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Abstract Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability.

In this study, the researchers produced a pear paste using typical Dangshan pear fruits. The mechanism that enables the paste to treat cough and related inflammatory responses was systematically investigated using an ammonia-induced mice cough model. The pear paste and its polar extracts relieved cough symptoms, as evidenced by 44.0%, 53.4%, and 47.2% decreases in cough frequency and 21.0%, 43.3%, and 53.4% increases in latent period for pear paste, ethyl acetate extract (EAE) and n-butanol extract (WBE), respectively. In addition, the paste and its polar extracts reduced lung injuries, including alveolar dilatation, alveolar wall damage, and airway thickening. The two polar extracts exhibited anti-inflammatory effects in the airway through the suppression of a Th1 cytokine (IFN-γ, significantly suppressed by 15.49% and 16.33% for EAE and WBE, separately). A spectrum-effect relationship analysis was conducted to identify arbutin, protocatechuic acid, chlorogenic acid and naringin as the primary bioactive substances contributing to the antitussive and anti-inflammatory activities of pear paste.

The 6 GHz band plays a crucial role in the development of the 6G. A profound comprehension of channel reciprocity is essential for designing time division duplexing/frequency division duplexing (TDD/FDD) systems within this band. Firstly, in an indoor corridor scenario, precise and impartial measurements are conducted for both the uplink (UL) and downlink (DL) channels in the 6 GHz band; A denoising algorithm is proposed to extract multipath components (MPCs) from the measurement data, enabling a more equitable assessment of channel reciprocity; Then, a comprehensive analysis of channel reciprocity has been conducted, focusing on four aspects: path loss, delay spread, cluster-based correlation coefficient (CBCC), and multipath power dissimilarity (MPD). The findings indicate that TDD systems demonstrate nearly perfect reciprocity, whereas FDD systems exhibit partial reciprocity in indoor scenarios. Specifically, in TDD systems, the CBCCs between UL and DL exceed 95%, while in FDD systems, they fluctuate between 80% and 90%. Additionally, a model has been provided to depict the relationship between MPD and center frequency, as well as frequency interval; Finally, a comparative analysis of measured and ray-tracing simulated results reveals the presence of numerous public MPCs, which share the same propagation delay and spatial angle between the UL and DL in FDD systems, as well as private MPCs that exist exclusively in either the UL or DL. They collectively influence the channel reciprocity.

Abstract Reissner’s fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Earth Hour, a global mass effort coordinated to show concern for green urban construction and sustainable development, was first organized by the World Wildlife Fund in Australia in 2007 with a growing trend of participation worldwide. However, analysis of participation in Earth Hour based on a large population are sparse, with only a few studies reporting details in positive results without a clear pattern that explains the potential low participation. This study focuses on the non-participants and analyzed the reasons for low participation in Earth Hour using a questionnaire with 401 college students based on the socio-ecological model. Two aspects are explored: (1) social-demographic features; (2) psychosocial traits (environmental awareness, acceptance for law, social support from family and friends and knowledge about the event). Barriers toward participation are included as mediators to explain how these basic features change students’ decision on joining large-scale environmental campaign. A participation analysis method using binary logistic regression and one-way MANOVA is applied in data analysis. This study highlights that the irrelevance between students’ belief and practice on environmental protection should not be overlooked, and that college students are inclined to join in groups in relevant activities—conversely, herd effect could greatly reduce their willingness to participation. The findings of this study have wider implications for school educators, practitioners and organizations involved in pro-environmental career. This paper highlights that, from an international perspective, the essence of collective action with a similar nature to Earth Hour and contributes to a global dialogue on fostering sustainable behaviors.

