ALBERT

Description: 〈p〉Publication date: October–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Mutation Research/Reviews in Mutation Research, Volume 782〈/p〉 〈p〉Author(s): Yuxiao Liao, Zhao Peng, Liangkai Chen, Liegang Liu, Qinghua Wu, Wei Yang〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mycotoxins, produced by fungi, are secondary metabolites causing adverse, toxic and pathological effects on human and animals. Studies about the association between mycotoxins and microRNAs (miRNAs) were developed since miRNAs have been demonstrated to play a critical role in many developmental processes for regulating messenger RNA (mRNA). As published studies showed, dozens of miRNAs were influenced by mycotoxins, indicating that miRNAs can play important roles in the occurrence and development of mycotoxicosis. Besides, a hypothesis called competing endogenous RNA (ceRNA) was reported to indirectly modulate the expression of mRNA 〈em〉via〈/em〉 miRNA response elements (MREs) to consequently regulate cell functions. As a result, four common miRNAs were focused to predict the corresponding ceRNAs based on their own characteristics and the effects of mycotoxins on them, in hope of providing potential ways or directions of miRNAs regulation for mycotoxicosis, and expanding the research field about mycotoxicosis from ceRNA.〈/p〉〈/div〉

Description: 〈p〉Publication date: October–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Mutation Research/Reviews in Mutation Research, Volume 782〈/p〉 〈p〉Author(s): Yanan Xu, Qian Zhang, Liang Tan, Xubiao Xie, Yong Zhao〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Niemann–Pick C disease (NPC) is a rare autosomal recessive disorder characterized by severe neurodegeneration of central nervous system. Linkage studies in multiplex NPC families and genetic complementation research revealed two disease genes, 〈em〉NPC1 and NPC2,〈/em〉 both of which are important transporters for cholesterol trafficking. NPC2 executes cholesterol-transport function through protein-protein interaction with NPC1 as well as through protein-membrane interaction directly with membrane of late endosome and lysosome. In addition, NPC2 may play many other roles as indicated by its widely expressing pattern in different cells and presenting in numerous secretory fluids, although it biological significance is less studied today. About 50 clinical cases have been reported documenting over twenty different mutations of 〈em〉NPC2〈/em〉 in NPC patients so far. In this review, we will mainly summarize the molecular characteristics and biological significance of NPC2, highlighting its vital roles in NPC disease.〈/p〉〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tao Li, Jing Li, Yang Yang, Yilin Han, Dirong Wu, Tao Xiao, Yang Wang, Ting Liu, Yonglong Zhao, Yongjun Li, Zeqin Dai, Xiaozhong Fu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono 〈span〉l〈/span〉-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na〈sup〉+〈/sup〉-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 〈strong〉6c〈/strong〉 as the optimal molecular candidate, with the highest antiviral activity (EC〈sub〉50〈/sub〉 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 〈strong〉6c〈/strong〉 exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 〈strong〉6c〈/strong〉 cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 〈strong〉6c〈/strong〉 indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and 〈span〉l〈/span〉-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 〈strong〉6c〈/strong〉 is a potential candidate as an anti-HBV therapy and therefore merits further investigation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619309034-ga1.jpg" width="327" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Bo Hou, Ze Liu, Xiao-Bei Yang, Wen-Fei Zhu, Jin-Yu Li, Liu Yang, Fu-Cai Reng, Yong-Feng Lv, Jiang-Miao Hu, Guo-Yang Liao, Jun Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The stems of 〈em〉Dryopteris crassirhizoma〈/em〉, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin 〈strong〉ABBA〈/strong〉 is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues (〈strong〉b5〈/strong〉 and 〈strong〉e2〈/strong〉) showed better NAs inhibitory activity against Anhui H7N9 with IC〈sub〉50〈/sub〉 values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues especially 〈strong〉AB〈/strong〉, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Total synthesis of dryocrassin ABBA and analogue structures with potential inhibitory activity against drug-resistant neuraminidases.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619308879-ga1.jpg" width="278" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1867, Issue 9〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes〈/p〉 〈p〉Author(s): Deo R. Singh, Christopher King, Matt Salotto, Kalina Hristova〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉EGFR is a receptor tyrosine kinase that plays a critical role in cell proliferation, differentiation, survival and migration. Its activating ligand, EGF, has long been believed to stabilize the EGFR dimer. Two research studies aimed at quantitative measurements of EGFR dimerization, however, have led to contradicting conclusions and have questioned this view. Given the controversy, here we sought to measure the dimerization of EGFR in the absence and in the presence of saturating EGF concentrations, and to tease out the effect of ligand on dimer stability, using a FRET-based quantitative method. Our measurements show that the dissociation constant is decreased ~150 times due to ligand binding, indicative of significant dimer stabilization. In addition, our measurements demonstrate that EGF binding induces a conformational change in the EGFR dimer.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0005273619301476-ga1.jpg" width="265" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics〈/p〉 〈p〉Author(s): Martina Paumann-Page, Rupert Tscheliessnig, Benjamin Sevcnikar, Romy-Sophie Katz, Irene Schwartz, Stefan Hofbauer, Vera Pfanzagl, Paul G. Furtmüller, Christian Obinger〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Human peroxidasin 1 is a multidomain peroxidase situated in the basement membrane. The iron enzyme with covalently bound heme oxidizes bromide to hypobromous acid which facilitates the formation of distinct sulfilimine cross-links in the collagen IV network and therefore contributes to its mechanical stability. Additional to the catalytically active peroxidase domain peroxidasin comprises a leucine rich repeat domain, four Ig domains and a C-terminal von Willebrand factor type C module (VWC). Peroxidasin has been shown to form homotrimers involving two redox-sensitive cysteine residues and to undergo posttranslational C-terminal proteolytic cleavage. The present study on several recombinantly produced truncated peroxidasin variants showed that the VWC is not required for trimer formation whereas the alpha-helical linker region located between the peroxidase domain and the VWC is crucial for trimerization. Our data furthermore implies that peroxidasin oligomerization occurs intracellularly before C-terminal cleavage. For the first time we present overall solution structures of monomeric and trimeric truncated peroxidasin variants which were determined by rotary shadowing combined with transmission electron microscopy and by small-angle X-ray scattering (SAXS). A triangular arrangement of the peroxidase domains to each other within the homotrimer was revealed and this structure was confirmed by a model of trimeric peroxidase domains. Our SAXS data showed that the Ig domains are highly flexible and interact with the peroxidase domain and that within the homotrimer each alpha-helical linker region interacts with the respective adjacent peroxidase domain. The implications of our findings on the structure-function relationship of peroxidasin are discussed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1570963919301219-ga1.jpg" width="240" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 The International Journal of Biochemistry & Cell Biology, Volume 114〈/p〉 〈p〉Author(s): Deep Pooja, Anusha Gunukula, Nitin Gupta, David J. Adams, Hitesh Kulhari〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The biggest challenge in delivering anticancer agents is the ability to direct these molecules specifically to cancer cells. With this in mind, modern research is focussing on improving the precision of cancer drug delivery by incorporating a ligand that has the ability to specifically recognize cancer cells. Peptides are emerging as a new tool in drug and gene delivery. Peptide-drug conjugates, peptide-modified drug delivery systems, and peptide-coupled imaging agents have been shown to increase on-site delivery. This has allowed better tumor mass contouring in imaging and increased therapeutic efficacy of chemotherapies, reducing adverse effects. Benefits of peptide ligands include their small size, easy and affordable production, high specificity and remarkable flexibility regarding their sequence and conjugation possibilities. Bombesin (Bn) receptors have shown great promise for tumor targeting due to their increased expression in a variety of human cancers, including prostate, breast, small cell lung, and pancreatic cells. This review discusses the overexpression of Bn receptors in different cancers and various approaches to target these receptors for therapeutic and diagnostic interventions in human malignancies.〈/p〉〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Free Radical Biology and Medicine, Volume 141〈/p〉 〈p〉Author(s): Chao Wang, Yuan Yuan, Jie Wu, Yuanlin Zhao, Xing Gao, Yihua Chen, Chao Sun, Liming Xiao, Pengfei Zheng, Peizhen Hu, Zengshan Li, Zhe Wang, Jing Ye, Lijun Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉While cardiac hypertrophy and heart failure are accompanied by significant alterations in energy metabolism, more than 50–70% of energy is obtained from fatty acid β-oxidation (FAO) in adult hearts under physiological conditions. Plin5 is involved in the metabolism of lipid droplets (LDs) and is highly abundant in oxidative tissues including heart, liver and skeletal muscle. Plin5 protects the storage of triglyceride (TG) in LDs by inhibiting lipolysis, thereby suppressing excess FAO and preventing excessive oxidative stress in the heart. In this study, we investigated the roles of Plin5 in cardiac hypertrophy and heart failure in mice treated with transverse aortic constriction (TAC). The results indicated that Plin5 deficiency aggravated myocardial hypertrophy in the TAC-treated mice and exacerbated the TAC-induced heart failure. We also found that Plin5 deficiency reduced the cardiac lipid accumulation and upregulated the levels of PPARα and PGC-1α, which stimulate mitochondrial proliferation. Moreover, Plin5 deficiency aggravated the TAC-induced oxidative stress. We consistently found that Plin5 knockdown disrupted TG storage and elevated FAO and lipolysis in H9C2 rat cardiomyocytes. In addition, Plin5 knockdown also provoked mitochondrial proliferation and lipotoxic injury in H9C2 cells. In conclusion, Plin5 deficiency increases myocardial lipolysis, elevates FAO and oxidative burden, and thereby exacerbates cardiac hypertrophy and heart failure in TAC-treated mice.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S089158491930471X-fx1.jpg" width="336" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 7 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Rong Jiang, Yan Liao, Fuhuang Yang, Yusi Cheng, Xiaoniu Dai, Jie Chao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Endothelial-mesenchymal transition (EndoMT) is a key step during lung fibrosis. Studies have shown that bone marrow mesenchymal stem cells (BMSCs) may act as therapeutic candidates for lung fibrosis. However, the effects of BMSCs on EndoMT induced by SiO〈sub〉2〈/sub〉 have not been elucidated, and means to label and track grafted cells have been lacking. The current study explored whether BMSCs prevented pulmonary fibrosis by targeting EndoMT, as well as analyzed the distribution of BMSCs labeled with superparamagnetic iron oxide (SPIO) nanoparticles during treatment. TIE2-GFP mice, human umbilical vein endothelial cells (HUVECs), and BMSCs labeled with SPIO nanoparticles were used to explore the distributions and therapeutic effects of BMSCs in vivo and in vitro. We found that BMSCs reversed lung fibrosis by targeting EndoMT in vivo. Furthermore, we show that BMSCs labeled with SPIO nanoparticles could be used to track stem cells reliably in the lungs for 14 days. Conditioned medium from BMSCs attenuated the increased functional changes and reversed the SiO〈sub〉2〈/sub〉-induced upregulation of ER stress and autophagy markers irrespective of whether they were nanoparticle labeled or not. Our findings identify novel methods to track labeled BMSCs with therapeutic potential.