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Poststroke cognitive impairment (PSCI) occurs frequently after stroke, but lacks effective treatments. Previous studies have revealed that high-frequency repetitive transcranial magnetic stimulation (rTMS) has a beneficial effect on PSCI and is often used with other cognitive training methods to improve its effect. This study aimed to evaluate the effect of different combinations of rTMS and cognitive training (rTMS-COG) on PSCI and identify the optimal combination protocol. A cerebral infarction rat model was established by transient middle cerebral artery occlusion (tMCAO). The Morris water maze test was conducted to assess the cognitive function of rats. RNA sequencing and bioinformatics analysis were employed to study the underlying mechanisms. rTMS, COG and rTMS-COG all had beneficial effects on PSCI, while cognitive training immediately after rTMS (rTMS-COG0h) achieved a better effect than cognitive training 1 h and 4 h after rTMS, rTMS and COG. We identified 179 differentially expressed genes (DEGs), including 24 upregulated and 155 downregulated genes, between the rTMS-COG0h and rTMS groups. GO analysis revealed that the major categories associated with the DEGs were antigen procession and presentation, regulation of protein phosphorylation and axoneme assembly. KEGG analysis showed that the DEGs were enriched in processes related to phagosome, circadian entrainment, dopaminergic synapse, apelin signaling pathway, long-term depression, neuroactive ligand-receptor interaction, axon guidance and glucagon signaling pathway. PPI analysis identified Calb2, Rsph1, Ccdc114, Acta2, Ttll9, Dnah1, Dlx2, Dlx1, Ccdc40 and Ccdc113 as related genes. These findings prompt exploration of the potential mechanisms and key genes involved in the effect of rTMS-COG0h on PSCI.

Poststroke cognitive impairment (PSCI) occurs frequently after stroke, but effective treatments are lacking. Previous studies have revealed that high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has a beneficial effect on PSCI, but the mechanism is unclear. This study aimed to evaluate the effect of 10 and 20 Hz HF-rTMS on PSCI and the possible mechanisms. An ischemic stroke rat model was established by transient middle cerebral artery occlusion (tMCAO). The modified neurological deficit score (mNSS) and Morris water maze tests were conducted to assess neurological function and cognitive function. Luxol Fast Blue (LFB) staining was performed to evaluate white matter damage. Proinflammatory and anti-inflammatory cytokines were measured using enzyme-linked immunosorbent assays (ELISA). Immunofluorescence was used to assess microglial activation and polarization. Western blotting was performed to measure JAK2-STAT3 pathway-related protein expression. We found that HF-rTMS decreased the neurological deficit score. Compared with 10 Hz HF-rTMS, 20 Hz HF-rTMS more markedly improved the cognitive function of tMCAO rats at day 28 after operation. Furthermore, 20 Hz HF-rTMS attenuates white matter lesion, decreased proinflammatory cytokine levels, and increased anti-inflammatory cytokine levels. It also decreased the number of CD68- and CD16/32-positive microglia and increased the number of CD206-positive microglia. In addition, p-JAK2, JAK2, p-STAT3 and STAT3 expression was increased. These findings suggest that HF-rTMS improves cognitive function and attenuates white matter lesion in tMCAO rats by shifting microglia toward the M2 phenotype. Mechanisms may be related to regulation JAK2-STAT3 pathways.

The pig breeding industry is one of the pillar industries of China's agriculture. The measurement of pig production efficiency, and the way to improve pig production efficiency through the measurement, thereby reducing pollution emissions, is of great significance to the development of China's pig industry. Existing research focuses on measuring the efficiency of pig breeding, while ignores the emissions of large amounts of pollutants in the breeding process, as well as the heterogeneity of scale and region. In view of this, based on the DEA model, this paper constructs a three-level Metafrontier-Malmquist-Luenberger index to evaluate the green total factor productivity of pig breeding (PBG) by considering negative output. The results indicate that: (i) China's PBG, overall, dropped by 0.34% from 2004 to 2018. In terms of scale, large-scale was the highest, medium-sized was the second and small-scale was the lowest. (ii) China's PBG is distributed in a stepped manner, with the highest in the eastern area, the second in the central area, and the lowest in the western area. The differences between regions and provinces are affected by factors, such as the level of economic development, the government's emphasis on the scale of pig breeding and local resource conditions. (iii) The three decomposition efficiencies of PBG are manifested in the decline of scale structure efficiency and management efficiency, and the improvement of technical efficiency. Among them, the low efficiency of scale structure is the leading reason for the decline of overall PBG. According to the above empirical results, this article finally puts forward policy suggestions and environmental protection recommendations for pig breeding to improve PBG.

