Search

Acute Intermittent Porphyria (AIP), an autosomal dominant hepatic disorder, results from hydroxymethylbilane synthase (HMBS) mutations that decrease the encoded enzymatic activity, thereby predisposing patients to life-threatening acute neurovisceral attacks. The ~1% penetrance of AIP suggests that other genetic factors modulate the onset and severity of the acute attacks. Here, we characterized the hepatic transcriptomic response to phenobarbital (PB) administration in AIP mice, which mimics the biochemical attacks of AIP. At baseline, the mRNA profiles of 14,138 hepatic genes prior to treatment were remarkably similar between AIP and the congenic wild-type (WT) mice. After PB treatment (~120 mg/kg x 3d), 1347 and 1120 genes in AIP mice and 422 and 404 genes in WT mice were uniquely up- and down-regulated, respectively, at a False Discovery Rate < 0.05. As expected, the ALAS1 expression increased 4.5-fold and 15.9-fold in the WT and AIP mice, respectively. ALA-dehydrogenase also was induced ~1.7-fold in PB-induced AIP mice, but was unchanged in PB-induced WT mice. There was no statistically significant difference in the overall expression of 155 hepatic cytochrome P450 enzymes, although Cyp2c40, Cyp2c68, Cyp2c69, Mgst3 were upregulated only in PB-induced AIP mice (>1.9-fold) and Cyp21a1 was upregulated only in PB-induced WT mice (>9-fold). Notably, the genes differentially expressed in induced AIP mice were enriched in circadian rhythm, mitochondria biogenesis and electron transport, suggesting these pathways were involved in AIP mice responding to PB treatment. These results advance our understanding of the hepatic metabolic changes in PB-induced AIP mice and have implications in the pathogenesis of AIP acute attacks. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel indole-2-carbonyl piperazine urea derivatives were discovered as FAAH inhibitors. • Active compound 4i showed potent FAAH activities (IC 50 = 0.12 μM) and high selectivity over CB receptors, CES2, ABHD6 and MAGL. • Compound 4i exhibited an adequate pharmacokinetics profile in rodents and superior metabolic stability in human liver microsome. • Compound 4i effectively ameliorated reserpine-induced depression-like behaviors and also exhibited remarkable analgesic activity in vivo test. Fatty acid amide hydrolase (FAAH), a serine hydrolase with significant role in the hydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC 50 = 0.12 μM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Oncolytic adenoviruses represent a promising therapeutic medicine for human cancer therapy, but successful translation into human clinical trials requires careful evaluation of their viral characteristics. While the function of adenovirus proteins has been analyzed in detail, the dynamics of adenovirus infection remain largely unknown due to technological constraints that prevent adequate tracking of adenovirus particles after infection. Fluorescence labeling of adenoviral particles is one new strategy designed to directly analyze the dynamic processes of viral infection in virus–host cell interactions. We hypothesized that the double labeling of an adenovirus with fluorescent proteins would allow us to properly analyze intracellular viruses and the fate of viral proteins in a live analysis of an adenovirus as compared to single labeling. Thus, we generated a fluorescently labeled adenovirus with both a red fluorescent minor capsid protein IX (pIX) [pIX monomeric red fluorescent protein 1 (mRFP1)] and a green fluorescent minor core protein V (pV) [pV enhanced green fluorescent protein (EGFP)], resulting in Ad5-IX-mRFP1-E3-V-EGFP. The fluorescent signals for pIX-mRFP1 and pV-EGFP were detected within 10 min in living cells. However, a growth curve analysis of Ad5-IX-mRFP1-E3-V-EGFP showed an approximately 150-fold reduced production of the viral progeny at 48 h postinfection as compared to adenovirus type 5. Interestingly, pIX-mRFP1 and pV-EGFP were initially localized in the cytoplasm and nucleolus, respectively, at 18 h postinfection. These proteins were observed in the nucleus during the late stage of infection, and relocalization of the proteins was observed in an adenoviral-replication-dependent manner. These results indicate that simultaneous detection of adenoviruses using dual-fluorescent proteins is suitable for real-time analysis, including identification of infected cells and monitoring of viral spread, which will be required for a complete evaluation of oncolytic adenoviruses. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of this study was to investigate the effect of preexisting neutralizing antibody (NAbs) in naive mice and the effect of induced NAbs in mice immunized with either an RGD or nonmodified Ad5 vector on the transduction efficiency of adenoviral vectors. Methods: BALB/c mice were immunized with Ad5LucRGD, with the unmodified Ad5Luc1, or with Opti-MEM intraperitoneally (ip) from one to three times. Sera were collected on day 27 and serially diluted to block Ad5Luc1 or Ad5LucRGD prior to infection of SKOV3.ip1 human ovarian carcinoma cells with these same vectors. Forty-eight hours post Ad infection, a luciferase assay was performed to determine the titer of NAbs. Results: Luciferase assay data showed that the gene transfer efficacy of Ad5LucRGD was 1.56-fold higher than Ad5Luc1 in the presence of serum from naive mice. In the presence of serum from Ad5Luc1-challenged mice, the transduction efficiency of Ad5LucRGD was 3.27-fold higher (single challenge) and 4.2-fold higher (triple challenge) than Ad5Luc1. In the presence of serum from Ad5LucRGD-challenged mice, the transduction efficiency of Ad5LucRGD was 2.24-fold higher (single challenge) and 2.53-fold higher (triple challenge) than Ad5Luc1. Conclusion: The RGD-modified human Ad vectors appear to be less recognizable than unmodified Ad to preexisting NAbs in mouse models. RGD-modified Ad vectors also appear to elicit a relatively lower level of NAbs that may also contribute to the higher gene transduction efficiency of these modified vectors. Therefore, RGD-modified Ad vectors may be reagents of clinical utility in the context of preformed anti-Ad immunity and in the setting of repetitive dosing. [Copyright &y& Elsevier]