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1862, Issue 8〈/p〉 〈p〉Author(s): Ruifan Wu, Guanqun Guo, Zhen Bi, Youhua Liu, Yuanling Zhao, Nana Chen, Fengqin Wang, Yizhen Wang, Xinxia Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉N〈/em〉〈sup〉6〈/sup〉-methyladenosine (m〈sup〉6〈/sup〉A), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Here, we reveal that deletion of m〈sup〉6〈/sup〉A demethylase FTO in porcine and mouse preadipocytes inhibits adipogenesis through JAK2-STAT3-C/EBPβ signaling. Mechanistically, FTO deficiency suppresses JAK2 expression and STAT3 phosphorylation, leading to attenuated transcription of C/EBPβ, which is essential for the early stage of adipocyte differentiation. Using dual-luciferase assay, we validate that knockdown of FTO reduces expression of JAK2 in an m〈sup〉6〈/sup〉A-dependent manner. Furthermore, we find that m〈sup〉6〈/sup〉A “reader” protein YTHDF2 directly targets m〈sup〉6〈/sup〉A-modified transcripts of JAK2 and accelerates mRNA decay, which results in decreased JAK2 expression and inactivated JAK2-STAT3-C/EBPβ signaling, thereby inhibiting adipogenesis. Collectively, our results provide a novel insight into the molecular mechanism of m〈sup〉6〈/sup〉A methylation in post-transcriptional regulation of JAK2-STAT3-C/EBPβ signaling axis and highlight the crucial role of m〈sup〉6〈/sup〉A modification and its modulators in adipogenesis.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 8〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1865, Issue 10〈/p〉 〈p〉Author(s): Tomonaga Ichikawa, Shingo Nakahata, Masahiro Fujii, Hidekatsu Iha, Kazuya Shimoda, Kazuhiro Morishita〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor that is frequently downregulated in adult T-cell leukemia/lymphoma (ATLL) and functions to negatively regulate several cellular signaling pathways as PP2A recruiter. To clarify the molecular mechanisms of suppression of NDRG2 expression, we initially determined the expression pattern of NDRG2 in various types of T-cells and ATLL cells. NDRG2 expression was significantly upregulated in HTLV-1/Tax-immortalized T-cells, which was mediated by NF-κB activation through Tax expression. On the other hand, NDRG2 expression was suppressed in HTLV-1-infected cell lines and various types of ATLL cells, which was dependent on the DNA methylation of the NDRG2 promoter. We found that the expression of enhancer of zeste homolog 2 (EZH2), a member of the polycomb family, is increased in ATLL, and that EZH2 directly binds to the NDRG2 promoter and induces DNA methylation of the NDRG2 promoter. Since the expression of EZH2 were anti-parallelly regulated with the NDRG2 expression, EZH2 might be one of the most important regulators of the downregulation of NDRG2, contributing to enhanced activation of signaling pathways during ATLL development.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Mariafrancesca Scalise, Michele Galluccio, Lorena Pochini, Jessica Cosco, Miriam Trotta, Manuele Rebsamen, Giulio Superti-Furga, Cesare Indiveri〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The lysosomal amino acid transporter SLC38A9 is referred to as transceptor, i.e. a transporter with a receptor function. The protein is responsible for coupling amino acid transport across the lysosomal membrane according to the substrate availability to mTORC1 signal transduction. This process allows cells to sense amino acid level responding to growth stimuli in physiological and pathological conditions triggering mTOR regulation. The main substrates underlying this function are glutamine and arginine. The functional and kinetic characterization of glutamine and arginine transport was performed using human SLC38A9 produced in 〈em〉E. coli〈/em〉, purified by affinity chromatography and reconstituted in liposomes. A cooperative behaviour for the wild type protein was revealed for both the substrates. A novel Na〈sup〉+〈/sup〉 binding site, namely T453, was described by combined approaches of bioinformatics, site-directed mutagenesis and transport assay. Stimulation by cholesterol of glutamine and arginine transport was observed. The biological function of SLC38A9 relies on the interaction between its N-terminus and components of the mTOR complex; a deletion mutant of the N-terminus tail was produced and transport of glutamine was assayed revealing that this portion does not play any role in the intrinsic transport function of the human SLC38A9. Different features for glutamine and arginine transport were revealed: human SLC38A9 is competent for glutamine efflux, while that of arginine is negligible. In line with these results, imposed ∆pH stimulated glutamine, not arginine transport. Arginine plays, on the contrary, a modulatory function and is able to stimulate glutamine efflux. Interestingly, reciprocal inhibition experiments also supported by bioinformatics, suggested that glutamine and arginine may bind to different sites in the human SLC38A9 transporter.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉Proteoliposome reconstitution of hSLC38A9 WT and mutants.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0005273619301567-ga1.jpg" width="301" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computer Methods and Programs in Biomedicine〈/p〉 〈p〉Author(s): Alae Ammour, Ibtissame Aouraghe, Ghizlane Khaissidi, Mostapha Mrabti, Ghita Aboulem, Faouzi Belhacen〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Parkinson's disease (PD) is the second most common neurodegenerative disease affecting significant portion of elderly population. One of the most frequent hallmarks and the first manifestation of PD is deterioration of handwriting. Since the diagnosis of Parkinson's disease is difficult, researchers have worked to develop a support tool based on algorithms to separate healthy controls from PD patients. On-line handwriting analysis is one of the methods that can be used to diagnose PD. In this study, we aimed to analyze the Arabic Handwriting of 28 Parkinson's disease patients and 28 healthy controls (HCs) who were the same age and have the same intellectual level. We focused on copying an Arabic text task. For each participant we have calculated 1482 features. Based on the most relevant features selected by the Pearson's coefficient correlation, the Hierarchical Ascendant Classification (HAC) was applied and generated 3 clusters of writers. The characterization of these clusters was carried out by using the quantitative and qualitative parameters. The obtained results show that the combination of these two aspects can discriminate at best PD patients from HCs.〈/p〉〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1863, Issue 9〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Oumaima Et-Thakafy, Fanny Guyomarc'h, Christelle Lopez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The biological membrane surrounding milk fat globules (MFGM) exhibits lateral phase separation of lipids, interpreted as gel or liquid-ordered phase sphingomyelin-rich (milk SM) domains dispersed in a fluid continuous lipid phase. The objective of this study was to investigate whether changes in the phase state of milk SM-rich domains induced by temperature (T 〈 Tm or T 〉 Tm) or cholesterol affected the Young modulus of the lipid membrane. Supported lipid bilayers composed of MFGM polar lipids, milk SM or milk SM/cholesterol (50:50 mol) were investigated at 20 °C and 50 °C using atomic force microscopy (AFM) and force spectroscopy. At 20 °C, gel-phase SM-rich domains and the surrounding fluid phase of the MFGM polar lipids exhibited Young modulus values of 10–20 MPa and 4–6 MPa, respectively. Upon heating at 50 °C, the milk SM-rich domains in MFGM bilayers as well as pure milk SM bilayers melted, leading to the formation of a homogeneous membrane with similar Young modulus values to that of a fluid phase (0–5 MPa). Upon addition of cholesterol to the milk SM to reach 50:50 mol%, membranes in the liquid-ordered phase exhibited Young modulus values of a few MPa, at either 20 or 50 °C. This indicated that the presence of cholesterol fluidized milk SM membranes and that the Young modulus was weakly affected by the temperature. These results open perspectives for the development of milk polar lipid based vesicles with modulated mechanical properties.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0005273619301555-ga1.jpg" width="317" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Yang Hu, Wei-Chao Chen, Yu-Feng Shen, Bin Zhu, Gao-Xue Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Viral diseases in aquaculture were challenging because there are few preventative measures and/or treatments. Our previous study indicated that imidazole arctigenin derivatives possessed antiviral activities against infectious hematopoietic necrosis virus (IHNV). Based on the structure-activity relationship in that study, a new imidazole arctigenin derivative, 4-(8-(2-ethylimidazole)octyloxy)-arctigenin (EOA), was designed, synthesized and its anti-IHNV activity was evaluated. By comparing inhibitory concentration at half-maximal activity (IC〈sub〉50〈/sub〉), we found that EOA (IC〈sub〉50〈/sub〉 = 0.56 mg/L) possessed a higher antiviral activity than those imidazole arctigenin derivatives in our previous study. Besides, EOA could significantly decrease cytopathic effect (CPE) and viral titer induced by IHNV in epithelioma papulosum cyprinid (EPC) cells. In addition, EOA significantly inhibited apoptosis induced by IHNV in EPC cells. Further data verified that EOA inhibited IHNV replication in rainbow trout, with reducing 32.0% mortality of IHNV-infected fish. The results suggested that EOA was more stable with a prolonged inhibitory half-life in the early stage of virus infection (1–4 days). Consistent with above results, EOA repressed IHNV glycoprotein gene expression in virus sensitive tissues (kidney and spleen) in the early stage of virus infection. Moreover, histopathological evaluation showed that tissues from the spleen and kidney of fish infected with IHNV exhibited pathological changes. But there were no lesions in any of the tissues from the control group and EOA-treaten group. In accordance with the histopathological assay, EOA could elicited anti-inflammation response in non-viral infected rainbow trout by down-regulating the expression of cytokine genes (〈em〉IL-8〈/em〉, 〈em〉IL-12p40〈/em〉, and 〈em〉TNF-α〈/em〉). Altogether, EOA was expected to be a therapeutic agent against IHNV infection in the field of aquaculture.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Junjun He, Haiying Liang, Jiaping Zhu, Xiaochen Fang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Antibacterial peptides (AMPs) constitute an important part of the body's innate immune system and are responsible for a wide range of inhibitory effects against pathogens such as bacteria, fungi, and viruses. In this study, multi-step high performance liquid chromatography (HPLC), combined with Mass Spectrometry (MS), was used to isolate and identify proteins with antibacterial activity from the serum of 〈em〉Pinctada fucata martensii〈/em〉 (〈em〉P.f. Martensii〈/em〉) and obtain a component named 〈em〉P.f. Martensii〈/em〉 antimicrobial peptide-1 (PmAMP-1). 〈em〉PmAMP-1〈/em〉 cDNA was cloned and sequenced by rapid amplification of cDNA ends (RACE) and mRNA expression of was analyzed by quantitative real-time PCR (qRT-PCR). From the results of this study, full-length 〈em〉PmAMP-1 c〈/em〉DNA was shown to be 700 base pairs (bp) long with an open reading frame (ORF) of 294 bp, encoding 97 amino acids with a predicted structure that is mostly α-helices. 〈em〉PmAMP-〈/em〉1 mRNA was constitutively expressed in all tested tissues including the adductor muscle, mantle, hepatopancreas, gill, gonads and hemocytes. The highest level of 〈em〉PmAMP-〈/em〉1 transcription was observed at 8 h and 2 h after bacterial challenge in hemocytes and adductor muscle (p 〈 0.01), respectively. Furthermore, PmAMP-1 caused significant morphological alterations in 〈em〉E. coli,〈/em〉 as shown by transmission electron microscopy (TEM). The results from this study provide a valuable base for further exploration of molluscan innate immunity and immune response.