Running wheel exercise training (RWE) and skilled reaching training (SRT) are physical training approaches with positive effects on cognitive function. However, few studies have compared the different effects of these exercises on long-term memory, and their mechanism remains unknown. This study investigated the effects of SRT and RWE, at the recovery stage, on the cognitive function of transient middle cerebral artery occlusion (tMCAO) rats and explored their association with NgR1/Rho-A/ROCK/LOTUS/LGI1 signaling. Adult Sprague-Dawley rats (n = 55) were divided into four groups after pretraining: SRT, RWE, tMCAO, and Sham. Rats were subjected to modified neurological severity score (mNSS) measurements and forelimb grip strength and the Morris water maze tests. Using immunofluorescence and western blotting, we evaluated axonal growth inhibitor expression in the peri-infarct cortex on days 28 and 56 after tMCAO. Results showed the mNSS reduced, whereas the grip strengths improved in RWE and SRT groups. The escape latency in the Morris water maze test was shorter, whereas the number of times of crossing the platform was higher in both the SRT and RWE groups than in the tMCAO group on day 56; furthermore, the parameters in the SRT group improved compared to those in the RWE group. Physical exercise training could improve cognitive functions by reducing the expression of the NgR1/RhoA/ROCK axon growth inhibitors and increasing the expression of the endogenous antagonists LOTUS/LGI1. Exercise training beginning at the recovery stage could improve the cognitive function in tMCAO rats through a mechanism probably associated with the axonal growth inhibitor pathway.

The type I pepsin-soluble collagen (type I PSC) from the red drum fish (Sciaenops ocellatus) scales was successfully purified by hydrophilic ultrafiltration (UF). The collagen purification process was appraised in depth and described in detail, respectively. Based on SDS-PAGE analysis, using proteomics analysis and Isoform-sequencing (Iso-Seq), it was confirmed to be the type I PSC, containing collagen α1 and α2 chains as the single components, with the absence of the non- collagenous proteins, non-type I collagens and potentially allergenic proteins. The type I PSC was verified to be non-denatured collagen monomers with integrated triple-helical structure using gel filtration chromatography (GFC), ion-exchange chromatography (IEC), reversed-phase HPLC (RP-HPLC), fourier transform infrared spectroscopy (FTIR), matrix-assisted laser desorption ionization-time of flight/mass spectrometry (MALDI-TOF/MS) and amino acid composition analysis. Thus, the accurate primary structures of the type I PSC with 100% matched peptide coverage were obtained for the first time. Additionally, our current study is the first to illustrate the protein component changes in collagen induced by hydrophilic UF and the primary structure changes in collagen molecules induced by pepsin solubilization.

Liguzinediol (2,5-dihydroxymethyl-3,6-dimethylpyrazine, LZDO) is a potential agent for the low-risk treatment of heart failure. 2-N-acetylcysteine-LZDO (2-NAC-LZDO) and 2-cysteine-LZDO (2-Cys-LZDO) are major LZDO metabolites found in the pharmacokinetic studies of rats and beagle dogs. To elucidate the biotransformation pathway and related enzymes, an incubation system with 3′-phosphoadenosine-5′-phosphosulfate (PAPS) as a cofactor and N-acetylcysteine (NAC) as a trapping agent was established using liver cytosol. An ultra-flow liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UFLC-QTOF-MS) method was used to identify the major metabolites. 2-NAC-LZDO could be detected among four species (humans, monkeys, dogs, and rats) and is the dominant metabolite in human liver cytosol (HLC). The sulfotransferase (SULT) inhibitors 2,6-dichloro-4-nitrophenol (DCNP) and quercetin at a concentration of 1 μM, suppressed 2-NAC-LZDO formation in HLC by 87 and 46%, respectively. This result suggested that sulfotransferase was involved in 2-NAC-LZDO formation. The metabolism of LZDO in different species indicated that SULT activity in dogs, rats, and monkeys was higher than that in humans. Further SULT phenotyping revealed that SULT1A1 is the predominant enzyme involved in the sulfation of LZDO. The underlying mechanism for the biotransformation of LZDO was demonstrated. The potential pathway is via the sulfation of LZDO to form sulfate, and the spontaneous cleavage of the sulfate group to generate highly reactive electrophilic cations, which can bind to NAC to form the major metabolites.

