ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Abscisic acid root-to-shoot translocation by transporter AtABCG25 mediates stomatal movements in Arabidopsis.

The phytohormone abscisic acid (ABA) plays a central role in regulating stomatal movements under drought conditions. The root-derived peptide CLAVATA3/EMBRYO SURROUNDING REGION-RELATED 25 (CLE25) moves from the root to shoot for activating ABA biosynthesis under drought conditions. However, the root-to-shoot translocation of root-derived ABA and its regulation of stomatal movements in the shoot remain to be clarified. Here, we reveal that the ABA transporter ATP-binding cassette subfamily G member 25 (AtABCG25) mediates root-to-shoot translocation of ABA and ABA-glucosyl ester (ABA-GE) in Arabidopsis (Arabidopsis thaliana). Isotope-labeled ABA tracer experiments and hormone quantification in xylem sap showed that the root-to-shoot translocation of ABA and ABA-GE was substantially impaired in the atabcg25 mutant under nondrought and drought conditions. However, the contents of ABA and ABA-GE in the leaves were lower in the atabcg25 mutant than in the wild type (WT) under nondrought but similar under drought conditions. Consistently, the stomatal closure was suppressed in the atabcg25 mutant under nondrought but not under drought conditions. The transporter activity assays showed that AtABCG25 directly exported ABA and ABA-GE in planta and in yeast (Saccharomyces cerevisiae) cells. Thus, we proposed a working model in which root-derived ABA transported by AtABCG25 via xylem mediates stomatal movements in the shoot under nondrought conditions but might exhibit little effect on stomatal movements under drought conditions. These findings extend the functions of AtABCG25 and provide insights into the long-distance translocation of ABA and its role in stomatal movements.

Regional Reliability of Combining CT Angiography-source Image and Non-contrast CT in Acute Ischemic Stroke.

Purpose: CT angiography-source image (CTA-SI) can be used as an effective alternative to diffusion-weighted imaging (DWI) for identifying acute ischemic stroke (AIS). This study investigates the reliability of combining CTA-SI with non-contrast CT (NCCT) for AIS diagnosis, with a focus on how different brain areas affect diagnostic accuracy. Methods: Patients with various subtypes of AIS who underwent NCCT, CTA, and DWI from January to December 2022 were included. Two experienced neuroradiologists analyzed ischemic core across NCCT, CTA-SI, and NCCT+CTA-SI models, evaluating interobserver reliability and lesion detection rate. Results: A total of 304 patients (63% male, age 67.2 ± 11.9 years) with AIS were included. The distribution of stroke subtypes was as follows: 23% large vessel trunk infarction, 46% deep perforator vessel infarction, 9% superficial perforator vessel infarction, 5% watershed infarction, and 17% infratentorial infarction. The interobserver reliability was substantial in the three image models, especially the NCCT+CTA-SI model (all p<0.05). The NCCT+CTA-SI model demonstrated higher lesion detection rate than the NCCT (59.20% vs 48.7%, p<0.05) and CTA-SI model (59.2% vs 45.4%, p<0.05), particularly when detecting large vessel trunk infarction (82.90% vs 58.60%, p<0.05) and deep perforator vessel infarctions (64.80% vs 44.40%, p<0.05). Conclusions: The NCCT+CTA-SI model may be a valuable tool for evaluating AIS when DWI is not feasible. Smaller hospitals might consider adopting this combination for improved stroke diagnosis, highlighting the need for careful evaluation of deep perforator vessel infarction when large vessel trunk infarction is not evident.

Toll9 from Bombyx mori functions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals.