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): A. Gallo, W.T. Franks, J.R. Lewandowski〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We present a suite of two-receiver solid-state NMR experiments for backbone and side chain resonance assignment. The experiments rely on either dipolar coupling or scalar coupling for polarization transfer and are devised to acquire a 〈sup〉1〈/sup〉H–detected 3D experiment AND a nested 〈sup〉13〈/sup〉C–detected 2D from a shared excitation pulse. In order to compensate for the lower sensitivity of detection on 〈sup〉13〈/sup〉C nucleus, 2D rows are signal averaged during 3D planes. The 3D dual receiver experiments do not suffer from any appreciable signal loss compared to their single receiver versions and require no extra optimization. The resulting data is higher in information content with no additional experiment time. The approach is expected to become widespread as multiple receivers become standard for new NMR spectrometers.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1090780719301302-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): Ibrahim A. Elabyad, M. Terekhov, M.R. Stefanescu, D. Lohr, M. Fischer, L.M. Schreiber〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The design, simulation, assembly and testing of a novel dedicated antisymmetric transmit/receive (Tx/Rx) coil array to demonstrate the feasibility of cardiac magnetic resonance imaging (cMRI) in pigs at 7 T was described. The novel antisymmetric array is composed of eight elements based on mirrored and reversed loop orientations to generate varying 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"〉〈mrow〉〈msubsup〉〈mi〉B〈/mi〉〈mrow〉〈mn〉1〈/mn〉〈/mrow〉〈mo〉+〈/mo〉〈/msubsup〉〈/mrow〉〈/math〉 field harmonics for RF shimming. The central four loop elements formed together a pair of antisymmetric L-shaped channels to allow good decoupling between all neighboring elements of the entire array. The antisymmetric array was compared to a standard symmetric rectilinear loop array with an identical housing dimension. Both arrays were driven in the parallel transmit (pTx) mode forming an 8-channel transmit and 16-channel receive (8Tx/16Rx) coil array, where the same posterior array was combined with both anterior arrays. The hardware and imaging performance of the dedicated cardiac arrays were validated and compared by means of electromagnetic (EM) simulations, bench-top measurements, phantom, and 〈em〉ex-vivo〈/em〉 MRI experiments with 46 kg female pig. Combined signal-to-noise ratio (SNR), geometry factor (g-factor), noise correlation maps, and high resolution 〈em〉ex-vivo〈/em〉 cardiac images were acquired with an in-plane resolution of 0.3 mm × 0.3 mm using both arrays. The novel antisymmetric array enhanced the SNR within the heart by about two times and demonstrated good decoupling and improved control of the 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"〉〈mrow〉〈msubsup〉〈mi〉B〈/mi〉〈mrow〉〈mn〉1〈/mn〉〈/mrow〉〈mo〉+〈/mo〉〈/msubsup〉〈/mrow〉〈/math〉 field distributions for RF shimming compared to the standard coil array. Parallel imaging with acceleration factor (R) up to 4 was possible using the novel antisymmetric coil array while maintaining the mean g-factor within the heart region of 1.13.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1090780719301284-ga1.jpg" width="356" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 6 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Yan Zhang, Hongyan Wang, Tao Yin, Yue Liu, Wenchao Zhou, Xinbin Fan, Liang Wu, Chao Song, Jin Shao, Tieyi Yang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Transmembrane protein 18 (〈em〉Tmem18〈/em〉) is an obesity-associated gene essential for adipogenesis; however, its function in the osteogenic differentiation of bone marrow–derived mesenchymal stem cells (BMSCs) is still unclear. In this study, we found that 〈em〉Tmem18〈/em〉 was significantly downregulated in rat BMSCs after osteogenic induction. TMEM18 overexpression remarkably downregulated osteo-specific genes including alkaline phosphatase (〈em〉Alp〈/em〉), Runt˗related transcription factor 2 (〈em〉Runx2〈/em〉), osteocalcin (〈em〉Ocn〈/em〉), and osteopontin (〈em〉Opn〈/em〉), and reduced the number of mineral deposits and ALP activity 〈em〉in vitro〈/em〉, whereas knockdown of 〈em〉Tmem18〈/em〉 yielded the opposite results. 〈em〉In vivo〈/em〉 assays also indicated that TMEM18 knockdown BMSCs have an increased bone formation potential in a rat model of calvarial defects. Analyses of the mechanism suggested that TMEM18 overexpression decreased β-catenin expression, whereas the TMEM18 knockdown enhanced β-catenin expression and promoted its nuclear translocation. The positive effects on osteogenic differentiation of rat BMSCs owing to the TMEM18 knockdown were attenuated by β-catenin downregulation. Taken together, these results indicate that TMEM18 plays an inhibitory role in osteogenic differentiation of BMSCs via inactivation of β-catenin.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Olaf Strømme, Katarzyna M. Psonka-Antonczyk, Bjørn Torger Stokke, Anders Sundan, Carl-Jørgen Arum, Gaute Brede〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Multiple myeloma is an incurable cancer of antibody-producing plasma cells. Hepatocyte growth factor (HGF), a cytokine aberrantly expressed in half of myeloma patients, is involved in myeloma pathogenesis by enhancing myeloma growth and invasiveness, and may play a role in myeloma bone disease by inhibiting osteoblastogenesis. In this study, we investigated whether extracellular vesicles (EVs) may play a role in HGF signaling between myeloma cells and osteoblast-like target cells. EVs from the HGF-positive cell line JJN-3 and the HGF-negative cell line INA-6, and from bone marrow plasma and primary human myeloma cells, were isolated using sequential centrifugation techniques and the presence of HGF on the EV-surface was investigated with ELISA. EVs from both cell lines were added to an established bioassay where HGF is known to induce interleukin-11 secretion in osteoblast-like cells. Our results show that HGF was bound to the surface of JJN-3-derived EVs, while INA-6-derived EVs were negative for HGF. Only JJN-3-derived EVs induced IL-11 secretion in osteoblast-like recipient cells. When osteoblast-like cells were preincubated with a specific HGF-receptor (c-Met) inhibitor, no induction of interleukin-11 was observed. Downstream c-Met phosphorylation was demonstrated by immunoblotting. EVs isolated from bone marrow plasma and primary myeloma cells were HGF-positive for a subset of myeloma patients. Taken together, this work shows for the first time that HGF bound on the surface of myeloma-derived EVs can effectuate HGF/c-Met signaling in osteoblast-like cells. Myeloma-derived EVs may play a role in myeloma bone disease by induction of the osteoclast-activating cytokine interleukin-11 in osteoblasts.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0014482719303313-fx1.jpg" width="280" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Kepeng Ou, Sonja Mertsch, Sofia Theodoropoulou, Jiahui Wu, Jian Liu, David A. Copland, Stefan Schrader, Lei Liu, Andrew D. Dick〈/p〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 218〈/p〉 〈p〉Author(s): Yuwei Liu, Biao Kuang, Benjamin B. Rothrauff, Rocky S. Tuan, Hang Lin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mesenchymal stem cells (MSCs) embedded in their secreted extracellular matrix (mECM) constitute an exogenous scaffold-free construct capable of generating different types of tissues. Whether MSC-mECM constructs can recapitulate endochondral ossification (ECO), a developmental process during 〈em〉in vivo〈/em〉 skeletogenesis, remains unknown. In this study, MSC-mECM constructs are shown to result in robust bone formation both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 through the process of endochondral ossification when sequentially exposed to chondrogenic and osteogenic cues. Of interest, a novel trypsin pre-treatment was introduced to change cell morphology, which allowed MSC-mECM constructs to undergo the N-cadherin-mediated developmental condensation process and subsequent chondrogenesis. Furthermore, bone formation by MSC-mECM constructs were significantly enhanced by the ECO protocol, as compared to conventional 〈em〉in vitro〈/em〉 culture in osteogenic medium alone. This was designed to promote direct bone formation as seen in intramembranous ossification (IMO). The developmentally informed method reported in this study represents a robust and efficacious approach for stem-cell based bone generation, which is superior to the conventional osteogenic induction procedure.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Gyeong Han Jeong, Jae-Hyeon Cho, Tae Hoon Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Convenient structure modification of (+)-catechin (〈strong〉1〈/strong〉) induced by nonthermal dielectric barrier discharge (DBD) plasma treatment afforded three novel methylene-linked flavan-3-ol oligomers, methylenetetracatechin (〈strong〉2〈/strong〉), methylenetricatechin (〈strong〉3〈/strong〉), and methylenedicatechin (〈strong〉4〈/strong〉), together with two known catechin dimers, 〈em〉bis〈/em〉 8,8′-catechinylmethane (〈strong〉5〈/strong〉) and 〈em〉bis〈/em〉 6,8′-catechinylmethane (〈strong〉6〈/strong〉). The structures of the three new catechin oligomers 〈strong〉2〈/strong〉–〈strong〉4〈/strong〉 with methylene bridges were elucidated by detailed 1D- and 2D-NMR analysis, and the absolute configurations were established by the observation of circular dichroism (CD). The novel products 〈strong〉2〈/strong〉 and 〈strong〉3〈/strong〉 showed significantly enhanced anti-adipogenic capacities against both pancreatic lipase and differentiation of 3T3-L1 preadipocytes compared to the parent (+)-catechin.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304536-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Miriam Rossi, Francesco Caruso, Ilaria Costanzini, Carmen Kloer, Aron Sulovari, Elena Monti, Marzia Gariboldi, Emanuela Marras, Neduri V. Balaji, Modukuri V. Ramani, Gottumukkala V. Subbaraju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619301907-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Yasushi Ogasawara, Yo Nakagawa, Chitose Maruyama, Yoshimitsu Hamano, Tohru Dairi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mitomycins, produced by several 〈em〉Streptomyces〈/em〉 strains, are potent anticancer antibiotics that comprise an aziridine ring fused to a tricyclic mitosane core. Mitomycins have remarkable ability to crosslink DNA with high efficiency. Despite long clinical history of mitomycin C, the biosynthesis of mitomycins, especially mitosane core formation, remains unknown. Here, we report 〈em〉in vitro〈/em〉 characterization of three proteins, MmcB (acyl carrier protein), MitE (acyl AMP ligase), and MitB (glycosyltransferase) involved in mitosane core formation. We show that 3-amino-5-hydroxybenzoic acid (AHBA) is first loaded onto MmcB by MitE at the expense of ATP. MitB then catalyzes glycosylation of AHBA-MmcB with uridine diphosphate-〈em〉N〈/em〉-acetylglucosamine (UDP-GlcNAc) to generate a key intermediate, GlcNAc-AHBA-MmcB, which contains all carbon and nitrogen atoms of the mitosane core. These results provide important insight into mitomycin biosynthesis.