The expression of therapeutic genes by oncolytic viruses is a promising strategy to improve viral oncolysis, to augment gene transfer compared with a nonreplicating adenoviral vector, or to combine virotherapy and gene therapy. Both the mode of transgene expression and the locale of transgene insertion into the virus genome critically determine the efficacy of this approach. We report here on the properties of oncolytic adenoviruses which contain the luciferase cDNA fused via an optimized internal ribosome entry site (IRES) to the immediate early adenoviral gene E1A (AdΔE1AIL), the early gene E2B (AdΔE2BIL), or the late fiber gene (AdΔfiberIL). These viruses showed distinct kinetics of transgene expression and luciferase activity. Early after infection, luciferase activities were lower for these viruses, especially for AdΔE2BIL, compared with nonreplicating AdTL, which contained the luciferase gene expressed from the strong CMV promoter. However, 6 days after infection, luciferase activities were approximately four (AdΔE1AIL) to six (AdΔfiberIL) orders of magnitude higher than for AdTL, reflecting virus replication and efficient transgene expression. Similar results were obtained in vivo after intratumoral injection of AdΔE2BIL, AdΔfiberIL, and AdTL. AdΔfiberIL and the parental virus, Ad5-Δ24, resulted in similar cytotoxicity, but AdΔE2BIL and AdΔE1AIL were slightly attenuated. Disruption of the expression of neighboring viral genes by insertion of the transgene was minimal for AdΔE2BIL and AdΔfiberIL, but substantial for AdΔE1AIL. Our observations suggest that insertion of IRES-transgene cassettes into viral transcription units is an attractive strategy for the development of armed oncolytic adenoviruses with defined kinetics and strength of transgene expression. [Copyright &y& Elsevier]

An efficient 3D bifunctional nanofiber electrocatalyst with synergistic multiple active sites for high-performance aqueous/solid ZABs was developed by electrospinning and MOF/COF in-situ growth strategy. [Display omitted] Covalent organic frameworks (COFs) and metal–organic frameworks (MOFs) have attracted growing attention in electrochemical energy storage and conversion systems (e.g., Zn-air batteries, ZABs) owing to their structural tunability, ordered porosity and high specific surface area. In this work, for the first time, the three-dimensional (3D) highly open catalyst (CNFs/CoZn-MOF@COF) possessing hierarchical porous structure and high-density active sites of uniform cobalt (Co) nanoparticles and metal-N x (M-N x , M = Co and Zn) is demonstrated, which is fabricated using electrospinning technique in combination with MOF/COF hybridization strategy and direct pyrolysis. Benefiting from the well-designed branch-leaf nanostructures, plentiful and uniform active sites on the MOF/COF-derived carbon frameworks, as well as the synergistic effect of multiple active sites, CNFs/CoZn-MOF@COF catalyst achieves superior electrocatalytic activity and stability towards both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) with a small potential gap (ΔE = 0.75 V). In situ Raman spectroscopy and X-ray photoelectron spectroscopy results indicate that the CoOOH intermediates are the main active species during OER/ORR. Significantly, both aqueous and all-solid-state rechargeable ZABs assembled with CNFs/CoZn-MOF@COF as the air cathode show high open-circuit potential, outstanding peak power density, large capacity and long cycle life. More impressively, the obtained all-solid-state ZAB also displays superb mechanical flexibility and device stability under different, showcasing great application deformations potential in portable and wearable electronics. This work provides a new insight into the design and exploitation of bifunctional catalysts from MOF/COF hybrid materials for energy storage and conversion devices. [ABSTRACT FROM AUTHOR]