Abstract It is of much importance to clarify the impact of technological innovation on carbon emission intensity for the low-carbon transformation of China's economy. This study, based on the panel data of 30 Chinese provinces and municipalities from 2010 to 2020, measures and analyzes the carbon emission intensity and the level of technological innovation, establishing a spatial econometric model to study the spatial spillover effect and a panel threshold model to analyze the nonlinear influence of technological innovation level on carbon emission intensity. The findings are as follows: First, the overall carbon emission intensity in China shows a decreasing trend from 2010 to 2020, with the average dropping from 3.09 in 2010 to 1.98 in 2020; Second, the spatial autocorrelation results reveal that the level of technological innovation and carbon emission intensity in China are obviously aggregated in the global spatial distribution pattern. Third, the regression results of the spatial econometric model show that the direct effect of technological innovation on carbon emission intensity is significantly negative at the level of 1%, that is, the improvement of the technological innovation in a certain area has a significant inhibitory effect on carbon emission intensity. Fourth, based on the level of economic development, there is a significant three-threshold effect of the level of technological innovation on carbon emission intensity in China, and the influence of the level of technological innovation on carbon emission intensity varies in the direction of existence and coefficient values within different threshold intervals. As economic development reaches the third interval, the technological innovation level has the most significant inhibition on carbon emission intensity. These findings enriches the research of the nonlinear relationship between technological innovation and carbon emission intensity, clarifies the spatial spillover effect and threshold effect between among them, and provides inspiration for better promote the low-carbon transformation of economy.

To date, five species of reddish-brown Neotriplax have been described, but their highly similar body color and other phenotypic traits make accurate taxonomy challenging. To clarify species-level taxonomy and validate potential new species, the cytochrome oxidase subunit I (COI) was used for phylogenetic analysis and the geometric morphometrics of elytron, pronotum, and hind wing were employed to distinguish all reddish-brown Neotriplax species. Phylogenetic results using maximum likelihood and Bayesian analyses of COI sequences aligned well with the current taxonomy of the Neotriplax species group. Significant K2P divergences, with no overlap between intra- and interspecific genetic distances, were obtained in Neotriplax species. The automatic barcode gap discovery (ABGD), assemble species by automatic partitioning (ASAP), and generalized mixed Yule coalescent (GMYC) approaches concurred, dividing the similar species into eight molecular operational taxonomic units (MOTUs). Geometric morphometric analysis using pronotum, elytron, hind wing shape and wing vein patterns also validated the classification of all eight species. By integrating these analytical approaches with morphological evidence, we successfully delineated the reddish-brown species of Neotriplax into eight species with three new species: N. qinghaiensis sp. nov., N. maoershanensis sp. nov., and N. guangxiensis sp. nov. Furthermore, we documented the first record of N. lewisii in China. This study underscores the utility of an integrative taxonomy approach in species delimitation within Neotriplax and serves as a reference for the taxonomic revision of other morphologically challenging beetles through integrative taxonomy.

Abstract Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

Abstract Regulation of the volume and electrolyte composition of the cerebrospinal fluid (CSF) is vital for brain development and function. The Na-K-Cl co-transporter NKCC1 in the choroid plexus (ChP) plays key roles in regulating CSF volume by co-transporting ions and mediating same-direction water movements. Our previous study showed ChP NKCC1 is highly phosphorylated in neonatal mice as the CSF K+ level drastically decreases and that overexpression of NKCC1 in the ChP accelerates CSF K+ clearance and reduces ventricle size [1]. These data suggest that NKCC1 mediates CSF K+ clearance following birth in mice. In this current study, we used CRISPR technology to create a conditional NKCC1 knockout mouse line and evaluated CSF K+ by Inductively Coupled Plasma Optical Emission spectroscopy (ICP-OES). We demonstrated ChP-specific reduction of total and phosphorylated NKCC1 in neonatal mice following embryonic intraventricular delivery of Cre recombinase using AAV2/5. ChP-NKCC1 knockdown was accompanied by a delayed perinatal clearance of CSF K+. No gross morphological disruptions were observed in the cerebral cortex. We extended our previous results by showing embryonic and perinatal rats shared key characteristics with mice, including decreased ChP NKCC1 expression level, increased ChP NKCC1 phosphorylation state, and increased CSF K+ levels compared to adult. Collectively, these follow up data support ChP NKCC1’s role in age-appropriate CSF K+ clearance during neonatal development.