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304548-ga1.jpg" width="490" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Zahra Mojallal-Tabatabaei, Parham Foroumadi, Mahsa Toolabi, Fereshteh Goli, Setareh Moghimi, Sussan Kaboudanian-Ardestani, Alireza Foroumadi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of 〈em〉Leishmania major〈/em〉 (〈em〉L. major)〈/em〉. Amongst the synthesized compounds, 2-([1,4′-bipiperidin]-1′-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (〈strong〉IIa〈/strong〉) and 1-(5-(1-methyl-5-nitro-1〈em〉H〈/em〉-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (〈strong〉IIc〈/strong〉) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of 〈em〉L. major〈/em〉 cells to 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303700-ga1.jpg" width="335" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Anargyros Doukas, Ekaterini Karena, Maria Botou, Konstantinos Papakostas, Amalia Papadaki, Olympia Tziouvara, Evaggelia Xingi, Stathis Frillingos, Haralabia Boleti〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recombinant expression systems for mammalian membrane transport proteins are often limited by insufficient yields to support structural studies, inadequate post-translational processing and problems related with improper membrane targeting or cytotoxicity. Use of alternative expression systems and optimization of expression/purification protocols are constantly needed. In this work, we explore the applicability of the laboratory strain LEXSY of the ancient eukaryotic microorganism 〈em〉Leishmania tarentolae〈/em〉 as a new expression system for mammalian nucleobase permeases of the NAT/NCS2 (Nucleobase-Ascorbate Transporter/Nucleobase-Cation Symporter-2) family. We achieved the heterologous expression of the purine-pyrimidine permease rSNBT1 from 〈em〉Rattus norvegicus〈/em〉 (tagged at C-terminus with a red fluorescent protein), as confirmed by confocal microscopy and biochemical analysis of the subcellular fractions enriched in membrane proteins. The cDNA of rSNBT1 has been subcloned in a pLEXSY-〈em〉sat-mrfp1〈/em〉vector and used to generate transgenic 〈em〉L〈/em〉. 〈em〉tarentolae-rsnbt1-mrfp1〈/em〉 strains carrying the pLEXSY-sat-〈em〉rsnbt1-mrfp1〈/em〉 plasmid either episomally or integrated in the chromosomal DNA. The chimeric transporter rSNBT1-mRFP1 is targeted to the ER and the plasma membrane of the 〈em〉L〈/em〉. 〈em〉tarentolae〈/em〉 promastigotes. The transgenic strains are capable of transporting nucleobases that are substrates of rSNBT1 but also of the endogenous 〈em〉L〈/em〉. 〈em〉tarentolae〈/em〉 nucleoside/nucleobase transporters. A dipyridamole-resistant Na〈sup〉+〈/sup〉-dependent fraction of uptake is attributed to the exogenously expressed rSNBT1.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0005273619301452-ga1.jpg" width="500" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 168〈/p〉 〈p〉Author(s): Daniel Lavall, Nadine Jacobs, Felix Mahfoud, Peter Kolkhof, Michael Böhm, Ulrich Laufs〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74 ± 15% of control, p = 0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase activator 〈span〉l〈/span〉-buthionine sulfoximine. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7 ± 8.0 vs. 93.8 ± 25.6 µl, p = 0.027) and end-systolic (28.0 ± 4.0 vs. 49.5 ± 16.7 µl, p = 0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100 ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function did not differ between the three groups. RacET mice exhibited overactivation of MR and 11ß hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p = 0.030, and 40%, p = 0.032, respectively). RacET mice demonstrated overexpression of TGF-ß, CTGF, LOX, osteopontin as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4 ± 1.5 vs. 4.7 ± 1.4 mg, p = 0.004) and left atrial fibrosis (17.8 ± 3.1 vs. 12.8 ± 3.1%, p = 0.046) compared to vehicle-treated RacET mice. In summary, finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial effects of finerenone.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295219302564-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cellular Signalling, Volume 62〈/p〉 〈p〉Author(s): Vitor de Miranda Ramos, Juciano Gasparotto, Fabrício Figueiró, Amanda de Fraga Dias, Diana Carolina Rostirolla, Nauana Somensi, Helen Tais da Rosa, Lucas Kich Grun, Florencia María Barbé-Tuana, Daniel Pens Gelain, José Cláudio Fonseca Moreira〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recent studies have investigated the use of retinoic acid (RA) molecule in combined chemotherapies to cancer cells as an attempt to increase treatment efficiency and circumvent cell resistance. Positive results were obtained in clinical trials from lung cancer patients treated with RA and cisplatin. Meanwhile, the signalling process that results from the interaction of both molecules remains unclear. One of the pathways that RA is able to modulate is the activity of NRF2 transcription factor, which is highly associated with tumour progression and resistance. Therefore, the aim of this work was to investigate molecular mechanism of RA and cisplatin co-treatment in A549 cells, focusing in NRF2 pathway. To this end, we investigated NRF2 and NRF2-target genes expression, cellular redox status, cisplatin-induced apoptosis, autophagy and DNA repair through homologous recombination. RA demonstrated to have an inhibitory effect over NRF2 activation, which regulates the expression of thiol antioxidants enzymes. Moreover, RA increased reactive species production associated with increased oxidation of thiol groups within the cells. The expression of proteins associated with DNA repair through homologous recombination was also suppressed by RA pre-treatment. All combined, these effects appear to create a more sensitive cellular environment to cisplatin treatment, increasing apoptosis frequency. Interestingly, autophagy was also increased by combination therapy, suggesting a resistance mechanism by A549 cells. In conclusion, these results provided new information about molecular mechanisms of RA and cisplatin treatment contributing to chemotherapy optimization.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0898656819301524-ga1.jpg" width="487" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Methods〈/p〉 〈p〉Author(s): Athanasia Mizi, Eduardo Gade Gusmao, Argyris Papantonis〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Genome organization is now understood to be tightly linked to all genomic functions. Thus, the high-resolution mapping of higher-order chromosomal structures via 3C-based approaches has become an integral tool for studying transcriptional and cell cycle regulation, signaling effects or disease onset. Nonetheless, 3C-based protocols are not without caveats, like dependencies on fixation conditions, restriction enzyme pervasiveness in crosslinked chromatin and ligation efficiency. To address some of these caveats, we describe here the streamlined iHi-C 2.0 protocol that allows for the genome-wide interrogation of native spatial chromatin contacts without a need for chemical fixation. This approach improves ligation efficiency and presents minimal material losses, and is thus suitable for analysing samples with limiting cell numbers. Following high throughput sequencing, iHi-C 2.0 generates high signal-to-noise and focal maps of the interactions within and between mammalian chromosomes under native conditions.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Shweta Sinha, Mukesh Doble, S.L. Manju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306777-ga1.jpg" width="412" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Fa-Qian Shen, Lu Shi, Ze-Feng Wang, Chen-Ru Wang, Jin-Jin Chen, Yi Liu, Han-Yue Qiu, Hai-Liang Zhu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 〈strong〉8h〈/strong〉 showed the best inhibitory activity (IC〈sub〉50〈/sub〉 = 0.34 ± 0.02 μM against VEGFR-2, IC〈sub〉50〈/sub〉 = 1.08 ± 0.06 μM and 2.44 ± 0.15 μM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 〈strong〉8h〈/strong〉 induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304043-ga1.jpg" width="353" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈p〉Binding mode of compound 〈strong〉8h〈/strong〉 with VEGFR-2 (PDB code: 〈strong〉4ASD〈/strong〉). The 3D diagram of the interaction between compound 〈strong〉8h〈/strong〉 and key amino acid residues.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): George Amato, Robert Wiethe, Amruta Manke, Vineetha Vasukuttan, Rodney Snyder, Scott Runyon, Rangan Maitra〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (〈strong〉1〈/strong〉) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (〈strong〉2〈/strong〉) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 〈strong〉1〈/strong〉 are explored to develop and test strategies for peripheralization. The piperidine of 〈strong〉1〈/strong〉 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 〈strong〉75〈/strong〉 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306431-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Hiroyuki Miyachi, Tomohiro Yuzuriha, Ryotaro Tabata, Syohei Fukuda, Kazuto Nunomura, Bangzhong Lin, Tadayuki Kobayashi, Kenji Ishimoto, Takefumi Doi, Keisuke Tachibana〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We previously reported that 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivative 〈strong〉6〈/strong〉 is an agonist of human peroxisome proliferator-activated receptor alpha (hPPARα). Here, we prepared a series of 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivatives in order to examine the structure-activity relationships (SAR). SAR studies clearly indicated that the steric bulkiness of the substituent on 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine ring, the position of the distal hydrophobic tail part, and the distance between the distal hydrophobic tail part and the acidic head part are critical for hPPARα agonistic activity. These SAR results are somewhat different from those reported for fibrate-class hPPARα agonists. A representative compound (〈strong〉10f〈/strong〉) was as effective as fenofibrate in reducing the elevated plasma triglyceride levels in a high-fructose-fed rat model.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304445-ga1.jpg" width="408" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Pedro Silvino Pereira, Maria do Carmo Alves de Lima, Pedro Paulo Marcelino Neto, Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Irwin Rose de Alencar Menezes, Jamerson Ferreira de Oliveira, Pascal Marchand, Henrique Douglas Melo Coutinho, Maria do Desterro Rodrigues, Teresinha Gonçalves da Silva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the 〈em〉Staphylococcus aureus〈/em〉 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the 〈em〉in silico〈/em〉 study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC 〉 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent 〈em〉in vitro〈/em〉 inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of −9.03 Kcal/mol and −9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against 〈em〉S. aureus〈/em〉 SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930481X-ga1.jpg" width="267" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tamila Galaka, Bruno N. Falcone, Catherine Li, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against 〈em〉Trypanosoma cruzi〈/em〉 and 〈em〉Toxoplasma gondii〈/em〉, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 〈strong〉21〈/strong〉–〈strong〉33〈/strong〉), that is, the position of the amino group was one carbon closer to the 〈em〉gem〈/em〉-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of 〈em〉T. cruzi〈/em〉. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 〈strong〉47〈/strong〉–〈strong〉49〈/strong〉 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 〈strong〉54〈/strong〉–〈strong〉56〈/strong〉, 〈strong〉59〈/strong〉, turned out to be nanomolar growth inhibitors of tachyzoites of 〈em〉T. gondii〈/em〉. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307400-ga1.jpg" width="413" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Neurosciences〈/p〉 〈p〉Author(s): Ruslan Rust, Lisa Grönnert, Rebecca Zoe Weber, Geertje Mulders, Martin E. Schwab〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Stroke patients have only limited therapeutic options and often remain with considerable disabilities. To promote neurological recovery, angiogenesis in the ischemic peri-infarct region has been recognized as an encouraging therapeutic target. Despite advances in mechanistic understanding of vascular growth and repair, effective and safe angiogenic treatments are currently missing. Besides the most intensively studied angiogenic growth factors, recent research has indicated that the process of vascular sprouting and migration also requires the participation of guidance molecules, many of which were initially identified as regulators of axonal growth. Here, we review the inhibitory and growth-promoting effects of guidance molecules on the vascular system and discuss their potential as novel angiogenic targets for neurovascular diseases.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Protein Expression and Purification, Volume 163〈/p〉 〈p〉Author(s): Derrick Afful, Liming Cai, Cory Momany〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The bacterial RNA polymerase (RNAP) is a large, complex molecular machine that is the engine of gene expression. Despite global conservation in their structures and function, RNAPs from different bacteria can have unique features in promoter and transcription factor recognition. Therefore, availability of purified RNAP from different bacteria is key to understanding these species-specific aspects and will be valuable for antibiotic drug discovery. 