Inhibition of the interactions of the tumor suppressor protein p53 with its negative regulators MDM2 in vitro and in vivo, representing a valuable therapeutic strategy for cancer treatment. The natural product chalcone exhibited moderate inhibitory activity against MDM2, thus based on the binding mode between chalcone and MDM2, a hit unsaturated pyrrolidone scaffold was obtained through virtual screening. Several unsaturated pyrrolidone derivatives were synthesized and biological evaluated. As a result, because the three critical hydrophobic pockets of MDM2 were occupied by the substituted-phenyl linked at the pyrrolidone fragment, compound 4 h demonstrated good binding affinity with the MDM2. Additionally, compound 4 h also showed excellent antitumor activity and selectivity, and no cytotoxicity against normal cells in vitro. The further antitumor mechanism studies were indicated that compound 4 h could successfully induce the activation of p53 and corresponding downstream p21 proteins, thus successfully causing HCT116 cell cycle arrest in the G1/M phase and apoptosis. Thus, the novel unsaturated pyrrolidone p53-MDM2 inhibitors could be developed as novel antitumor agents.

China is a large country of egg consumption, the study on China's laying hens breeding green total factor productivity (LHBG) is conducive to reducing pollution emissions while improving the productivity of laying hens to promote the cleaner production. Obviously, existing studies on laying hens breeding neglect regional and scale differences as well as serious pollution issues. Therefore, based on the directional distance function (DDF) - Data Envelopment Analysis (DEA) model, this paper constructs a three-level Metafrontier-Malmquist-Luenberger (MML) index, considering negative output, to evaluate LHBG from 2004 to 2018. Firstly, in terms of scale, the results show that LHBG is the largest in middle scale, followed by small scale and large scale. Secondly, from a regional point of view, the results indicate that China's LHBG presents a reverse stair-step distribution, that is, LHBG is the lowest in the eastern region, followed by the central region and the highest in the western region. The differences between regions and provinces are affected by the traditional farming habits, non-agricultural employment opportunities, the level of urbanization and resource conditions. Thirdly, this paper obtained that the three decomposition efficiencies of LHBG are manifested as the decrease in management efficiency, and the increase in scale structure efficiency and technical efficiency. Fourthly, climate factors have an impact on the laying hens breeding. According to the empirical results, this paper finally puts forward policy suggestions for improving LHBG and environmental protection policy recommendations for layer breeding.

In the present study, the chemical compositions of Atractylodes macrocephala Koidz. (AMK) were analyzed systematically and influence of sulfur fumigation on the chemical profiles was evaluated by ultrafast flow liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UFLC-QTOF-MS) combined with multivariate statistical analysis. 52 components were detected from non-fumigated AMK (NF-AMK) and 28 components were newly produced after sulfur fumigation, out of which 59 major peaks were identified. The concentrations of 20 compounds significantly decreased and 37 compounds obviously increased. The potential structural transformation mechanism of terpenoids was explored to illustrate the correlation of the components contents before and after sulfur fumigation. Eight sulfur-containing/dehydrated-integrated atractylenolides that evolved from the NF-AMK were screened out as potential characteristic chemical markers to examine the post-harvest handling procedures of commercial AMK with excessive sulfur fumigation and maintain consistent quality.

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat because there are no targeted therapies. Currently, chemotherapy is the only clinical option for TNBC despite development of resistance. New therapeutic agents with unique mechanisms of action are urgently needed; therefore, this study investigated the potential anti-TNBC effects of budlein A methylacrylate (BAM), a natural sesquiterpene lactone isolated from plants of the Helianthus genus. We discovered that BAM selectively suppressed and induced apoptosis TNBC cell growth versus other breast cancer or normal mammary epithelial cells. Mechanistically, BAM co-inhibited inhibitor of nuclear factor κBα (IκBα) kinase subunit β (IKKβ) and exportin-1 (XPO-1; chromosome region maintenance 1, CRM1), which are two dysregulated onco-related proteins in TNBC cells, by covalently modifying key functional cysteine residues (Cys179 of IKKβ, Cys528 of XPO-1). Dual inhibition led to the stabilization and nuclear retention of IκBα, impairment of NF-κB transcriptional activity, and consequent induction of TNBC cell apoptosis. In conclusion, this study provides evidence that co-inhibition of IKKβ and XPO-1 by BAM was effective against TNBC, demonstrating it as a representative new generation inhibitor with potential for TNBC treatment.