In high-penetration renewable-energy grid systems, conventional virtual synchronous generator (VSG) control faces a number of challenges, especially the difficulty of maintaining synchronization during grid voltage drops. This difficulty may lead to current overloads and equipment disconnections, and it has an impact on the security and reliability of the system, as well as limiting the dynamic reactive power support capability of the system. To solve this problem, in this study, a wind–solar hybrid power generation system is designed with a battery energy storage device connected on the DC side, and proposes a low voltage ride-through (LVRT) control strategy for the grid-connected inverter based on an improved VSG. The control strategy employs an integrated current limiting technique combining virtual impedance and vector current limiting to ensure that the VSG exhibits good dynamic power support characteristics during symmetrical faults by adjusting the setpoint value of reactive power. At the same time, it maintains the synchronization and power angle stability of the VSG itself to achieve the goal of LVRT. Simulation results show that the proposed control strategy can effectively suppress the renewable power fluctuations (about 30% reduction in fluctuations compared to the conventional strategy) and ensure the safe and reliable operation of the renewable energy sources and VSGs during grid-side faults. In addition, it provides a given reactive power support and stable grid voltage control (voltage dips reduced by about 20%), which significantly enhances the LVRT capability of the hybrid wind–solar-storage generation system.

The question of how to simultaneously perform frequency regulation and integrated economic scheduling for microgrids with low-inertia islanding operation under communication constraints is a difficult problem that needs to be solved for many current applications. To this end, this paper establishes a microgrid scheduling control model containing a virtual synchronous generator (VSG) with multiple types of power sources and proposes a distributed optimization algorithm that integrates frequency regulation and comprehensive economic scheduling to simultaneously realize frequency regulation and economic scheduling in a microgrid. Firstly, a distributed economic dispatch problem is proposed based on a comprehensive consideration of the costs and benefits of various types of power VSGs, as well as the overall inertia and standby capacity requirements of the microgrid, which minimizes the integrated costs incurred by the participation of each type of VSG in the frequency regulation and improves the stable operation of the microgrid in terms of frequency under perturbation. Then, the optimal scheduling problem is solved by reconstructing the optimization problem based on considering the dynamic characteristics of microgrid inverters and using event-triggered communication to sense and compensate for the supply-demand imbalance online. The proposed method can avoid inter-layer coordination across time scales, improve the inertia, frequency regulation capability, and economy of the system, and enhance its robustness to short-term communication failures. Finally, simulation results are used to verify the effectiveness of the method.

The genus Rhodotritoma Arrow, 1925 (Coleoptera, Erotylidae, Erotylinae, Tritomini) includes 12 known species worldwide, including three species distributed in China. In the last four decades, no work was conducted on Rhodotritoma in China. In this paper, we review the taxonomy of this genus for Chinese fauna and redescribe a newly-recorded species in China.Rhodotritoma manipurica Arrow, 1925 is recorded from China for the first time. The morphological characters of the adult are redescribed in detail and illustrated. A key to species of the genus Rhodotritoma Arrow, 1925 in China is provided. Chinese specimens were collected from Tibet Autonomous Region and Yunnan Province, which were then deposited in the Museum of Hebei University. The holotype examined is kept in the Natural History Museum.