〈em〉Pseudomonas aeruginosa〈/em〉 is one of the leading causes of hospital and community acquired infections worldwide - making the organism an important public health pathogen. We developed a method for producing high quantities of highly pure and active recombinant 〈em〉P. aeruginosa〈/em〉 str. PAO1 RNAP core and holoenzyme complexes that employed two-vector systems for expressing the core enzyme (α, β, β’, and ω subunits) and for expressing the holoenzyme complex (core + σ〈sup〉70〈/sup〉). Unlike other RNAP expression approaches, we used a low temperature autoinduction system in 〈em〉E. coli〈/em〉 with T7 promoters that produced high cell yields and stable protein expression. The purification strategy comprised of four chromatographic separation steps (metal chelate, heparin, and ion-exchange) with yields of up to 11 mg per 500 mL culture. Purified holoenzyme and reconstituted holoenzyme from core and σ〈sup〉70〈/sup〉 were highly active at transcribing both small and large-sized DNA templates, with a determined elongation rate of ~18 nt/s for the holoenzyme. The successful purification of the 〈em〉P. aeruginosa〈/em〉 RNAP provides a gateway for studies focusing on 〈em〉in vitro〈/em〉 transcriptional regulation in this pathogen.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): Michael Mullen, Alexander Gutierrez, Naoharu Kobayashi, Jarvis Haupt, Michael Garwood〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Large magnetic field inhomogeneity can be a significant cause of spatial flip-angle variation when using ordinary, limited-bandwidth RF pulses. Multidimensional RF pulses are particularly sensitive to inhomogeneity due to their extended pulse length, which decreases their bandwidth. Previously, it was shown that, by breaking a 2D pulse into multiple undersampled k-space segments, the excitation bandwidth can be increased at the expense of increased imaging time. The present study shows how this increased imaging time can be offset by undersampling acquisition k-space in a phase-encoded dimension that is in the direction of excitation segmentation. Data from each segment are viewed as originating from “virtual receive coils” rather than multiple physical coils. The undersampled data are reconstructed using parallel imaging techniques (e.g. as in GRAPPA). The method was tested in vivo with brain imaging at both 3 T and 4 T, and used in conjunction with a 32-channel head coil and conventional GRAPPA on the 3 T data. Relationships with existing techniques and future applications are discussed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1090780719301259-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Free Radical Biology and Medicine, Volume 141〈/p〉 〈p〉Author(s): Ningning Wang, Yanan Ma, Zhuoqun Liu, Lei Liu, Keming Yang, Yaguang Wei, Yang Liu, Xin Chen, Xiance Sun, Deliang Wen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Exposure to fine particular matter (≤2.5 μM, PM〈sub〉2.5〈/sub〉) contributes to increased risk of obesity and type 2 diabetes. Hydroxytyrosol (HT), a simple polyphenol found in virgin olive oil, is considered to be beneficial for cardiovascular and metabolic disorders. The current study determined whether HT could improve PM〈sub〉2.5〈/sub〉-induced adiposity and insulin resistance (IR), and explored the underlying mechanisms. Fifteen adult female C57BL/6j mice on a chow diet were randomly divided into three groups receiving (1) sterile PBS, (2) PM〈sub〉2.5〈/sub〉 suspended in sterile PBS (1 mg/mL) and (3) PM〈sub〉2.5〈/sub〉+HT (50 mg/kg/day). PM〈sub〉2.5〈/sub〉/PBS exposure was administered by oropharynx instillation every other day and HT supplementation was achieved by gavage every day. Four-week PM〈sub〉2.5〈/sub〉 exposure did not affect body weight, but significantly increased visceral fat mass. The abdominal adiposity coincided with adipocyte hypertrophy and proliferation in visceral white adipose tissue (WAT), as well as decreased metabolic activity in brown adipose tissue and subcutaneous WAT. PM〈sub〉2.5〈/sub〉 enhanced the oxidative stress by diminishing antioxidant enzyme activities in liver and serum, whereas contents of 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) levels in liver and serum were elevated. These changes were accompanied by macrophage infiltration and activation of NF-κB pathway in the liver. Moreover, PM〈sub〉2.5〈/sub〉 exposure led to glucose intolerance and insulin insensitivity, impaired hepatic glycogenesis, and decreased insulin-stimulated Akt phosphorylation in peripheral tissues. Importantly, HT treatment prevented PM〈sub〉2.5〈/sub〉-induced visceral adipogenesis, oxidative stress, hepatic inflammation and NF-κB activation, systemic and peripheral IR. In vitro, after HepG2 cells were incubated with PM〈sub〉2.5〈/sub〉 (0, 5, 25, 50, 100 and 200 μg/mL), reduced glutathione depletion and 4-HNE, 8-hydroxy-2'-deoxyguanosine, MDA increment in a dose-dependent manner were observed; likewise, insulin-stimulated glucose uptake decreased in a dose-dependent manner. Further, with antioxidant NAC and NF-κB inhibitor PDTC, we confirmed that HT attenuated PM〈sub〉2.5〈/sub〉-induced IR through restraining NF-κB activation evoked by oxidative stress. In addition, HT could expand gut microbiota richness, reduce pathogenic bacteria and accommodate the microbial architecture in PM〈sub〉2.5〈/sub〉-exposed mice, which were correlated with parameters of adiposity, oxidative stress and glycometabolism. HT could effectively correct imbalanced oxidative stress triggered by PM〈sub〉2.5〈/sub〉, in turn ameliorated NF-κB pathway and insulin signaling. Gut microbiota may mediate the actions of HT.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉A schematic illustration of how HT interfered with PM〈sub〉2.5〈/sub〉-induced oxidative stress and metabolic disorders in vivo and in vitro. vWAT, visceral white adipose tissue; scWAT, subcutaneous WAT; BAT, brown adipose tissue; PPARγ, peroxisome proliferator-activated receptor gamma; C/EBPα, CCAAT/enhancer-binding protein alpha; UCP1, uncoupling protein 1; COX2, cyclooxygenase 2; IL-1β, interleukin 1beta; TNFα, tumor necrosis factor alpha; GSK3β, glycogen synthase kinase 3β; GS, glycogen synthase; ↑indicates increase, ↓indicates decrease.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0891584919301856-fx1.jpg" width="281" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Genomics〈/p〉 〈p〉Author(s): Filipe P. Matteoli, Hemanoel Passarelli-Araujo, Francisnei Pedrosa-Silva, Fabio L. Olivares, Thiago M. Venancio〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Enterobacter bugandensis〈/em〉 is a recently described species that has been largely associated with nosocomial infections. We report the genome of a non-clinical 〈em〉E. bugandensis〈/em〉 strain, which was integrated with publicly available genomes to study the pangenome and general population structure of 〈em〉E. bugandensis〈/em〉. Core- and whole-genome multilocus sequence typing allowed the detection of five 〈em〉E. bugandensis〈/em〉 phylogroups (PG-A to E), which contain important antimicrobial resistance and virulence determinants. We uncovered several extended-spectrum β-lactamases, including 〈em〉bla〈/em〉〈sub〉CTX-M-55〈/sub〉 and 〈em〉bla〈/em〉〈sub〉NDM-5〈/sub〉, present in an IncX replicon type plasmid, described here for the first time in 〈em〉E. bugandensis〈/em〉. Genetic context analysis of 〈em〉bla〈/em〉〈sub〉NDM-5〈/sub〉 revealed the resemblance of this plasmid with other IncX plasmids from other bacteria from the same country. Three distinctive siderophore producing operons were found in 〈em〉E. bugandensis〈/em〉: 〈em〉ent〈/em〉erobactin (〈em〉ent〈/em〉), aerobactin (〈em〉iuc〈/em〉/〈em〉iut〈/em〉), and salmochelin (〈em〉iro〈/em〉). Our findings provide novel insights on the lifestyle, physiology, antimicrobial, and virulence profiles of 〈em〉E. bugandensis〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computer Methods and Programs in Biomedicine, Volume 178〈/p〉 〈p〉Author(s): Ángel E. Esteban, Miguel López-Pérez, Adrián Colomer, María A. Sales, Rafael Molina, Valery Naranjo〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background and objective〈/h6〉 〈p〉Prostate cancer is one of the most common male tumors. The increasing use of whole slide digital scanners has led to an enormous interest in the application of machine learning techniques to histopathological image classification. Here we introduce a novel family of morphological descriptors which, extracted in the appropriate image space and combined with shallow and deep Gaussian process based classifiers, improves early prostate cancer diagnosis.〈/p〉 〈/div〉 〈div〉 〈h6〉Method〈/h6〉 〈p〉We decompose the acquired RGB image in its RGB and optical density hematoxylin and eosin components. Then, we define two novel granulometry-based descriptors which work in both, RGB and optical density, spaces but perform better when used on the latter. In this space they clearly encapsulate knowledge used by pathologists to identify cancer lesions. The obtained features become the inputs to shallow and deep Gaussian process classifiers which achieve an accurate prediction of cancer.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉We have used a real and unique dataset. The dataset is composed of 60 Whole Slide Images. For a five fold cross validation, shallow and deep Gaussian Processes obtain area under ROC curve values higher than 0.98. They outperform current state of the art patch based shallow classifiers and are very competitive to the best performing deep learning method. Models were also compared on 17 Whole Slide test Images using the FROC curve. With the cost of one false positive, the best performing method, the one layer Gaussian process, identifies 83.87% (sensitivity) of all annotated cancer in the Whole Slide Image. This result corroborates the quality of the extracted features, no more than a layer is needed to achieve excellent generalization results.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusion〈/h6〉 〈p〉Two new descriptors to extract morphological features from histological images have been proposed. They collect very relevant information for cancer detection. From these descriptors, shallow and deep Gaussian Processes are capable of extracting the complex structure of prostate histological images. The new space/descriptor/classifier paradigm outperforms state-of-art shallow classifiers. Furthermore, despite being much simpler, it is competitive to state-of-art CNN architectures both on the proposed SICAPv1 database and on an external database.〈/p〉 〈/div〉