Toll/Toll-like receptors (TLRs) are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian TLRs directly recognize pathogen-associated molecular patterns, the insect Toll pathway is thought to be primarily activated by binding Spätzle cytokines that are processed from inactive precursors in response to microbial infection. Phylogenetic and structural data generated in this study supported earlier results showing that Toll9 members differ from other insect Tolls by clustering with the mammalian TLR4 group, which recognizes lipopolysaccharide (LPS) through interaction with myeloid differentiation-2 (MD-2)-like proteins. Functional experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2-like proteins, previously named BmEsr16 and BmPP, that we refer to in this study as BmMD-2A and BmMD-2B, respectively. A chimeric BmToll9-TLR4 receptor consisting of the BmToll9 ectodomain and mouse TLR4 transmembrane and Toll/interleukin-1 (TIR) domains also activated LPS-induced release of inflammatory factors in murine cells but only in the presence of BmMD-2A or BmMD-2B. Overall, our results indicate that BmToll9 is a pattern recognition receptor for LPS that shares conserved features with the mammalian TLR4-MD-2-LPS pathway.

Revealing the Complete Bispecific Phosphatase Genes (DUSPs) across the Genome and Investigating the Expression Patterns of GH_A11G3500 Resistance against Verticillium wilt.

DUSPs, a diverse group of protein phosphatases, play a pivotal role in orchestrating cellular growth and development through intricate signaling pathways. Notably, they actively participate in the MAPK pathway, which governs crucial aspects of plant physiology, including growth regulation, disease resistance, pest resistance, and stress response. DUSP is a key enzyme, and it is the enzyme that limits the rate of cell metabolism. At present, complete understanding of the DUSP gene family in cotton and its specific roles in resistance to Verticillium wilt (VW) remains elusive. To address this knowledge gap, we conducted a comprehensive identification and analysis of four key cotton species: Gossypium arboreum, Gossypium barbadense, Gossypium hirsutum, and Gossypium raimondii. The results revealed the identification of a total of 120 DUSP genes in the four cotton varieties, which were categorized into six subgroups and randomly distributed at both ends of 26 chromosomes, predominantly localized within the nucleus. Our analysis demonstrated that closely related DUSP genes exhibited similarities in terms of the conserved motif composition and gene structure. A promoter analysis performed on the GhDUSP gene promoter revealed the presence of several cis-acting elements, which are associated with abiotic and biotic stress responses, as well as hormone signaling. A tissue expression pattern analysis demonstrated significant variations in GhDUSP gene expression under different stress conditions, with roots exhibiting the highest levels, followed by stems and leaves. In terms of tissue-specific detection, petals, leaves, stems, stamens, and receptacles exhibited higher expression levels of the GhDUSP gene. The gene expression analysis results for GhDUSPs under stress suggest that DUSP genes may have a crucial role in the cotton response to stress in cotton. Through Virus-Induced Gene Silencing (VIGS) experiments, the silencing of the target gene significantly reduced the resistance efficiency of disease-resistant varieties against Verticillium wilt (VW). Consequently, we conclude that GH_A11G3500-mediated bispecific phosphorylated genes may serve as key regulators in the resistance of G. hirsutum to Verticillium wilt (VW). This study presents a comprehensive structure designed to provide an in-depth understanding of the potential biological functions of cotton, providing a strong foundation for further research into molecular breeding and resistance to plant pathogens.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia.

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8­12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.

Development of a blood proteins-based model for bronchopulmonary dysplasia prediction in premature infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease in premature infants. Blood proteins may be early predictors of the development of this disease. METHODS: In this study, protein expression profiles (blood samples during their first week of life) and clinical data of the GSE121097 was downloaded from the Gene Expression Omnibus. Weighted gene co-expression network analysis (WGCNA) and differential protein analysis were carried out for variable dimensionality reduction and feature selection. Least absolute shrinkage and selection operator (LASSO) were conducted for BPD prediction model development. The performance of the model was evaluated by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve. RESULTS: The results showed that black module, magenta module and turquoise module, which included 270 proteins, were significantly correlated with the occurrence of BPD. 59 proteins overlapped between differential analysis results and above three modules. These proteins were significantly enriched in 253 GO terms and 11 KEGG signaling pathways. Then, 59 proteins were reduced to 8 proteins by LASSO analysis in the training cohort. The proteins model showed good BPD predictive performance, with an AUC of 1.00 (95% CI 0.99-1.00) and 0.96 (95% CI 0.90-1.00) in training cohort and test cohort, respectively. CONCLUSION: Our study established a reliable blood-protein based model for early prediction of BPD in premature infants. This may help elucidate pathways to target in lessening the burden or severity of BPD.