[Display omitted] Lignin upgrading to various functional products is promising to realize high-value utilization of low-cost and renewable biomass waste, but is still in its infancy. Herein, using industry waste lignosulfonate as the biomass-based carbon source and urea as the dopant, we constructed a heteroatom-doped porous carbon nanosheet structure by a simple NaCl template-assisted pyrolytic strategy. Through the synergistic effect of the NaCl template and urea, the optimized lignin-derived porous carbon catalyst with high content of active nitrogen species and large specific surface area can be obtained. As a result, the fabricated catalysts exhibited excellent electrocatalytic oxygen reduction activity, as well as good methanol tolerance and stability, comparable to that of commercial Pt/C. Moreover, rechargeable Zn-air batteries assembled with this electrocatalyst have a peak power density of up to 150 mW cm-2 and prominent long-term cycling stability. This study offers an inexpensive and efficient way for the massive production of highly active metal-free catalysts from the plentiful, inexpensive and environmentally friendly lignin, offering a good direction for biomass waste recycling and utilization. [ABSTRACT FROM AUTHOR]

A MOF-derived low Ru-loaded high entropy alloy self-supporting electrode is proposed for ZABs. This work provides a good guide for improving catalytic performance. [Display omitted] Exploiting the high-entropy alloy (HEA) electrocatalysts with the synergistic effect of multi-metal components is an effective approach to address the slow kinetics and undesirable stability of the oxygen evolution reaction (OER) in Zn-air batteries (ZABs), but still faces many challenges. In this study, a multimetallic Metal-organic framework (MOF)-derived HEA catalyst was successfully fabricated on carbon fiber as a flexible self-supporting electrode (denoted as CC@FeCoNiMoRu-HEA/C) for high-performance liquid/flexible ZABs using a facile and cost-effective strategy. The three-dimensional (3D) highly open network framework and hierarchical porous structure accelerate the mass transport of OH−/O 2 and charge transfer. The electronic structure adjustment, lattice defects and high entropy effects enable the CC@FeCoNiMoRu-HEA/C catalysts to perform high OER catalytic activity and strong durability while reducing the Ru content and lowering the economic cost. In situ Raman spectra and XPS results reveal the generation of metal-OOH intermediates on the HEA surface during the OER process. In a practical demonstration, the liquid ZAB assembled with CC@FeCoNiMoRu-HEA/C + Pt/C as the air electrode offers stable open-circuit voltage, large power density, excellent specific capacity and satisfactory cycle life, outperforming the commercial RuO 2 + Pt/C-based reference ZAB. More attractively, the flexible solid-state ZAB also achieves fast dynamic response, high peak power density, robust cycling stability as well as favorable mechanical flexibility, indicating a promising application prospect in future flexible electronics and wearable devices. This work provides a viable pathway to develop low precious metal-loaded HEAs as advanced OER self-supporting electrocatalysts and realize high-performance flexible energy storage devices. [ABSTRACT FROM AUTHOR]

Open-hollow microcapsule with oxygen vacancies and Ni/NiO hybrids is used as host materials of anchoring sulfur. Chemisorption, physical confinement and catalyst effect accelerate kinetics and improve the electrochemical performance of Li-S battery synergistically. [Display omitted] The fast development of lithium-sulfur (Li-S) batteries is catching more attention to improve cycling stability and kinetics. Herein, a hierarchical porous Ni/NiO/C microsphere (NIONC) with openings assembled by ultrathin nanosheets is introduced to solve the poor conductivity, shuttle effect, and slow electrochemical kinetics of Li-S batteries. The structure of NIONC open-hollow microcapsules combines several advantageous properties for the improvement of electrochemical performances. Primarily, a well-developed hollow structure and openings can perform as containers and doors for sulfur immobilization. Therefore, the confinement effect to sulfur species is obtained by this hollow sphere. Secondly, the nanosheets with oxygen vacancies and Ni active sites provide abundant active sites for the chemical absorption of polysulfides. Based on the open structure and oxygen vacancies of Ni/NiO, both the physical absorption and chemical immobilization of sulfur are realized, with high stability and fast kinetics. The S-injected NIONC (NIONC/S) cathode exhibits outstanding rate performance at 5 A g-1 with a high capability of 794 mAh g-1 and excellent long-cycle performance of 653 mAh g-1 after 300 cycles at 1 A g-1. We proposed a simple and controllable route to fabricate sulfur hosts by structure and composition adjustment, which will inspire the commercial application of Li-S batteries. [ABSTRACT FROM AUTHOR]

Abstract: Adenoviral infection induces nucleoplasmic redistribution of a nucleolar nucleophosmin 1/NPM1/B23.1. NPM1 is preferentially localized in the nucleoli of normal cells, whereas it is also present at the nuclear matrix in cancer cells. However, the biological roles of NPM1 during infection are unknown. Here, by analyzing a pV-deletion mutant, Ad5-dV/TSB, we demonstrate that pV promotes the NPM1 translocation from the nucleoli to the nucleoplasm in normal cells, and the NPM1 translocation is correlated with adenoviral replication. Lack of pV causes a dramatic reduction of adenoviral replication in normal cells, but not cancer cells, and Ad5-dV/TSB was defective in viral assembly in normal cells. NPM1 knockdown inhibits adenoviral replication, suggesting an involvement of NPM1 in adenoviral biology. Further, we show that NPM1 interacts with empty adenovirus particles which are an intermediate during virion maturation by immunoelectron microscopy. Collectively, these data implicate that pV participates in a process of viral assembly through NPM1. [Copyright &y& Elsevier]