Description: 〈p〉Publication date: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics〈/p〉 〈p〉Author(s): Carlos Eduardo Pena, Mauricio G.S. Costa, Paulo Ricardo Batista〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fungi cellulases are used to degrade cellulose-containing biomass for bioethanol production. Industrial cellulases such as Cel7A from 〈em〉Trichoderma reesei〈/em〉 (〈em〉Tr〈/em〉Cel7A) are critical in this process. Thus, the understanding of structure and dynamics is crucial for engineering variants with improved cellulolytic activity. This cellulase consists of two domains connected by a flexible and highly glycosylated linker. However, the linker flexibility has hindered the determination of Cel7A complete structure. Herein, based on atomic and sparse data, we applied integrative modelling to build a model of the complete enzyme structure. Next, through simulations, we studied the glycosylation effects on the structure and dynamics of a solubilized 〈em〉Tr〈/em〉Cel7A. Essential dynamics analysis showed that O-glycosylation in the linker led to the stabilization of protein overall dynamics. O-linked glycans seem to restrict protein dihedral angles distribution in this region, selecting more elongated conformations. Besides the reduced flexibility, functional interdomain motions occurred in a more concerted way in the glycosylated system. In contrast, in the absence of glycosylation, we observed vast conformational plasticity with the functional domains frequently collapsing. We report here evidence that targeting Cel7A linker flexibility by point mutations including modification of glycosylation sites could be a promising design strategy to improve cellulase activity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1570963919301207-ga1.jpg" width="500" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Bin Zhong, Zeyin Jiang, Zhenhuang Chen, Kazue Ishihara, Huilin Mao, Shanghong Wang, Gang Lin, Chengyu Hu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recently, studies have shown that IκB kinase β (IKKβ), a critical kinase in the nucleus factor kappa-B (NF-κB) pathway, participates in inflammatory responses associated with unfolded protein response (UPR) and plays an important role in ER stress-induced cell death. The unfolded protein response (UPR), which is a regulatory system to restore cellular homeostasis in the endoplasmic reticulum (ER), such as oxidative stress, bacterial infection, and virus invasion. The UPR pathways have been reported to be involved in immune responses in mammals, including the classical NF-κB pathway. However, the molecular mechanism of their crosstalk remains to be elucidated. Previously, we demonstrated that IKKβ also has some conserved functions between fish and human, as grass carp (〈em〉Ctenopharyngodon idella〈/em〉) IKKβ (CiIKKβ) can activate NF-κB pathway. In this study, we found that CiIKKβ level in nucleus was elevated under ER stress and CiIKKβ can interact with grass carp X-box-binding protein 1 (CiXBP1S), a key transcription factor in UPR. Consistently, fluorescent histochemical analysis of grass carp kidney (CIK) cells indicated that CiIKKβ and CiXBP1S colocalized under ER stress. Furthermore, overexpression of CiIKKβ in CIK cells enhanced ER stress tolerance by regulating UPR signaling and resulted in the significant increase of cell viability.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Lu-Yun Ni, Qing Han, Hong-Ping Chen, Xiao-Chun Luo, An-Xing Li, Xue-Ming Dan, Yan-Wei Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Macrophage expressed gene 1 (Mpeg1) is a molecule that can form pores and destroy the cell membrane of invading pathogens. In this study, we identified two Mpeg1 isoforms from the orange-spotted grouper (〈em〉Epinephelus coioides〈/em〉) and named them EcMpeg1a and EcMpeg1b. Predicted proteins of the two EcMpeg1s contained a signal peptide, a conserved membrane attack complex/perforin (MACPF) domain, a transmembrane segment, and an intracellular region. Sequence alignment demonstrated that two EcMpeg1 proteins share a high sequence identity with that of other teleosts. Tissue distribution analysis showed that EcMpeg1s were expressed in all tissues tested in healthy grouper, with the highest expression in the head kidney and spleen. After infection with the ciliate parasite 〈em〉Cryptocaryon irritans〈/em〉, expression of the two EcMpeg1s was significantly upregulated in the spleen and gills. Furthermore, the recombinant EcMpeg1a showed antiparasitic and antibacterial activity against Gram-negative and -positive bacteria, whereas EcMpeg1b had an inhibitory effect only against Gram-positive bacteria. These results indicated that EcMpeg1s play an important role in the host response against invading pathogens.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Molecular Cell〈/p〉 〈p〉Author(s): Konstantinos Boulias, Diana Toczydłowska-Socha, Ben R. Hawley, Noa Liberman, Ken Takashima, Sara Zaccara, Théo Guez, Jean-Jacques Vasseur, Françoise Debart, L. Aravind, Samie R. Jaffrey, Eric Lieberman Greer〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉mRNAs are regulated by nucleotide modifications that influence their cellular fate. Two of the most abundant modified nucleotides are 〈em〉N〈/em〉〈sup〉6〈/sup〉-methyladenosine (m〈sup〉6〈/sup〉A), found within mRNAs, and 〈em〉N〈/em〉〈sup〉6〈/sup〉,2′-〈em〉O〈/em〉-dimethyladenosine (m〈sup〉6〈/sup〉Am), which is found at the first transcribed nucleotide. Distinguishing these modifications in mapping studies has been difficult. Here, we identify and biochemically characterize PCIF1, the methyltransferase that generates m〈sup〉6〈/sup〉Am. We find that PCIF1 binds and is dependent on the m〈sup〉7〈/sup〉G cap. By depleting PCIF1, we generated transcriptome-wide maps that distinguish m〈sup〉6〈/sup〉Am and m〈sup〉6〈/sup〉A. We find that m〈sup〉6〈/sup〉A and m〈sup〉6〈/sup〉Am misannotations arise from mRNA isoforms with alternative transcription start sites (TSSs). These isoforms contain m〈sup〉6〈/sup〉Am that maps to “internal” sites, increasing the likelihood of misannotation. We find that depleting PCIF1 does not substantially affect mRNA translation but is associated with reduced stability of a subset of m〈sup〉6〈/sup〉Am-annotated mRNAs. The discovery of PCIF1 and our accurate mapping technique will facilitate future studies to characterize m〈sup〉6〈/sup〉Am’s function.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1097276519304393-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Molecular Cell〈/p〉 〈p〉Author(s): Erdem Sendinc, David Valle-Garcia, Abhinav Dhall, Hao Chen, Telmo Henriques, Jose Navarrete-Perea, Wanqiang Sheng, Steven P. Gygi, Karen Adelman, Yang Shi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉mRNA modifications play important roles in regulating gene expression. One of the most abundant mRNA modifications is N6,2-O-dimethyladenosine (m6Am). Here, we demonstrate that m6Am is an evolutionarily conserved mRNA modification mediated by the Phosphorylated CTD Interacting Factor 1 (PCIF1), which catalyzes m6A methylation on 2-O-methylated adenine located at the 5′ ends of mRNAs. Furthermore, PCIF1 catalyzes only 5′ m6Am methylation of capped mRNAs but not internal m6A methylation 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. To study the biological role of m6Am, we developed a robust methodology (m6Am-Exo-Seq) to map its transcriptome-wide distribution, which revealed no global crosstalk between m6Am and m6A under assayed conditions, suggesting that m6Am is functionally distinct from m6A. Importantly, we find that m6Am does not alter mRNA transcription or stability but negatively impacts cap-dependent translation of methylated mRNAs. Together, we identify the only human mRNA m6Am methyltransferase and demonstrate a mechanism of gene expression regulation through PCIF1-mediated m6Am mRNA methylation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1097276519304022-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Pharmacological Sciences, Volume 40, Issue 8〈/p〉 〈p〉Author(s): Alex Zhavoronkov, Polina Mamoshina〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉First published in 2016, predictors of chronological and biological age developed using deep learning (DL) are rapidly gaining popularity in the aging research community. These deep aging clocks can be used in a broad range of applications in the pharmaceutical industry, spanning target identification, drug discovery, data economics, and synthetic patient data generation. We provide here a brief overview of recent advances in this important subset, or perhaps superset, of aging clocks that have been developed using artificial intelligence (AI).〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Biochemical Sciences〈/p〉 〈p〉Author(s): Huimin Zhang, Swaminath Srinivas, Yongchang Xu, Wenhui Wei, Youjun Feng〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Polymyxins are a group of detergent-like antimicrobial peptides that are the ultimate line of defense against carbapenem-resistant pathogens in clinical settings. Polymyxin resistance primarily originates from structural remodeling of lipid A anchored on bacterial surfaces. We integrate genetic, structural, and biochemical aspects of three major types of lipid A modifiers that have been shown to confer intrinsic colistin resistance. Namely, we highlight ArnT, a glycosyltransferase, EptA, a phosphoethanolamine transferase, and the AlmEFG tripartite system, which is restricted to EI Tor biotype of 〈em〉Vibrio cholerae〈/em〉 O1. We also discuss the growing family of mobile colistin resistance (MCR) enzymes, each of which is analogous to EptA, and which pose great challenges to global public health.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 The International Journal of Biochemistry & Cell Biology, Volume 114〈/p〉 〈p〉Author(s): Chao Huang, Xiao-fen Wu, Xiu-lian Wang〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tumor-associated fibroblasts (TAFs) contribute to transdifferentiation of stromal cells in tumor microenvironment. Epithelial-mesenchymal transition (EMT) is a procedure of phenotypic remodeling of epithelial cells and extensively exists in local tumoral stroma. Histone deacetylase (HDAC) inhibitor Tricostatin A (TSA) and sodium butyrate (SB) are reported to play important roles in the regulation of biological behaviour of cancer cells. However, whether TSA or SB is involved in control of EMT in colon epithelial cells induced by TAFs remains unidentified. In present study, we used conditioned medium (CM) form TAF-like CCD-18Co cells to stimulate 2D- and 3D-cultured colon epithelial HCoEpiC cells for 24 h and 4 d. We found that the CCD-18Co CM triggered multiple morphological changes in HCoEpiCs including prolonged cell diameters, down-regulation of E-cadherin and up-regulation of vimentin and α-SMA. Besides, ZEB1 and Snail expression and migration were also promoted by the CM. These phenomena were abolised by 5 μg/ml LY364947, a TGF-β receptor inhibitor. CCD-18Co induced up-regulation of HDAC1 and HDAC2 in the 2D and 3D models, while no change of HDAC4 exprerssion was found. Treatment of 2 μg/ml TSA reversed the CCD-18Co-induced morphological changes and migration of the HCoEpiCs, and suppressed the downregulation of E-cadherin and upregulation of vimentin, α-SMA, ZEB1 and Snail. However, the suppressive effect of 4 mg/ml SB on the EMT was not observed. TSA down-regulated the expressions of Smad2/3, p-Smad2/3 amd HDAC4. Besides, TSA promoted the apoptosis rate (36.84 ± 6.52%) comparing with the CCD-18Co-treated HCoEpiCs (3.52 ± 0.85%, 〈em〉P〈/em〉 〈 0.05), with promotion of Bax (0.5893±0.0498 in 2D and 0.8867±0.0916 in 3D) and reduction of Bcl-2 (0.0476±0.0053 in 2D and 0.0294±0.0075 in 3D). TSA stimulated expression of phosphorylated-p38 MAPK in 2D (0.3472±0.0249) and 3D (0.3188±0.0248). After pre-treatment with p38 MAPK inhibitor VX-702 (0.5 mg/ml), the apoptosis rate of TSA was decreased in 2D (10.32%) and 3D (5.26%). Our observations demonstrate that epigenetic treatment with HDAC inhibitor TSA may be a useful therapeutic tool for the reversion of TAF-induced EMT in colon epithelium through mediating canonical Smads pathway and non-canonical p38 MAPK signalling.〈/p〉〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Pharmacological Sciences, Volume 40, Issue 8〈/p〉 〈p〉Author(s): Óscar Díaz, James A.R. Dalton, Jesús Giraldo〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Molecular dynamics (MD) simulations can mechanistically explain receptor function. However, the enormous data sets that they may imply can be a hurdle. Plante and colleagues (〈em〉Molecules〈/em〉, 2019) recently described a machine learning approach to the analysis of MD simulations. The approach successfully classified ligands and identified functional receptor motifs and thus it seems promising for mechanism-based drug discovery.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Neurosciences〈/p〉 〈p〉Author(s): Katherine R. Tonn Eisinger, Anne E. West〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Whether dynamic changes in genome architecture underlie transcriptional and functional plasticity in mature neurons has been technically challenging to address. A recent study (Yamada 〈em〉et al〈/em〉., 〈em〉Nature〈/em〉, 2019) exploited experimental advantages of the cerebellum to reveal cell type-specific changes in chromatin architecture that coordinate neural activity-induced changes in gene transcription and contribute to sensorimotor learning.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 217〈/p〉 〈p〉Author(s): Jun Yang, Shaodong Zhai, Huan Qin, He Yan, Da Xing, Xianglong Hu〈/p〉