This study was undertaken to identify oat (Avena sativa L.) varieties optimal for cultivation in the Jiuquan region, China, in 2021. A selection of 27 domestic and international oat varieties were analyzed, considering ten key agronomic traits, including plant height, stem diameter, spike length, leaf width, and yield. Employing methods such as cluster analysis, principal component analysis, and grey correlation degree, a comprehensive evaluation was conducted. The principal component analysis distilled the ten indicators to three core components. The most influential factors in the first principal component were plant height, ear length, and hay yield, while leaf length and leaf area index were the highest contributors to the second component. The stem-to-leaf ratio emerged as the principal indicator in the third component. The cluster analysis resulted in the classification of the 27 oat varieties into 3 categories. Following a comprehensive evaluation through the grey correlation degree and principal component analysis methodologies, we found that the oat varieties Sweety 1, Fuyan 1, Dingyan 2, Baler, Quebec, and Longyan 2 received the highest scores. These varieties, hence, appear to be the most suitable for cultivation and promotion in the Jiuquan region. This study thus provides invaluable insights into oat cultivation practices, offering guidance for farmers, agricultural policymakers, and future research in the field.

Abnormal CSF accumulation in the brain can lead to hydrocephalus. The mechanisms regulating CSF clearance during early development are unclear. Here, the authors show that NKCC1 regulates the clearance of both CSF K+ and fluid volume through the choroid plexus during postnatal development in mice.

Abstract Background The human leukocyte antigen (HLA) gene family plays a key role in the immune response and thus is crucial in many biomedical and clinical settings. Utilizing Sanger sequencing, the golden standard technology for HLA typing enables accurate identification of HLA alleles in high-resolution. However, only the commercial software, such as uTYPE, SBT-Assign, and SBTEngine, and very few open-source tools could be applied to perform HLA typing based on Sanger sequencing. Results We developed a user-friendly, cross-platform and open-source desktop application, known as SOAPTyping, for Sanger-based typing in HLA class I and II alleles. SOAPTyping can produce accurate results with a comprehensible protocol and featured functions. Moreover, SOAPTyping supports a more advanced group-specific sequencing primers (GSSP) module to solve the ambiguous typing results. We used SOAPTyping to analyze 36 samples with known HLA typing from the University of California Los Angeles (UCLA) International HLA DNA Exchange platform and 100 anonymous clinical samples, and the HLA typing results from SOAPTyping are identical to the golden results and 5.5 times faster than commercial software uTYPE, which shows the usability of SOAPTyping. Conclusions We introduce the SOAPTyping as the first open-source and cross-platform HLA typing software with the capability of producing high-resolution HLA typing predictions from Sanger sequence data.

In this paper, we propose a neural network channel pruning method based on the joint reconstruction error (JRE). To preserve the global discrimination ability of a pruned neural network, we propose the global reconstruction error. To ensure the integrity of information in the forward propagation process of a neural network, we propose the local reconstruction error. Finally, through normalization, the two magnitude mismatched losses are combined to obtain the joint error. The baseline network and pruned network are symmetrical structures. The importance of each channel in the pruned network is determined by the joint error between the channel and the corresponding channel in the baseline network. The proposed method prunes the channels in the pruned network according to the importance score and then restores its accuracy. The proposed method reduces the scale of the neural network and speeds up the model inferring speed without losing the accuracy of the neural network. Experimental results show the effectiveness of the method. For example, on the CIFAR-10 dataset, the proposed method prunes 50% of the channels of the VGG16 model, and the accuracy of the pruned model is 0.46% higher than that of the original model.

Abstract Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti‐inflammatory protection of brain microglia against soluble oligomers of human amyloid β‐protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β‐adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β‐adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ‐induced inflammation as did mice in EE. Conversely, mice in EE fed the β‐adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2‐adrenergic receptors showed no protection of microglia by EE. In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial‐specific analysis of β2‐adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE. Thus, enhanced β‐adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers in vivo.