Abstract: Human adenovirus serotype 5 (HAdV-5) attaches to its primary receptor, the coxsackie and adenovirus receptor (CAR) as the first step of infection. However, CAR expression decreases as tumors progress, thereby diminishing the utility of HAdV-5-based vectors for cancer therapy. In contrast, many aggressive tumor cells highly express CD46, a cellular receptor for HAdV-3. We hypothesized that a mosaic HAdV vector, containing two kinds of fiber proteins, would provide extensive transduction in a heterogeneous population of tumor cells with varying expression levels of HAdV receptors. We therefore generated a fiber-mosaic HAdV vector displaying both a chimeric HAdV-3 fiber and the HAdV-5 fiber protein. We verified the structural integrity of purified viral particles and confirmed that the fiber-mosaic HAdV vector has expanded tropism. We conclude that the use of fiber-mosaic HAdV vectors is a promising approach for transducing a heterogeneous cell population with different expression levels of adenovirus receptors. [ABSTRACT FROM AUTHOR]

• Species-specific ubiquitination site prediction method superior to general method. • Studies species-specific ubiquitination site prediction by using transfer learning technique. • The proposed DeepTL-Ubi method is very excellent in species-specific ubiquitination site prediction work. Ubiquitination is one of the most important post-translational modifications which involves in many biological processes. Because mass spectrometry-based ubiquitination site identification methods are costly and time consuming, computational approaches provide alternative ways to the determination of ubiquitination sites. Although machine learning based methods can effectively predict ubiquitination sites, most of them rely on feature engineering, which may lead to bias or incomplete feature. Recently, deep learning has achieved great success in prediction of post-translational modification sites. However, deep learning method has not been explored in the prediction of species-specific ubiquitination sites. In this paper, we propose a novel transfer deep learning method, named DeepTL-Ubi, for predicting ubiquitination sites of multiple species. DeepTL-Ubi enhances the performance of species-specific ubiquitination site prediction by transferring common knowledge from the large amount of human data to other species, which effectively solves the problem of insufficient training data for other species. Besides, we train and test our model by collecting ubiquitination sites for multiple species from several sources. Experiment results show that our transfer learning technique can effectively improve the predictive performance of species with small sample size, and DeepTL-Ubi is superior to existing tools in many species. The source code and training data of DeepTL-Ubi are publicly deposited at https://github.com/USTC-HIlab/DeepTL-Ubi. [ABSTRACT FROM AUTHOR]

Episodic memory of scatter-hoarding animals involves encoding and storage of memories of cached food items, in conjunction with subsequent retrieval or recovery. Although the reward values mediate the interaction of item memory and source memory, whether nonhuman animals divide their spatial memory resources between cached items of different values has never been tested. Here, we used a unique scatter-hoarder/seed system to test our 'cache value hypothesis', which proposes that scatter-hoarding animals will preferentially allocate spatial memory resources towards higher-valued caches. By making Edwards's long-tailed rats, Leopoldamys edwardsi , anosmic, using Triton X-100, we showed that L. edwardsi recovered more caches containing large nuts than those containing small ones, although the two kinds of nuts were equivalently cached. Our results therefore support the hypothesis that scatter-hoarding animals allocate more spatial memory resources to caches containing high-valued items. This is one of the few studies to investigate how item memory regulates source memory (order information) in the context of food storing and recovery by animals, especially by scatter-hoarding rodents. That high-valued items were remembered better than low-valued ones in our study suggests that item memory appears to be contextually associated with order information of items in animal memory processes, which is not in agreement with a previous suggestion that order information is independent of content or item information. • We used a scatter-hoarding rodent to test episodic memory. • Edward's long-tailed rats allocated more memory on high-valued caches. • High-valued items were remembered better than low-valued ones. • The rats know 'what food' was cached 'where' or 'when'. [ABSTRACT FROM AUTHOR]

• Desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group was designed and synthesized. • The most active B14 exhibited activities at submicromolar concentration against a panel of MRSA strains. • B14 also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. • Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 μg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity. [ABSTRACT FROM AUTHOR]

Panax ginseng and Panax quinquefolium are two valuable Chinese herbal medicines that should not be mixed because they differ in drug properties and efficacy. The traditional identification method is easily affected by subjective factors and cannot effectively distinguish between ginseng products. This study aimed to develop a new chemical analysis method to visually identify P. ginseng and P. quinquefolium. In this method, a large number of sequences containing G-quadruplex were generated by loop-mediated isothermal amplification, and the combination of G-quadruplex and hemin was used to form deoxyribozyme, which catalyzed the color change of H 2 O 2. Artificial simulation of adulteration experiments revealed that this method could detect more than 20% adulterated P. quinquefolium. Compared with the traditional identification methods, this technology was simpler and more efficient, providing a reference for developing rapid visual identification methods and reagents for P. ginseng and P. quinquefolium. [Display omitted] • Find the difference region between Panax ginseng and Panax quinquefolium and establish LAMP reaction. • To facilitate the observation of LAMP reaction results, G-4 complementary sequence was introduced into BIP sequence. • The visual detection method based on LAMP and DNAzyme can be used to identify the components of ginseng products. [ABSTRACT FROM AUTHOR]