Genetic Channelization Mechanism of Four Chalcone Isomerase Homologous Genes for Synergistic Resistance to Fusarium wilt in Gossypium barbadense L.

Duplication events occur very frequently during plant evolution. The genes in the duplicated pathway or network can evolve new functions through neofunctionalization and subfunctionalization. Flavonoids are secondary metabolites involved in plant development and defense. Our previous transcriptomic analysis of F6 recombinant inbred lines (RILs) and the parent lines after Fusarium oxysporum f. sp. vasinfectum (Fov) infection showed that CHI genes have important functions in cotton. However, there are few reports on the possible neofunctionalization differences of CHI family paralogous genes involved in Fusarium wilt resistance in cotton. In this study, the resistance to Fusarium wilt, expression of metabolic pathway-related genes, metabolite content, endogenous hormone content, reactive oxygen species (ROS) content and subcellular localization of four paralogous CHI family genes in cotton were investigated. The results show that the four paralogous CHI family genes may play a synergistic role in Fusarium wilt resistance. These results revealed a genetic channelization mechanism that can regulate the metabolic flux homeostasis of flavonoids under the mediation of endogenous salicylic acid (SA) and methyl jasmonate (MeJA) via the four paralogous CHI genes, thereby achieving disease resistance. Our study provides a theoretical basis for studying the evolutionary patterns of homologous plant genes and using homologous genes for molecular breeding.

Single Solution-Phase Synthesis of Charged Covalent Organic Framework Nanosheets with High Volume Yield.

Covalent organic framework nanosheets (COF-NSs) are emerging building blocks for functional materials, and their scalable fabrication is highly desirable. Current synthetic methods suffer from low volume yields resulting from confined on-surface/at-interface growth space and complex multiple-phase synthesis systems. Herein, we report the synthesis of charged COF-NSs in open space using a single-phase organic solution system, achieving magnitudes higher volume yields of up to 18.7 mg mL-1 . Charge-induced electrostatic repulsion forces enable in-plane anisotropic secondary growth from initial discrete and disordered polymers into large and crystalline COF-NSs. The charged COF-NS colloidal suspensions are cast into thin and compact proton exchange membranes (PEMs) with lamellar morphology and oriented crystallinity, displaying outstanding proton conductivity, negligible dimensional swelling, and good H2 /O2 fuel cell performance.

Genome-wide analysis of serine carboxypeptidase-like protein (SCPL) family and functional validation of Gh_SCPL42 unchromosome conferring cotton Verticillium der Verticillium wilt stress in Gossypium hirsutum.