Description: 〈p〉Publication date: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - General Subjects〈/p〉 〈p〉Author(s): Ester Tellone, Davide Barreca, Annamaria Russo, Antonio Galtieri, Silvana Ficarra〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉Aerobic organisms have to overcame the dangerous species derived from the unquestionable favorable effects due to the utilization of oxygen in the cellular respiration. 2,3-Diphosphoglycerate (DPG) could be one of the molecules able to perform different role inside the cells and (from the data obtained from our experimental work) may help cellular components, in particular hemoglobin, to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS).〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉Therefore, we have investigated the kinetic and antioxidant properties of this molecule against the main biological reactive species and the protective role of this molecules on hemoglobin treated with strong oxidant.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉DPG, at the physiological concentration is able to scavenge hydroxyl radical, peroxyl radical, cation radicals and to chelate iron in the reduced state. Moreover it is able to avoid oxidation of iron inside the hemoglobin following treatment with nitrite and tert-butyl hydroperoxide (t-BOOH). On the other side, it is not able to protect membrane components from oxidative burning. This different behavior towards radical species is probably linked to the polarity of the molecule and also the high levels of charged groups present on the surface of DPG, that avoid the possibility to act in an environment almost completely hydrophobic, as inside the membrane, where reactive species produce the main damages during the reactions of peroxidation.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusions〈/h6〉 〈p〉This is the first paper dealing with the potential role of DPG not only as a modulator of oxygen affinity in hemoglobin, but also as a scavenger of radicals.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0304416519301655-ga1.jpg" width="301" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - General Subjects〈/p〉 〈p〉Author(s): Guenhaël Sanz, Nathalie Daniel, Marie-Christine Aubrière, Catherine Archilla, Luc Jouneau, Yan Jaszczyszyn, Véronique Duranthon, Pascale Chavatte-Palmer, Alice Jouneau〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉The placenta controls exchanges between the mother and the fetus and therefore fetal development and growth. The maternal environment can lead to disturbance of placental functions, with consequences on the health of the offspring. Since the rabbit placenta is very close to that of humans, rabbit models can provide biomedical data to study human placental function. Yet, to limit the use of animal experiments and to investigate the mechanistic aspects of placental function, we developed a new cell culture model in which rabbit trophoblast cells are differentiated from rabbit trophoblast stem cells.〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉Rabbit trophoblast stems cells were derived from blastocysts and differentiated onto a collagen gel and in the presence of a flow of culture medium to mimic maternal blood flow. Transcriptome analysis was performed on the stem and differentiated cells.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉Our culture model allows the differentiation of trophoblast stem cells. In particular, the fluid shear stress enhances microvilli formation on the differentiated cell surface, lipid droplets formation and fusion of cytotrophoblasts into syncytiotrophoblasts. In addition, the transcriptome analysis confirms the early trophoblast identity of the derived stem cells and reveals upregulation of signaling pathways involved in trophoblast differentiation.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusion〈/h6〉 〈p〉Thereby, the culture model allows mimicking the 〈em〉in vivo〈/em〉 conditions in which maternal blood flow exerts a shear stress on trophoblast cells that influences their phenotype.〈/p〉 〈p〉General significance: Our culture model can be used to study the differentiation of trophoblast stem cells into cytotrophoblasts and syncytiotrophoblasts, as well as the trophoblast function in physiological and pathological conditions.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 June–1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Methods, Volumes 162–163〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 The American Journal of Human Genetics, Volume 105, Issue 1〈/p〉 〈p〉Author(s): Zornitza Stark, Tiffany Boughtwood, Peta Phillips, John Christodoulou, David P. Hansen, Jeffrey Braithwaite, Ainsley J. Newson, Clara L. Gaff, Andrew H. Sinclair, Kathryn N. North〈/p〉 〈div〉〈p〉Australian Genomics is a national collaborative research partnership of more than 80 organizations piloting a whole-of-system approach to integrating genomics into healthcare that is based on federation principles. The aim of Australian Genomics is to assess the application of genomic testing in healthcare at the translational interface between research and clinical delivery, with an emphasis on robust evaluation of outcomes. It encompasses two bodies of work: a research program prospectively providing genomic testing through exemplar clinical projects in rare diseases, cancers, and reproductive carrier screening and interdependent programs for advancing the diagnostic, health informatics, regulatory, ethical, policy, and workforce infrastructure necessary for the integration of genomics into the Australian health system.〈/p〉〈/div〉

Description: 〈p〉Publication date: 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Neuron, Volume 103, Issue 1〈/p〉 〈p〉Author(s): Hugues Petitjean, Philippe Séguéla, Reza Sharif-Naeini〈/p〉 〈div〉〈p〉In this issue of 〈em〉Neuron〈/em〉, Pagani et al. (2019) find that itch signaling occurs only when GRP neurons fire action potentials in bursts. This enables GRP release and the activation of GRPR neurons, which help carry the itch signal to the brain.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Dawanna S. White, Cindy J. Choy, Timothy W. Moural, Stacy E. Martin, Jing Wang, Samantha Gargaro, ChulHee Kang, Clifford E. Berkman〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of 〈em〉Mycobacterium tuberculosis〈/em〉 (〈em〉Mtb〈/em〉), one of the causative agents for Tuberculosis in humans. 〈em〉Mtb〈/em〉 has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (〈strong〉1〈/strong〉–〈strong〉10〈/strong〉). Substituent effects ranged from σ〈sub〉p〈/sub〉 = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 〈strong〉1〈/strong〉, 〈strong〉4〈/strong〉 and 〈strong〉5〈/strong〉 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (k〈sub〉obs〈/sub〉 = 0.212, 0.324, and 0.450 mn〈sup〉−1〈/sup〉 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 〈strong〉4〈/strong〉 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304470-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 The International Journal of Biochemistry & Cell Biology, Volume 114〈/p〉 〈p〉Author(s): Sara Khademi, Saeed Sarkar, Ali Shakeri-Zadeh, Neda Attaran, Sharmin Kharrazi, Mohammad Reza Ay, Hosein Azimian, Hossein Ghadiri〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The development of various cost-effective multifunctional contrast agent for specific targeting molecular imaging of tumors presents a great challenge. We report here the 〈em〉in vivo〈/em〉 targeting imaging of folic acid (FA) gold nanoparticles (AuNPs) through cysteamine (Cys) linking for targeted of human nasopharyngeal head and neck cancer by computed tomography (CT). The toxicity of nanoparticles in kidney, heart, spleen, brain and liver was evaluated by H&E (hematoxylin and eosin) assay. We showed that the formed FA-Cys-AuNPs with an Au core size of ˜13 nm are non-cytotoxic in the particle concentration of 3 × 10〈sup〉3〈/sup〉 μg/ ml. The nude mice were scanned using a 64-slice CT scan with parameters (80 kVp, slice thickness: 0.625 mm, mAs: 200, pitch: 1). CT scan was performed before and after (Three and six hours) I.V (Intra Venous) injection of AuNPs and FA-Cys-AuNPs. The distribution of nanoparticles in the nude mice was evaluated by imaging and coupled plasma optical emission spectrometry (ICP-OES) analysis. The findings clearly illustrated that a small tumor, which is undetectable via computed tomography, is enhanced by X-ray attenuation and becomes visible (4.30-times) by the molecularly targeted AuNPs. It was further demonstrated that active tumor cells targeting (FA-Cys-AuNPs) is more specific and efficient (2.03-times) than passive targeting AuNPs. According to the results, FA-Cys-AuNPs can be employed as a promising contrast agent in CT scan imaging and maybe in radiotherapy that require enhanced radiation dose.〈/p〉〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1357272519301256-ga1.jpg" width="266" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Cell Biology〈/p〉 〈p〉Author(s): Wladyslaw A. Krajewski〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Steric hindrances by bulky histone modifications (such as ubiquitylation) could destabilize and remodel canonical nucleosome structure. This highlights a novel mechanism by which bulky modifications directly regulate chromatin, distinct from the more generally accepted roles of histone modifications in the recruitment of downstream effectors and histone charge shielding.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cytokine, Volume 123〈/p〉 〈p〉Author(s): Alicja E. Grzegorzewska, Monika K. Świderska, Hanna Winnicka, Leszek Niepolski, Maciej Bura, Małgorzata Łagiedo-Żelazowska, Paweł P. Jagodziński〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Responsiveness to the hepatitis B virus (HBV) vaccination in hemodialysis (HD) patients who had been exposed to the hepatitis E virus (HEV) and persistently generate antibodies against HEV remains unknown. Interferon (IFN)-λ3 positively correlates with the surface HBV antibodies (anti-HBs) in both healthy and HD subjects. We aimed to show whether HD patients differ in circulating IFN-λ3 and vaccine-induced anti-HBs titers concerning natural HEV immunization. HBV/HCV negative HD patients (31 HEV IgG positive, 45 HEV negative), HBV vaccinated and receiving booster doses as needed, had been tested for anti-HBs titers (CMIA) and IFN-λ3 concentrations (ELISA) in the blood collected before a dialysis session. There were no differences in circulating IFN-λ3 and anti-HBs titers between both groups. In responders to the HBV vaccine, there was a positive correlation between plasma IFN-λ3 levels and anti-HBs titers (r = 0.505, adjusted P = 0.01 in HEV exposed subjects; r = 0.523, adjusted P = 0.001 in controls). HEV past infection does not attenuate post-vaccination anti-HBs generation and does not influence a correlation between circulating IFN-λ3 levels and anti-HBs titers.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1867, Issue 10〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research〈/p〉 〈p〉Author(s): Galina Dvoriantchikova, Rajeev J. Seemungal, Dmitry Ivanov〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The ability to regenerate the entire retina and restore lost sight after injury is found in some species and relies mostly on the epigenetic plasticity of Müller glia. To understand the role of mammalian Müller glia as a source of progenitors for retinal regeneration, we investigated changes in gene expression during differentiation of retinal progenitor cells (RPCs) into Müller glia and analyzed the global epigenetic profile of adult Müller glia. We observed significant changes in gene expression during differentiation of RPCs into Müller glia in only a small group of genes and found a high similarity between RPCs and Müller glia on the transcriptomic and epigenomic levels. Our findings also indicate that Müller glia are epigenetically very close to late-born retinal neurons, but not early-born retinal neurons. Importantly, we found that key genes required for phototransduction were highly methylated. Thus, our data suggest that Müller glia are epigenetically very similar to late RPCs; however, obstacles for regeneration of the entire mammalian retina from Müller glia may consist of repressive chromatin and highly methylated DNA in the promoter regions of many genes required for the development of early-born retinal neurons. In addition, DNA demethylation may be required for proper reprogramming and differentiation of Müller glia into rod photoreceptors.