5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5HHMF) and 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone (5HPMF) are the predominant polymethoxyflavones in orange peel. Here, we showed how 5HHMF or 5HPMF modulated the amount of pre-existing and newly synthesized glycosaminoglycans (GAG) in lung and colon cancer cells. 5HPMF treatment disrupted the formation of FGF/FGFR1c/GAG ternary signaling complex in cell surface. Moreover, 5HHMF remarkably decreased the content of nonsulfated and 3- or 6-sulfated disaccharides of heparan sulfate while no significant changes occurred in that of chondroitin sulfate detected by 1-phenyl-3-methyl-5-pyrazolone (PMP) isotope labeling plus LC/MS analysis. Furthermore, quantification of metabolic incorporating 34S isotope-labeled sulfate into GAG of cultured cells indicated that 5HHMF decreased the sulfated disaccharides of the newly synthesized GAGs by 54%. Overall, the results indicated that 5HHMF and 5HPMF were potential inhibitors of GAG biosynthesis. Our results indicated that GAGs might be the long sought signaling molecules affected by 5HHMF and 5HPMF that lead to lung and colon cancer cell death.

With the aim to solve issues of robot object recognition in complex scenes, this paper proposes an object recognition method based on scene text reading. The proposed method simulates human-like behavior and accurately identifies objects with texts through careful reading. First, deep learning models with high accuracy are adopted to detect and recognize text in multi-view. Second, datasets including 102,000 Chinese and English scene text images and their inverse are generated. The F-measure of text detection is improved by 0.4% and the recognition accuracy is improved by 1.26% because the model is trained by these two datasets. Finally, a robot object recognition method is proposed based on the scene text reading. The robot detects and recognizes texts in the image and then stores the recognition results in a text file. When the user gives the robot a fetching instruction, the robot searches for corresponding keywords from the text files and achieves the confidence of multiple objects in the scene image. Then, the object with the maximum confidence is selected as the target. The results show that the robot can accurately distinguish objects with arbitrary shape and category, and it can effectively solve the problem of object recognition in home environments.

Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP–spike (E–S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAβ increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.

Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis; thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial−mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.

With the speedy development of sequencing technologies, noninvasive prenatal testing (NIPT) has been widely applied in clinical practice for testing for fetal aneuploidy. The cell-free fetal DNA (cffDNA) concentration in maternal plasma is the most critical parameter for this technology because it affects the accuracy of NIPT-based sequencing for fetal trisomies 21, 18 and 13. Several approaches have been developed to calculate the cffDNA fraction of the total cell-free DNA in the maternal plasma. However, most approaches depend on specific single nucleotide polymorphism (SNP) allele information or are restricted to male fetuses.In this study, we present an innovative method to accurately deduce the concentration of the cffDNA fraction using only maternal plasma DNA. SNPs were classified into four maternal-fetal genotype combinations and three boundaries were added to capture effective SNP loci in which the mother was homozygous and the fetus was heterozygous. The median value of the concentration of the fetal DNA fraction was estimated using the effective SNPs. A depth-bias correction was performed using simulated data and corresponding regression equations for adjustments when the depth of the sequencing data was below 100-fold or the cffDNA fraction is less than 10%.Using our approach, the median of the relative bias was 0.4% in 18 maternal plasma samples with a median sequencing depth of 125-fold. There was a significant association (r = 0.935) between our estimations and the estimations inferred from the Y chromosome. Furthermore, this approach could precisely estimate a cffDNA fraction as low as 3%, using only maternal plasma DNA at the targeted region with a sequencing depth of 65-fold. We also used PCR instead of parallel sequencing to calculate the cffDNA fraction. There was a significant association (r = 98.2%) between our estimations and those inferred from the Y chromosome.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-α (PPAR-α) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-α is still unknown. Fenofibrate is a PPAR-α agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. METHODS: Adult maleWistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved-caspase-9 protein expression, PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. RESULTS: Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. CONCLUSIONS: The PPAR-α activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis. [ABSTRACT FROM AUTHOR]

Background: Norcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study.Methods: Two human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho-EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis.Results: NCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment.Conclusions: NCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients. [ABSTRACT FROM AUTHOR]