BACKGROUND: Serine carboxypeptidase-like protein (SCPL) plays an important role in response to stress in plant. However, our knowledge of the function of the SCPL gene family is limited. RESULTS: In this study, a comprehensive and systematic analysis of SCPL gene family was conducted to explore the phylogeny and evolution of the SCPL gene in Gossypium hirsutum. The phenotype and molecular mechanism of silencing of the Gh_SCPL42 under Verticillium wilt stress was also studied. Our results showed that 96 SCPL genes were observed in genome of G. hirsutum, which distributed on 25 chromosomes and most of them were located in the nucleus. The phylogenetic tree analysis showed that members of SCPL gene family can be divided into three subgroups in G. hirsutum, which are relatively conservative in evolution. SCPL gene has a wide range of tissue expression types in G. hirsutum. Promoter analysis showed that the most cis-acting elements related to MeJA and ABA were contained. Through RNA-seq combined with genotyping, it was found that 11 GhSCPL genes not only had significant expression changes during Verticillium wilt stress but also had differential SNPs in the upstream, downstream, exonic or intronic regions. The expression of these 11 genes in the resistant (Zhongzhimian 2) and susceptible (Junmian 1) materials was further analyzed by qRT-PCR, it was found that 6 genes showed significant expression differences in the two materials. Among them, Gh_SCPL42 has the most obvious expression change. Furthermore, virus-induced gene silencing (VIGS) showed necrosis and yellowing of leaves and significantly higher disease severity index (DSI) and disease severity rate (DSR) values in VIGS plants than in control silenced Gh_SCPL42 plants. Moreover, the expression levels of genes related to the SA and JA pathways were significantly downregulated. These results show that Gh_SCPL42 might improve resistance to Verticillium wilt through the SA and JA pathways in G. hirsutum. CONCLUSION: In conclusion, our findings indicated that Gh_SCPL42 gene plays an important role in resistance to Verticillium wilt in cotton. It was provided an important theoretical basis for further research on the function of SCPL gene family and the molecular mechanism of resistance to Verticillium wilt in cotton.

Phloem unloading via the apoplastic pathway is essential for shoot distribution of root-synthesized cytokinins.

Root-synthesized cytokinins are transported to the shoot and regulate the growth, development, and stress responses of aerial tissues. Previous studies have demonstrated that Arabidopsis (Arabidopsis thaliana) ATP binding cassette (ABC) transporter G family member 14 (AtABCG14) participates in xylem loading of root-synthesized cytokinins. However, the mechanism by which these root-derived cytokinins are distributed in the shoot remains unclear. Here, we revealed that AtABCG14-mediated phloem unloading through the apoplastic pathway is required for the appropriate shoot distribution of root-synthesized cytokinins in Arabidopsis. Wild-type rootstocks grafted to atabcg14 scions successfully restored trans-zeatin xylem loading. However, only low levels of root-synthesized cytokinins and induced shoot signaling were rescued. Reciprocal grafting and tissue-specific genetic complementation demonstrated that AtABCG14 disruption in the shoot considerably increased the retention of root-synthesized cytokinins in the phloem and substantially impaired their distribution in the leaf apoplast. The translocation of root-synthesized cytokinins from the xylem to the phloem and the subsequent unloading from the phloem is required for the shoot distribution and long-distance shootward transport of root-synthesized cytokinins. This study revealed a mechanism by which the phloem regulates systemic signaling of xylem-mediated transport of root-synthesized cytokinins from the root to the shoot.

TUFM is involved in Alzheimer's disease-like pathologies that are associated with ROS.

Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) is part of the mitochondrial translation machinery. It is reported that TUFM expression is reduced in the brain of Alzheimer's disease (AD), suggesting that TUFM might play a role in the pathophysiology. In this study, we found that TUFM protein level was decreased in the hippocampus and cortex especially in the aged APP/PS1 mice, an animal model of AD. In HEK cells that stably express full-length human amyloid-ß precursor protein (HEK-APP), TUFM knockdown or overexpression increased or reduced the protein levels of ß-amyloid protein (Aß) and ß-amyloid converting enzyme 1 (BACE1), respectively. TUFM-mediated reduction of BACE1 was attenuated by translation inhibitor cycloheximide (CHX) or α-[2-[4-(3,4-Dichlorophenyl)-2-thiazolyl]hydrazinylidene]-2-nitro-benzenepropanoic acid (4EGI1), and in cells overexpressing BACE1 constructs deleting the 5' untranslated region (5'UTR). TUFM silencing increased the half-life of BACE1 mRNA, suggesting that RNA stability was affected by TUFM. In support, transcription inhibitor Actinomycin D (ActD) and silencing of nuclear factor κB (NFκB) failed to abolish TUFM-mediated regulation of BACE1 protein and mRNA. We further found that the mitochondria-targeted antioxidant TEMPO diminished the effects of TUFM on BACE1, suggesting that reactive oxygen species (ROS) played an important role. Indeed, cellular ROS levels were affected by TUFM knockdown or overexpression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation at selective sites was attenuated by TEMPO. Collectively, TUFM protein levels were decreased in APP/PS1 mice. TUFM is involved in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role.

Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression.

Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-ß precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, ß-amyloid protein (Aß) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline. Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.

A genome-wide survey of copy number variations reveals an asymmetric evolution of duplicated genes in rice.

BACKGROUND: Copy number variations (CNVs) are an important type of structural variations in the genome that usually affect gene expression levels by gene dosage effect. Understanding CNVs as part of genome evolution may provide insights into the genetic basis of important agricultural traits and contribute to the crop breeding in the future. While available methods to detect CNVs utilizing next-generation sequencing technology have helped shed light on prevalence and effects of CNVs, the complexity of crop genomes poses a major challenge and requires development of additional tools. RESULTS: Here, we generated genomic and transcriptomic data of 93 rice (Oryza sativa L.) accessions and developed a comprehensive pipeline to call CNVs in this large-scale dataset. We analyzed the correlation between CNVs and gene expression levels and found that approximately 13% of the identified genes showed a significant correlation between their expression levels and copy numbers. Further analysis showed that about 36% of duplicate pairs were involved in pseudogenetic events while only 5% of them showed functional differentiation. Moreover, the offspring copy mainly contributed to the expression levels and seemed more likely to become a pseudogene, whereas the parent copy tended to maintain the function of ancestral gene. CONCLUSION: We provide a high-accuracy CNV dataset that will contribute to functional genomics studies and molecular breeding in rice. We also showed that gene dosage effect of CNVs in rice is not exponential or linear. Our work demonstrates that the evolution of duplicated genes is asymmetric in both expression levels and gene fates, shedding a new insight into the evolution of duplicated genes.

MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation.

MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer's disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5' untranslated region (5'UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5'UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer's disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-ß precursor protein processing, amyloid-ß load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer's disease, via the translational regulation of BACE1.

Furin promotes dendritic morphogenesis and learning and memory in transgenic mice.

Furin is a proprotein convertase implicated in a variety of pathological processes including neurodegenerative diseases. However, the role of furin in neuronal plasticity and learning and memory remains to be elucidated. Here, we report that in brain-specific furin transgenic (Furin-Tg) mice, the dendritic spine density and proliferation of neural progenitor cells were significantly increased. These mice exhibited enhanced long-term potentiation (LTP) and spatial learning and memory performance, without alterations of miniature excitatory/inhibitory postsynaptic currents. In the cortex and hippocampus of Furin-Tg mice, the ratio of mature brain-derived neurotrophic factor (mBDNF) to pro-BDNF, and the activities of extracellular signal-related kinase (ERK) and cAMP response element-binding protein (CREB) were significantly elevated. We also found that hippocampal knockdown of CREB diminished the facilitation of LTP and cognitive function in Furin-Tg mice. Together, our results demonstrate that furin enhances dendritic morphogenesis and learning and memory in transgenic mice, which may be associated with BDNF-ERK-CREB signaling pathway.

Projection data smoothing through noise-level weighted total variation regularization for low-dose computed tomography.

Reducing radiation dose while maintaining the quality of the reconstructed images is a major challenge in the computed tomography (CT) community. In light of the non-stationary Gaussian noise distribution, we developed a model that incorporates a noise-level weighted total variation (NWTV) regularization term for denoising the projection data. Contrary to the well-known edge-weighted total variation method, which aims for better edge preserving, the proposed NWTV tries to adapt the regularization with the spatially varying noise levels. Experiments on simulated data as well as the real imaging data suggest that the proposed NWTV regularization could achieve quite competitive results. For sinograms with sharp edges, the NWTV could do a better job at balancing noise reduction and edge preserving, such that noise is removed in a more uniform manner. Another conclusion from our experiments is that the well-recognized stair-casing artifacts of TV regularization play little role in the reconstructed images when the NWTV method is applied to low-dose CT imaging data.