Mitochondrion is important organelle of most eukaryotes and play an important role in participating in various life activities of cells. However, some functions of mitochondria can only be achieved in specific submitochondrial location, the study of submitochondrial locations will help to further understand the biological function of protein, which is a hotspot in proteomics research. In this paper, we propose a new method for protein submitochondrial locations prediction. Firstly, the features of protein sequence are extracted by combining Chou's pseudo-amino acid composition (PseAAC) and pseudo-position specific scoring matrix (PsePSSM). Then the extracted feature information is denoised by two-dimensional (2-D) wavelet denoising. Finally, the optimal feature vectors are input to the SVM classifier to predict the protein submitochondrial locations. We obtained the ideal prediction results by jackknife test and compared with other prediction methods. The results indicate that the proposed method is significantly better than the existing research results, which can provide a new method to predict protein locations in other organelles. The source code and all datasets are available at https://github.com/QUST-BSBRC/PseAAC-PsePSSM-WD/ for academic use. [ABSTRACT FROM AUTHOR]

It has been widely reported that the general population was at an increased risk of allergy diseases, which probably be related with household allergens exposure. However, the difference of local and systemic allergic reactions exposure to allergens has not been reported in the general population previously. The data of 1094 U.S. adults from the National Health and Nutrition Examination Survey (NHANES) 2005–2006 data bank were analyzed. Dust, allergens (Bia g 1, Bia g 2, Can f 1, Feld 1, Derp 1, Mus m 1, Rat n 1, Alternaria alternate , and Aspergillus fumigatus), and endotoxin, were measured to estimate sensitizing source exposure. And allergy-related outcomes indicators including hay fever, sneezing, allergic rhinitis (AR), immunoglobulin E (IgE), and allergic sensitization, were evaluzted to estimate local and systemic allergic reactions. Multiple linear regression and logistic regression models were used to examine the associations of sensitizer and allergy-related outcomes. The mean or median concentration of dust and endotoxin were 0.66 g and 12.98 EU/mg dust. The Derp 1, Mus m 1, Rat n 1, Alternaria alternate , and Aspergillus fumigatus were the main allergens in the dust, with the concentrations of 30.66 ng/g dust, 30.73 ng/g dust, 5.94 ng/g dust, 5.20 ng/g dust, and 207.68 μg/g dust, respectively. The prevalence of AR was 34.2% among the general population. After controlling for sociodemographic factors, we found that the allergens, such as Can f 1 and Feld 1, were positively associated with AR. The prevalence of allergic sensitization was about 20%. Dust and endotoxin were found positively associated with allergic sensitization, while Bia g 2, Rat n 1, Alternaria alternate , and Aspergillus fumigatus were inversely associated with that. Dust and endotoxin probably be associated with higher risk of local allergic reactions, while some allergens, such as Bia g 2, Rat n 1, Alternaria alternate , and Aspergillus fumigatus probably be associated with lower risk of systemic allergic reactions. [Display omitted] • Household low concentration of dust, allergens, and endotoxin exposure probably be related with allergy-related outcomes. • Dust and endotoxin probably be associated with higher risk of local allergic reactions. • Some allergens probably be associated with lower risk of systemic allergic reactions. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we identified that miR-599 is up-regulated in non-small cell lung cancer (NSCLC) patients. It promoted NSCLC cell proliferation by negatively regulating SATB2. In NSCLC cell lines, CCK-8 proliferation assay indicated that the cell proliferation is promoted by miR-599 mimics. Transwell assay showed that miR-599 mimics promoted the invasion and migration of NSCLC cells. Luciferase assays confirmed that miR-599 directly binds to the 3'untranslated region of SATB2, and western blotting showed that miR-599 suppresses the expression of SATB2 at the protein level. This study indicates that miR-599 promotes proliferation and invasion of NSCLC cell lines via SATB2. The miR-599 may represent a potential therapeutic target for NSCLC treatment. [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription 3 (STAT3) signaling pathway was involved in regulation of endothelial cell survival/apoptosis and was regarded as a target for prevention of atherosclerosis or other cardiovascular diseases. Factors, regulating STAT3 expression and activity, have aroused a wide range of interest, such as miRNAs or transcription factors. The aim of this study is to explore the role of miR-351, a miRNA found not long before, in the regulation of STAT3 expression and endothelial cell survival in the model mice with atherosclerosis (AS). Expression of miR-351 in the serum and cardiac arterial endothelial cells of the WT mice and AS mice was detected. Real-time qPCR analysis showed that miR-351 was upregulated in the serum and endothelial cells of the AS mice, displaying an opposite expression pattern with STAT3. To explore the role and mechanism of miR-351 in the endothelial cell survival, the miR-351 mimic was transfected in to the endothelial cells. MTT and Trypan Blue assays showed miR-351 attenuated the survival of endothelial cells. Our results of the TargetScan output and the 3′UTR luciferase reporter assay indicated that STAT3 was target of miR-351. Additionally, miR-351 resisted the elevation of STAT3 protein level and promotion of endothelial cell survival caused by SD19. Finally, our in vitro angiogenesis assay revealed that miR-351 suppressed angiogenesis and resisted the promotion of angiogenesis caused by SD19. In conclusion, miR-351 was upregulated in the atherosclerotic mice. MiR-351 can attenuate the survival of endothelial cells and suppress angiogenesis through targeting STAT3 in vitro. [ABSTRACT FROM AUTHOR]