A silver nanoparticles (AgNPs)-enhanced time-resolved fluorescence (TR-FL) sensor based on long-lived fluorescent Mn-doped ZnS quantum dots (QDs) is developed for the sensitive detection of vascular endothelial growth factor-165 (VEGF165), a predominant cancer biomarker in cancer angiogenesis. The aptamers bond with the Mn-doped ZnS QDs and the BHQ-2 quencher-labelling strands hybridized in duplex are coupled with streptavidin (SA)-functionalized AgNPs to form the AgNPs-enhanced TR-FL sensor, showing lower fluorescence intensity in the duplex state due to the fluorescence resonance energy transfer (FRET) between the Mn-doped ZnS QDs and quenchers. Upon the addition of VEGF165, the BHQ-2 quencher-labelling strands of the duplex are displaced, leading to the disruption of the FRET. As a result, the fluorescence of the Mn-doped QDs within the proximity of the AgNPs is recovered. The FL signal can be measured free of the interference of short-lived background by setting appropriate delay time and gate time, which offers a signal with high signal-to-noise ratio in photoluminescent biodetection. Compared with the bare TR-FL sensor, the AgNPs-based TR-FL sensor showed a huge improvement in fluorescence based on metal-enhanced fluorescence (MEF) effect, and the sensitivity increased 11-fold with the detection limit of 0.08 nM. In addition, the sensor provided a wide range of linear detection from 0.1 nM to 16 nM.

The early immature CD34+ acute myeloid leukemia (AML) cell subpopulation-acute myeloid leukemia progenitor cells (APCs), is often resistant to conventional chemotherapy, making them largely responsible for the relapse of AML. However, to date, the eradication of APCs remains a major challenge. We previously reported a naturally occurring secolignan- Peperomin E (PepE) and its analog 6-methyl (hydroxyethyl) amino-2, 6-dihydropeperomin E (DMAPE) that selectively target and induce oxidative stress-mediated apoptosis in KG-1a CD34+ cells (an APCs-like cell line) in vitro. We therefore further evaluated the efficacy and the mechanism of action of these compounds in this study. We found that PepE and DMAPE have similar potential to eliminate primary APCs, with no substantial toxicities to the normal cells in vitro and in vivo. Mechanistically, these agents selectively inhibit TrxR1, an antioxidant enzyme aberrantly expressed in APCs, by covalently binding to its selenocysteine residue at the C-terminal redox center. TrxR1 inhibition mediated by PepE (DMAPE) leads to the formation of cellular selenium compromised thioredoxin reductase-derived apoptotic protein (SecTRAP), oxidation of Trx, induction of oxidative stress and finally activation of apoptosis of APCs. Our results demonstrate a potential anti-APCs molecular target – TrxR1 and provide valuable insights into the mechanism underlying PepE (DMAPE)-induced cytotoxicity of APCs, and support the further preclinical investigations on PepE (DMAPE)-related therapies for the treatment of relapsed AML., Graphical abstract Image 1

Management of operational risk is of prime importance in risk management for commercial banks, and many theoretical and practical studies of operational risk management have been carried out. Conditional value-at-risk (CVaR) models based on the peak value method of extreme value theory are used here to measure operational risk. Loss data for commercial banks are used in an empirical analysis. Tests are carried out using a CVaR model to calculate VaR and CVaR at 95% and 99% confidence levels to assess expected and unexpected losses for operational risks.

For patients with heart failure (HF) due to ischemic cardiomyopathy (ICM), reconstruction and volume reduction of the scarred left ventricle (LV) may be beneficial. The Revivent “Less Invasive Ventricular Enhancement” procedure (BioVentrix, Inc, San Ramon, CA) , is a minimally invasive method

Recent experimental studies showed that the ductility of NiTi is not affected by moisture, while addition of iron beyond 9 a/o in NiTi leads to moisture-induced embrittlement. To explore the nature of this embrittlement, we studied the chemical interaction between water vapor and (Ni,Fe)Ti(110) surfaces with 5 a/o and 10 a/o Fe. Temperature-programmed desorption and X-ray photoelectron spectroscopy show that decomposition of water to produce atomic hydrogen occurs on both surfaces. Activation energy for surface diffusion was calculated by density functional theory, showing that addition of Fe decreases H surface diffusivity, in agreement with experiment. Together with the observation that addition of 9 a/o Fe increases the strength of NiTi, this indicates that moisture-induced embrittlement in higher strength NiTi alloys is not due to faster H surface diffusion, but lower critical hydrogen concentration required for embrittlement.