Phylogeography and population genetic analyses reveal the speciation of the Tuber indicum complex.

Tuber indicum is an ectomycorrhizal ascomycete that produces edible ascocarps. Based on a number of specimens with known exact origin, we investigate the speciation of the Tuber indicum complex in southwest China. Internal transcribed spacer (ITS) and simple sequence repeat (SSR) markers were used in the study. Phylogeography and population genetics analyses were combined to detect 31 wild populations of the T. indicum complex. Two distinct lineages, Tuber cf. indicum and Tuber cf. himalayense, were identified in the T. indicum complex that exhibited significant phylogeographic structures and genetic differentiation. The characteristics of haplotypes distributing along the river demonstrate that the diffusion and modern distribution pattern of species was influenced by river expansion. These findings are critical for the protection of the diversity of truffles in this region.

Histone deacetylase inhibitor apicidin increases expression of the α-secretase ADAM10 through transcription factor USF1-mediated mechanisms.

ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) is the α-secretase that is involved in APP (ß-amyloid precursor protein) processing. Enhancement of the nonamyloidogenic APP pathway by ADAM10 provides therapeutic potential for Alzheimer's disease (AD). By using high-throughput screening that targeted ADAM10, we determined that apicidin-an inhibitor of HDACs (histone deacetylases)-significantly increased mRNA and protein levels of ADAM10 in SH-SY5Y cells. A luciferase assay revealed that the nucleotides -444 to -300 in the ADAM10 promoter were sufficient to mediate this effect. In addition, knockdown of USF1 (upstream transcription factor 1) and HDAC2/3 prevented apicidin regulation of ADAM10. Moreover, USF1 acetylation was increased by apicidin, which enhanced the association of USF1 with HDAC2/3 and with the ADAM10 promoter. We further found that apicidin did not affect the phosphorylation of ERK or USF1; however, ERK inhibitor U0126 blocked the effect of apicidin on ADAM10. Finally, apicidin increased the level of α-site C-terminal fragment from APP and reduced the production of ß-amyloid peptide 1-42. Collectively, our study provides evidence that ADAM10 expression can be regulated by HDAC2/3 inhibitor apicidin via USF1-dependent mechanisms in which ERK signaling plays an important role. Thus, HDAC regulation of ADAM10 might shed new light on the understanding of AD pathology.-Hu, X.-T., Zhu, B.-L., Zhao, L.-G., Wang, J.-W., Liu, L., Lai, Y.-J., He, L., Deng, X.-J., Chen, G.-J. Histone deacetylase inhibitor apicidin increases expression of the α-secretase ADAM10 through transcription factor USF1-mediated mechanisms.

Enantioselective separation of RS-mandelic acid using ß-cyclodextrin modified Fe3O4@SiO2/Au microspheres.

Chiral magnetic microspheres show great potential in direct enantioseparation. Herein novel chiral magnetic microspheres were prepared by self-assembling ß-cyclodextrin on magnetic Fe3O4@SiO2/Au composite microspheres. The prepared materials were characterized by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), vibrating sample magnetometry (VSM) and Fourier transform infrared spectroscopy (FTIR). The results showed that the functional microspheres have a three-ply structure and high saturation magnetization. ß-Cyclodextrin-immobilized magnetic Fe3O4@SiO2/Au microspheres (Fe3O4@SiO2/Au/ß-CD) were applied in the direct chiral separation of RS-mandelic acid. The analysis results of HPLC revealed that the Fe3O4@SiO2/Au/ß-CD magnetic microspheres exhibited stronger enantioselective adsorption for R-mandelic acid than S-mandelic acid. The chiral selector functionalized magnetic microspheres are therefore expected to be an efficient and economical chiral separation method for use in further research.