Highlights: [•] Automatically extracting information of substrates, kinases and sites from literature. [•] Employing dependency parse trees to precisely reflect syntactic structure of sentence. [•] Significantly improved performance as compared with existing tool. [•] A powerful bioinformatics tool freely available to researchers. [Copyright &y& Elsevier]

Abstract: This paper presents a novel method for fusing multi-exposure images into a low dynamic range (LDR) image that is suitable for display and visualization but it contains details in the high dynamic range (HDR) counterpart. Fused gradient field is derived from the structure tensor of inputs based on multi-dimensional Riemannian geometry with a Euclidean metric assumed. Afterwards, a new method is proposed for modifying the gradient field iteratively with twice average filtering and nonlinearly compressing in multi-scales. These modification operations are all done at the finest resolution. The result is obtained through solving a Poisson equation then linearly stretching to the common range. Experimental results demonstrate the efficiency and effectiveness of this method. [Copyright &y& Elsevier]

Abstract: Background. : Hec1 (Highly Expressed in Cancer gene 1) has recently been shown to play an important role in the proper segregation of chromosomes during mitosis. Recently, an adenovirus delivery system carrying RNA interference (RNAi) of Hec1 has been reported in a cervical adenocarcinoma model. Adenoviral delivery systems, however, have the main limitation of poor viral infectivity due to lack of the native receptor, Coxsackie–Adenovirus Receptor (CAR), on the surface of tumor cells. We hypothesize that the viral infectivity of the adenovirus vector would be enhanced via a CAR-independent pathway by altering the targeting tropism, thus increasing the knockdown effect of Hec1 expression in ovarian carcinoma cells. Methods. : Two adenoviruses (Ad-siRNA-Hec1 and Ad-siRNA-Hec1.F5/3), along with a negative control (Ad-siRNA-GAPDH.F5/3), were created using homologous recombination. HEY and SKOV3.ip1 cell lines were used to perform experiments. The following assays were then used to determine RNAi knockdown efficiency: (1) quantitative PCR (QPCR), (2) Western blot, (3) MTS assay, (4) Annexin V–FITC FACS, (5) crystal violet staining. In all experiments, a negative control served as a baseline measure. Results. : QPCR demonstrated a 2-log viral infectivity enhancement with Ad-siRNA-Hec1.F5/3 over Ad-siRNA-Hec1. QPCR at 72 h revealed mRNA knockdown induced by Ad-siRNA-Hec1 and Ad-siRNA-Hec1.F5/3 in SKOV3.ip1 and HEY cells, respectively (71%/60%, and 32%/78% mRNA knockdown compared to negative control). Western blot revealed translational inhibition induced by both Hec1 Ads with the least knockdown seen with Ad-siRNA-GAPDH.F5/3. FACS analysis revealed increased annexin V positivity in RNAi-infected cells, suggesting a higher rate of apoptosis. MTS assay indicated increased cell death 8 days post-infection with Ad-siRNA-Hec1 and Ad-siRNA-Hec1.F5/3 in SKOV3.ip1 and HEY cell lines, respectively (75% vs. 35% and 43% vs. 12% viable cells). Crystal violet staining revealed increased cell death with Ad-siRNA-Hec1.F5/3 in all tested cell lines. Conclusions. : RNAi against Hec1 results in gene expression knockdown and apoptosis in vitro. The infectivity-enhanced adenovirus as delivery mechanism shows potential application in future gene therapy models of RNAi in ovarian cancer. [Copyright &y& Elsevier]

