying process in acidic solution. The balance of the dealloying effect and the alloying effect should be accentuated in this field in the future.

A novel coordination polymer [Pb(1,4-phda)]n (1) has been hydrothermally synthesized through the reaction of 1,4-phenylenediacetic acid (1,4-H2phda) with divalent lead salt and characterized by IR spectra, elemental analysis and single crystal X-ray diffraction. The crystal structure of complex (1) shows a novel three-dimensional framework with 4, 4-connected 3D PtS topology. Moreover, this framework is reinforced by C–H···O hydrogen bonds and Pb2+···π interaction. The thermal stability of the complex 1 was studied by thermal gravimetric analyses, and the photoluminescent property of complex 1 was also investigated.

An exercise-linked hormone, FNDC5/irisin, mediates the benefit of exercise in Alzheimer’s disease models by enhancing synaptic plasticity and memory.

Extended naive Bayesian classifier (ENBC) is a general framework of NBCs, which is developed based on $$t$$ -norm based ordered weighted averaging ( $$t$$ -OWA) operator and uses the weighted summation of products of margin probabilities to determine class-conditional probability. Since ENBC was proposed in 2006, there is no such a study which tests the performances of ENBC on the real classification datasets. Thus, in this paper we conduct an experimental investigation to ENBC’s generalization capability based on 44 benchmark KEEL and UCI datasets. The analysis shows that (1) ENBC is instable and its aggregation weights are sensitive to the order of training samples and (2) ENBC indeed has higher generalization capability than the existing NBCs, e.g., normal naive Bayesian and flexible naive Bayesian when its weight is properly selected.

A new strain isolated from activated sludge and identified as Burkholderia vietnamiensis C09V was used to biodegrade crystal violet (CV) from aqueous solution. To understand the degradation pathways of CV, batch experiments showed that the degradation using B. vietnamiensis C09V significantly depended on conditions such as pH, initial dye concentration and media components, carbon and nitrogen sources. Acceleration in the biodegradation of CV was observed in presence of metal ions such as Cd and Mn. More than 98.86C of CV (30 mg l−1) was degraded within 42 h at pH 5 and 30 °C. The biodegradation kinetics of CV corresponded to the pseudo first-order rate model with a rate constant of 0.046 h−1. UV–visible and Fourier transform infrared spectroscopy (FTIR) were used to identify degradation metabolites. Which further confirmed by LC-MS analysis, indicating that CV was biodegraded to N,N-dimethylaminophenol and Michler’s ketone prior to these intermediates being further degraded. Finally, the ability of B. vietnamiensis C09V to remove CV in wastewater was demonstrated. Refereed/Peer-reviewed

Mobile sources contribute large percentages of each pollutant, but technol- ogy is not yet available to measure and tax emissions from each vehicle. We build a behavioral model of household choices about vehicles and miles traveled. The ideal- but-unavailable emissions tax would encourage drivers to abate emissions through many behaviors, some of which involve market transactions that can be observed for feasible market incentives (such as a gas tax, subsidy to new cars, or tax by vehicle type). Our model can calculate behavioral effects of each such price and thus calculate car choices, miles, and emissions. A nested logit structure is used to model discrete choicesamongdifferentvehiclebundles.Wealsoconsidercontinuouschoicesofmiles driven and the age of each vehicle. We propose a consistent estimation method for both discrete and continuous demands in one step, to capture the interactive effects of simultaneous decisions. Results are compared with those of the traditional sequential estimation procedure.

Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau's ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.

Based on the significant differences in the resistance to Sclerotinia sclerotiorum between two Brassica napus cultivars, ZhongR888 and Zhongyou821, near isogenic lines (NILs) were established. The resistance differences between Zhongyou821 and BC5 progeny (the fifth generation from a cross between Zhongyou821 and ZhongR888 with Zhongyou821 as successive backcross parent) was displayed by cDNA-AFLP and differential transcripts-derived fragments (TDFs). The full-length cDNA of 1,707 bp with 1,323 bp open reading frame (ORF, open box), named Rsk was identified by RT-RACE from the resistance related fragment 40-2 in Zhongyou821. It encoded a protein of 440 amino acid residues, which contained a putative extracellular domain, a transmembrane domain, and an intracellular domain. Analysis of the deduced amino acid sequence of Rsk revealed that it had high homology to Arabidopsis thaliana kinase involved in protein binding, and had a conserved region of LRR-RI, indicating it might be a member of leucine-rich repeats, ribonuclease inhibitor-like subfamily. DNA sequences of 1,685 bp and 1,703 bp without an intron were also identified from Zhongyou821 and BC5, respectively. Expression analysis showed that Rsk might play a role in disease resistance pathways.

Adaptive predistortion of nonlinear systems described using Hammerstein and Wiener models is considered in this paper. The adaptive predistorter is modeled as a Wiener or Hammerstein system, respectively. The parameters of the linear and nonlinear blocks of the predistorter are estimated simultaneously using the Nonlinear Filtered-x Prediction Error Method (NFxPEM) algorithm. The NFxPEM algorithm is derived under the assumption that the parameters of the Wiener and Hammerstein predistorters are changing slowly during adaptation. Simulation study shows that the suggested predistorter using the NFxPEM algorithm can well compensate nonlinear distortion and effectively reduce spectral regrowth. Moreover, the suggested NFxPEM algorithm achieves much better results as compared to the Nonlinear Filtered-x Least Mean Squares (NFxLMS) algorithm.

Aging is the predominant risk factor for major neurodegenerative diseases. The underlying mechanisms are largely unknown. Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend lifespan when upregulated. Sirtuins are involved in fundamental mechanisms in age-related neurodegenerative diseases, including protein aggregation and homeostasis, survival and stress responses, and inflammatory processes. In this review, we will discuss the neurobiology of sirtuins and their multifaceted roles in the pathogenesis of neurodegenerative diseases. We will also examine the potential and challenges of targeting sirtuin pathways to treat these devastating conditions.

To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P(app) compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36+/-38.93 ng.mL(-1).min.microg(-1), which was significantly higher than that of FB Na eye drops (P0.01). Compared with FB Na eye drops, the T(max) of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P0.001).This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.

In this paper, ion-exclusion chromatography with electrospray ionization mass spectrometry was investigated as an alternative method to confirm and determine sugar (glucose, fructose and sucrose) using volatile acidic eluent. Under the positive or negative ionization mode, the ESI-MS provided reasonable signals from positive ion mode as [M+H]+ and [M+NH4]+, or from negative ion mode as [M−H]− and [M+Cl–H]−. However, higher mass spectral intensity for ions was obtained under the positive mode. The separation of target sugars was achieved within 8 min using an eluent containing 0.1% (v/v) acetic acid. Linear plots of peak area versus concentration were obtained over the range 20–5,000 μg L−1. The detection limits of these compounds ranged from 10 to 15 μg L−1. The proposed method was used for the confirmation and quantification of sugars in soft drinks.

Redispersible, dry emulsion of lovastatin protects against intestinal metabolism and improves bioavailability