Soluble oligomers of amyloid β-protein (oAβ) isolated from the brains of Alzheimer's disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble Aβ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These species have little or no cytotoxic activity in several bioassays. However, incubation ofHMWoAβ in mildly alkaline buffer led to their quantitative dissociation into low molecular weight oligomers (β8 -70 kDa), and these were now far more bioactive: they impaired hippocampal LTP, decreased neuronal levels of β2-adrenergic receptors, and activated microglia in wt mice in vivo. Thus, most soluble Aβ assemblies in AD cortex are large and inactive but under certain circumstances can dissociate into smaller, highly bioactive species. Insoluble amyloid plaques likely sequester solubleHMWoligomers, limiting their potential to dissociate. Weconclude that conditions that destabilize HMW oligomers or retard the sequestration of their smaller, morebioactive components are important drivers of Aβ toxicity. Selectively targeting these small, cytotoxic forms should be therapeutically beneficial. [ABSTRACT FROM AUTHOR]

Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing isknownabout whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble Aβ oligomers (oAβ) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oAβ-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFα) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oAβ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oAβ, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system. [ABSTRACT FROM AUTHOR]

APOBEC3A belongs to a family of single-stranded DNA (ssDNA) DNA cytosine deaminases that are known for restriction of HIV through deamination-induced mutational inactivation, e.g. APOBEC3G, or initiation of somatic hypermutation and class switch recombination (activation-induced cytidine deaminase). APOBEC3A, which is localized to both the cytoplasm and nucleus, not only restricts HIV but can also initiate catabolism of cellular DNA. Despite being ascribed these roles, there is a paucity of data available on the biochemical mechanism by which APOBEC3A deaminates ssDNA. Here we assessed APOBEC3A deamination activity on ssDNA and in dynamic systems modeling HIV replication (cytoplasmic event) and DNA transcription (nuclear event). We find that APOBEC3A, unlike the highly processive APOBEC3G, exhibits low or no processivity when deaminating synthetic ssDNA substrates with two cytosines located 5-63 nucleotides apart, likely because of an apparent Kd in the micromolar range (9.1 μM). APOBEC3A was able to deaminate nascently synthesized (-)DNA in an in vitro model HIV replication assay but induced fewer mutations overall in comparison to APOBEC3G. However, the data indicate that the target deamination motif (5′-TC for APOBEC3A and 5′-CC for APOBEC3G) and not the number of mutations best predicted the ability to mutationally inactivate HIV. We further assessed APOBEC3A for the ability to deaminate dsDNA undergoing transcription, which could allow for collateral deaminations to occur in genomic DNA similar to the action of activation-induced cytidine deaminase. That APOBEC3A was able to deaminate dsDNA undergoing transcription suggests a genomic cost of a deamination-based retroviral restriction system. [ABSTRACT FROM AUTHOR]

Long-term changes (2003-14) of water temperature, DO, pH, TN, NH4-N, TP, and CODMn were examined at eight sampling stations along the Liujiang River. Water quality parameters showed considerable spatial and temporal variability. Annual averages of those parameters were 22.1°C, 7.8 mg/L, 7.58, 1.35 mg/L, 0.27 mg/L, 0.06 mg/L, and 1.7 mg/L, respectively. An increasing trend for TN/TP and a decreasing trend for pH were observed in all parts of the Liujiang. Pollution levels were generally higher in the lower Liujiang than in the upper and middle parts of the river due to the impact of urban sewage. All indicators reached level III water quality standards except TN, which suggests that the control of nitrogen emissions should be strengthened. Relatively high N/P ratios in the Liujiang contribute to a potential for phosphorus limitation of phytoplankton. The average concentration of Chlorophyll-a was 1.2 μg/L in 2014. The TLI index indicated that the eutrophication state of the Liujiang was mesotrophic, while the downstream water was polluted due to its nutrient inputs from agriculture and urban sources. The water quality of the river keeps well by comparison to other major rivers of the world, which provided the basis for urban development and river protection in Liuzhou City. [ABSTRACT FROM AUTHOR]