Abstract: Objectives. : Current virotherapy strategies for ovarian cancer have been hampered by limitations in target cell infectivity and nonspecific tissue replication. In an effort to circumvent these limitations, we evaluated various CRAds modified to incorporate novel capsid targeting motifs (RGD and chimeric Ad5/3) with a novel tissue-specific promoter (CXCR4). Methods. : Two novel CRAds (Ad5-CXCR4-F5/3 and Ad5-CXCR4-RGD) were constructed via homologous recombination and verified by PCR and DNA sequencing. The infectivity and viral replication rates of these two CRAds were analyzed via quantitative real-time PCR (QRT-PCR) in cell line experiments using three ovarian cancer cell lines (SKOV3.ip1, Hey, and OV4) and compared to that achieved with a clinical grade CRAd (Δ24-RGD) to be evaluated in a Phase I trial. Cytocidal effects were determined by crystal violet staining in these same cell lines infected with different concentrations of viral particles per cell (0, 0.1, 1, 10, 100, and 500). Additionally, viral replication was evaluated by QRT-PCR in primary ovarian cancer tissue slices from multiple patients with ovarian cancer as well as in primary human normal liver tissue slices in order to establish CRAd selectivity. All experiments incorporated appropriate controls and repeated in triplicate. Results. : Compared to RGD-capsid CRAds (Δ24-RGD and CXCR4-RGD), the F5/3-capsid CRAd (CXCR4-F5/3) demonstrated significant improvements in infection rates (p =0.025, 0.006, and 0.006) in all ovarian cancer cell lines tested (SKOV3.ip1, Hey, and OV4, respectively). In addition to improved transduction of virus into the cells, the TSP CXCR4-based CRAds demonstrated improved viral replication. Specifically, CXCR4-F5/3 further enhanced viral replication 89-fold (p =0.009, 0.010, 0.003) in the same cancer cell lines. Furthermore, CXCR4-F5/3 showed a 4-log improvement in oncolytic potential over Δ24-RGD. In the ex vivo primary ovarian tissue slices, CXCR4-F5/3 showed a 58-fold improvement in viral replication (p =0.005) compared to the clinical grade Δ24-RGD. Both CXCR4-F5/3 and CXCR4-RGD demonstrated significant reduction of viral replication in normal liver slices (p =0.001). Conclusions. : These data suggest that a dual targeted approach is feasible for the combined enhancement of infectivity and replication in ovarian cancer with a specificity that was attenuated in normal liver tissues. In fact, CXCR4-F5/3 outperformed our best CRAd agent to date nearly 60-fold in our most stringent ex vivo model of primary ovarian cancer tissue slices and suggests that this novel agent could be useful for the treatment of ovarian cancer. [Copyright &y& Elsevier]

Abstract: Mastadenoviruses represent one of the four major genera of the Adenoviridae family comprising a variety of mammalian pathogens including human adenovirus (Ad), whose genomes encode a gene for minor core protein V (pV), not found in other genera of Adenoviridae. Deletion of other genus-specific genes (gene IX and E3 genes) from the Ad type 5 (Ad5) genome has been studied experimentally in vitro and the results on biological characterization of the mutants support the phylogenetic evidence of those genes being non-essential for Ad viability. On this basis it seemed logical to suggest that a deletion of gene V from the Ad5 genome could also be tolerated. To test this hypothesis we constructed and rescued the first pV-deletion mutant of human Ad5. As compared to Ad5, this mutant formed small plaques, had dramatically reduced thermostability and lower infectivity. A subsequent thermoselection screen of the pV-deleted Ad5 allowed isolation of a suppressor mutant Ad5-dV/TSB with restored biological characteristics. Since replication and viral assembly of Ad5-dV/TSB could still occur in the absence of pV, we conclude that pV is a non-essential component of the virion. The observed rescue of the biological defects appears to be associated with a cluster of point mutations in the gene encoding the precursor for the other core protein, X/Mu. This finding, thus, suggests possible roles of pV and protein X/Mu precursor in viral assembly. It also provides an interesting insight into genetic events that mediate molecular adaptation of viruses to possible changes in the genetic background in the course of their evolutionary divergence. The possible mechanism of the observed genetic suppression is discussed. [Copyright &y& Elsevier]

Abstract: Protein acetylation is an important and reversible post-translational modification (PTM), and it governs a variety of cellular dynamics and plasticity. Experimental identification of acetylation sites is labor-intensive and often limited by the availability of reagents such as acetyl-specific antibodies and optimization of enzymatic reactions. Computational analyses may facilitate the identification of potential acetylation sites and provide insights into further experimentation. In this manuscript, we present a novel protein acetylation prediction program named PAIL, prediction of acetylation on internal lysines, implemented in a BDM (Bayesian Discriminant Method) algorithm. The accuracies of PAIL are 85.13%, 87.97%, and 89.21% at low, medium, and high thresholds, respectively. Both Jack–Knife validation and n-fold cross-validation have been performed to show that PAIL is accurate and robust. Taken together, we propose that PAIL is a novel predictor for identification of protein acetylation sites and may serve as an important tool to study the function of protein acetylation. PAIL has been implemented in PHP and is freely available on a web server at: http://bioinformatics.lcd-ustc.org/pail. [Copyright &y& Elsevier]

Abstract: Objective. : Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods. : Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20%) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS+Δ24-RGD, or icodextrin+Δ24-RGD. Survival data were plotted on Kaplan–Meier curve and statistical calculations performed using the log-rank test. Results. : There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS+Δ24-RGD group, and 105 days for icodextrin+Δ24-RGD (p =0.023). Of note, 5 of the 10 mice in the icodextrin+Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions. : These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development. [Copyright &y& Elsevier]

Adenoviral vectors have a poor record of transgene delivery efficiency through physical barriers such as the epithelium or endothelium. We report here the construction of an adenoviral vector that has the capability to be transported across polarized epithelial monolayers of Caco-2 cells (a colon carcinoma cell line) by transcytosis. This transcytosis is transferrin receptor (TfR)-mediated with use of a bifunctional adaptor, soluble coxsackie adenovirus receptor (sCAR)-Tf, and is both temperature and iron dependent. Under experimental conditions, the adenoviral transcytosis was inhibited by pretreatment of Caco-2 cells with colchicine, an inhibitor of transcytosis, and was not enhanced by pretreatment with Brefeldin A (BFA), an enhancer of transcytosis. In these Caco-2 cells, the transcytosis rate was 0.3 ± 1.3% (SD). The transcytosed adenoviruses remain biologically functional. These data suggest the potential clinical benefit under conditions where drug delivery is a challenge, such as within the airway epithelium, at the bladder lumen urothelial cell interface, and across the blood–brain barrier for clinical treatment of lung, urogenital, and brain disorders, respectively, by adenoviral transcytosis of transgene delivery. [Copyright &y& Elsevier]

The Co&z.sbnd;B amorphous alloy catalyst was prepared by chemical reduction of Co2+ ions with BH4− in aqueous solution. Its activity and selectivity were measured during the liquid phase hydrogenation of acetonitrile and the effects of various factors, such as the reaction time, acetonitrile concentration, hydrogen pressure, reaction temperature, and solvent, were investigated. The following results were obtained: (1) The maximum ethylamine yield of 69% was obtained at the total conversion of acetonitrile. (2) The acetonitrile hydrogenation was zero-order with respect to acetonitrile and first-order with respect to hydrogen. Meanwhile, the selectivity to ethylamine increased slightly with the increase of either hydrogen pressure or acetonitrile concentration. (3) Increased reaction temperature resulted in a great enhancement in the activity (the apparent activation energy was determined as 46 kJ/mol) but a slight decrease in the selectivity to ethylamine. (4) Addition of a little H2O may result in an increase in the activity. All these effects are discussed based on the reaction mechanism. In comparison with other Co-based catalysts, such as Raney Co, pure Co powder catalyst, and the crystallized Co&z.sbnd;B catalyst, the amorphous Co&z.sbnd;B catalyst exhibited much higher activity and better selectivity to ethylamine. Although Ni-based catalysts had higher activity, their poorer selectivity to ethylamine suggested that they were not suitable for the title reaction under the present conditions. Based on the reaction mechanism and various characterizations, including SAED, XRD, SEM, TEM, EXAFS, XPS, hydrogen chemisorption, and DSC, the promoting effects on the activity and selectivity of the Co&z.sbnd;B amorphous catalyst are discussed briefly by considering both the structural characteristics and the electronic interaction between the Co and the alloying B. [Copyright &y& Elsevier]

l A novel method (SGL-SVM) for tumor classification on two-class and multi-class tumor datasets. l Gene primary selection reduces the computational complexity of the selection largely. l Sparse group Lasso considers the group effect variables and select more effective feature genes. l We investigate different feature gene selection methods and classifiers on the results. l The proposed method has better performance than other methods. At present, with the in-depth study of gene expression data, the significant role of tumor classification in clinical medicine has become more apparent. In particular, the sparse characteristics of gene expression data within and between groups. Therefore, this paper focuses on the study of tumor classification based on the sparsity characteristics of genes. On this basis, we propose a new method of tumor classification—Sparse Group Lasso (least absolute shrinkage and selection operator) and Support Vector Machine (SGL-SVM). Firstly, the primary selection of feature genes is performed on the normalized tumor datasets using the Kruskal–Wallis rank sum test. Secondly, using a sparse group Lasso for further selection, and finally, the support vector machine serves as a classifier for classification. We validate proposed method on microarray and NGS datasets respectively. Formerly, on three two-class and five multi-class microarray datasets it is tested by 10-fold cross-validation and compared with other three classifiers. SGL-SVM is then applied on BRCA and GBM datasets and tested by 5-fold cross-validation. Satisfactory accuracy is obtained by above experiments and compared with other proposed methods. The experimental results show that the proposed method achieves a higher classification accuracy and selects fewer feature genes, which can be widely applied in classification for high-dimensional and small-sample tumor datasets. The source code and all datasets are available at https://github.com/QUST-AIBBDRC/SGL-SVM/. [ABSTRACT FROM AUTHOR]