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 3 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Veronica Persico, Giuliano Callaini, Maria Giovanna Riparbelli〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The 〈em〉Drosophila〈/em〉 male stem cell niche is a well characterized structure in which a small cluster of somatic cells send self-renewal signals to neighbouring germ cells. Although the molecular information involved in the stem cell fate have been identified, much less is understand on the mechanisms driving their short-range specific release. Our ultrastructural analysis reveals distinct protrusions of the stem cell plasma membrane that interdigitate with membrane protrusions of the facing hub cells. Some of these protrusions are very elongated and extend into the hub and could correspond to the Mt-Nanotubes. Therefore, the interface between the stem cells and the hub appears more complex than previously reported and the membrane protrusions of the stem cells might represent specialized surface areas involved in the niche-stem cell communication. We also noticed the presence of clathrin-coated vesicles in the germline plasma membrane that might be also involved in delivering information from the hub.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cytokine, Volume 123〈/p〉 〈p〉Author(s): Alan Valaperti, Pascal Bezel, Maya Vonow-Eisenring, Daniel Franzen, Urs C. Steiner〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Measurement of cytokines in peripheral blood and bronchoalveolar lavage fluid (BALF) is a useful method to assess human immune responses in a large range of pulmonary diseases. One of the major pre-analytical challenges of cytokine analysis is the quality and stability of cytokines in the timeframe between sample collection and the separation of supernatant from cells.〈/p〉 〈p〉To evaluate if the method of storage may affect cytokine quantification, whole blood and BALF were collected, aliquoted, and left at room temperature (RT) to be processed at different time points. In addition, sera and BALF were left either at RT or at 4 °C for 24 h after cell separation to test cytokine variations in the absence of cells. Samples were analysed by a multiple array containing ten cytokines.〈/p〉 〈p〉Most of the cytokines analysed (interleukin (IL)-4, IL-5, IL-6, IL-12p70, IL-13, IL-17A, IL-23, interferon (IFN)-γ, and tumour necrosis factor (TNF)-α) did not show significant variations in whole blood and BALF. Levels of IL-8 however, increased after storage of whole blood and BALF for 24 h at RT. 〈em〉Ex vivo〈/em〉 IL-8 production seems to correlate with higher numbers of macrophages in collected BALF.〈/p〉 〈p〉These data demonstrate that many cytokines are stable for a brief time after sample collection. For IL-8, freshly collected whole blood and BALF should be quickly processed and frozen to avoid false positive results.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics〈/p〉 〈p〉Author(s): Hajime Julie Yuasa〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) have an independent origin; however, they have distinctly evolved to catalyze the same reaction. In general, 〈em〉TDO〈/em〉 is a single-copy gene in each metazoan species, and TDO enzymes demonstrate similar enzyme activity regardless of their biological origin. In contrast, multiple IDO paralogues are observed in many species, and they display various enzymatic properties. Similar to vertebrate IDO2, invertebrate IDOs generally show low affinity/catalytic efficiency for L-Trp. Meanwhile, two IDO isoforms from scallop (IDO-I and -III) and sponge IDOs show high L-Trp catalytic activity, which is comparable to vertebrate IDO1. Site-directed mutagenesis experiments have revealed that primarily two residues, Tyr located at the 2nd residue on the F-helix (F2〈sup〉nd〈/sup〉) and His located at the 9th residue on the G-helix (G9〈sup〉th〈/sup〉), are crucial for the high affinity/catalytic efficiency of these ‘high performance’ invertebrate IDOs. Conversely, those two amino acid substitutions (F2〈sup〉nd〈/sup〉/Tyr and G9〈sup〉th〈/sup〉/His) resulted in high affinity and catalytic activity in other molluscan ‘low performance’ IDOs. In human IDO1, G9〈sup〉th〈/sup〉 is Ser〈sup〉167〈/sup〉, whereas the counterpart residue of G9〈sup〉th〈/sup〉 in human TDO is His〈sup〉76〈/sup〉. Previous studies have shown that Ser〈sup〉167〈/sup〉 could not be substituted by His because the human IDO1 Ser〈sup〉167〈/sup〉His variant showed significantly low catalytic activity. However, this may be specific for human IDO1 because G9〈sup〉th〈/sup〉/His was demonstrated to be very effective in increasing the L-Trp affinity even in vertebrate IDOs. Therefore, these findings indicate that the active sites of TDO and IDO are more similar to each other than previously expected.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Current Opinion in Neurobiology, Volume 59〈/p〉 〈p〉Author(s): Javed M Chitaman, Peter Fraser, Jian Feng〈/p〉 〈div〉〈p〉Aberrant gene expression underlies drug addiction. Therefore, studying the regulation of gene expression in drug addiction may provide mechanistic insights into this disease, for which there are still only limited treatments. Recently, the three-dimensional (3D) organization of linear DNA in the nucleus has been recognized as having a major influence on gene transcription. Here, we review its roles in both basic brain function and neuropsychiatric disorders, while also highlighting its emerging implications in drug addiction. Unraveling the 3D architecture of chromosomes in drug addiction is adding to our understanding of this disease and has the potential to trigger novel approaches for better diagnosis and therapy.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - General Subjects〈/p〉 〈p〉Author(s): Maja Hanić, Irena Trbojević-Akmačić, Gordan Lauc〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉Inflammatory bowel disease (IBD) pathogenesis is still not well understood. It is considered to result from genetic susceptibility, environment, microbiota composition and aberrant immune response. Crohn's disease (CD) and ulcerative colitis (UC), forms of IBD, are sometimes indistinguishable by typical laboratory and clinical characteristics making timely diagnosis and subsequent therapy hit-and-miss. Glycosylation has shown a promising biomarker potential for early IBD diagnosis and effective response to treatment prediction.〈/p〉 〈/div〉 〈div〉 〈h6〉Scope of review〈/h6〉 〈p〉This mini-review briefly covers present knowledge of IBD pathophysiology, with a focus on recent research on the role of glycosylation in IBD pathogenesis and disease progression.〈/p〉 〈/div〉 〈div〉 〈h6〉Major conclusions〈/h6〉 〈p〉Aberrant glycosylation significantly changes functionality of key proteins in intestinal niche and is involved in IBD etiology.〈/p〉 〈/div〉 〈div〉 〈h6〉General significance〈/h6〉 〈p〉Elucidating mechanisms of IBD development is one of critical goals in managing this disease. Glycans are important for fine-tuning of intestinal processes that ensure homeostatic conditions which, if disrupted, lead to IBD.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms〈/p〉 〈p〉Author(s): Hossein Shenasa, Klemens J. Hertel〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The generation of protein coding mRNAs from pre-mRNA is a fundamental biological process that is required for gene expression. Alternative pre-mRNA splicing is responsible for much of the transcriptomic and proteomic diversity observed in higher order eukaryotes. Aberrations that disrupt regular alternative splicing patterns are known to cause human diseases, including various cancers. Alternative splicing is a combinatorial process, meaning many factors affect which two splice sites are ligated together. The features that dictate exon inclusion are comprised of splice site strength, intron-exon architecture, RNA secondary structure, splicing regulatory elements, promoter use and transcription speed by RNA polymerase and the presence of post-transcriptional nucleotide modifications. A comprehensive view of all of the factors that influence alternative splicing decisions is necessary to predict splicing outcomes and to understand the molecular basis of disease. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease〈/p〉 〈p〉Author(s): Arubala P. Reddy, Janani Ravichandran, Nurgul Carkici-Salli〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Pengfei Chu, Libo He, Cheng Yang, Wencheng Zeng, Rong Huang, Lanjie Liao, Yongming Li, Zuoyan Zhu, Yaping Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Autophagy is an essential and conserved process that plays an important role in physiological homeostasis, adaptive response to stress and the immune response. Autophagy-related proteins (ATGs) are key components of the autophagic machinery. In the study, grass carp (〈em〉Ctenopharyngodon idella〈/em〉) autophagy-related gene 5 (〈em〉ATG5〈/em〉) and 12 (〈em〉ATG12〈/em〉) were identified. In the gill and intestine, 〈em〉ATG5〈/em〉 and 〈em〉ATG12〈/em〉 were highly expressed, but after grass carp reovirus (GCRV) infection, they were decreased significantly. In 〈em〉Ctenopharyngodon idella〈/em〉 kidney (CIK) cells, the sharp variation of 〈em〉ATG5〈/em〉 and 〈em〉ATG12〈/em〉 expression was observed after poly(I:C) infection. Subcellular localisation showed that ATG5 and ATG12 were evenly distributed in the cytoplasm and nucleus. However, the interaction between ATG5 and ATG12 was only found in cytoplasm in both 293T cells and CIK cells. In addition, the overexpression of ATG5 or ATG12 in 293T cells showed enhanced autophagy, and autophagic process was facilitated when ATG5 and ATG12 were simultaneously overexpressed. Dual-luciferase activity assay indicated that both ATG5 and ATG12 remarkably suppressed the promoter activity of 〈em〉IRF3〈/em〉, 〈em〉IRF7〈/em〉, and 〈em〉IFN-I〈/em〉. Further, ATG5 and ATG12 conjugate showed far stronger inhibitory affection on the expression of 〈em〉IFN-I〈/em〉 than either ATG5 or ATG12 in response to poly(I:C) or GCRV infection. Taken together, the results demonstrate that grass carp ATG5 and ATG12 play an important role in innate immunity and autophagy.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Chao Xu, Wen-Bin Liu, Sofie Charlotte Remø, Bing-Ke Wang, Hua-Juan Shi, Li Zhang, Jia-Dai Liu, Xiang-Fei Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This study investigated the effects of restricted feeding on the growth performance, oxidative stress and inflammation of 〈em〉Megalobrama amblycephala〈/em〉 fed high-carbohydrate (HC) diets. Fish (46.94 ± 0.04 g) were randomly assigned to four groups containing the satiation of a control diet (30% carbohydrate) and three satiate levels (100% (HC1), 80% (HC2) and 60% (HC3)) of the HC diets (43% carbohydrate) for 8 weeks. Results showed that HC1 diet remarkably decreased final weight (FW), weight gain rate (WGR), specific growth rate (SGR), feed conversion ratio (FCR), hepatic activities of total anti-oxidation capacity (T-AOC), superoxide dismutase (SOD) and catalase (CAT), the AMP/ATP ratio, the p-AMPKα/t-AMPKα ratio, sirtuin-1 (SIRT1) protein expression and hepatic transcriptions of AMPKα2, SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), manganese superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1) and interleukin10 (IL 10) compared to the control group, whereas the opposite was true for protein efficiency ratio (PER), nitrogen retention efficiency (NRE), energy retention efficiency (ERE), plasma glucose levels, alanine transaminase (AST) and aspartate aminotransferase (ALT) activities, hepatic contents of malondialdehyde (MDA), tumour necrosis factor α (TNF α) and interleukin 1β (IL 1β), ATP and AMP contents and hepatic transcriptions of kelch-like ECH associating protein 1 (Keap1), IkB kinase α (IKK α), nuclear factor kappa B (NF-κB), TNF α, IL 1β, interleukin 6 (IL 6) and transforming growth factor β (TGF β). As for the HC groups, fish fed the HC2 diet obtained relatively high values of SGR, PER, NRE, ERE, hepatic activities of T-AOC, SOD and CAT, the AMP/ATP ratio, the p-AMPKα/t-AMPKα ratio, SIRT1 protein expression and hepatic transcriptions of AMPKα2, Nrf2, CAT, copper/zinc superoxide dismutase (Cu/Zn-SOD), Mn-SOD, GPx1, glutathione S-transferase (GST) and interleukin10 (IL 10), while the opposite was true for hepatic content of IL 6 and transcription of IKK α. Overall, an 80% satiation improved the growth performance and alleviated the oxidative stress and inflammation of blunt snout bream fed HC diets via the activation of the AMPK-SIRT1 pathway and the up-regulation of the activities and transcriptions of Nrf2-modulated antioxidant enzymes coupled with the depression of the levels and transcriptions of the NF-κB-mediated pro-inflammatory cytokines.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Jiangfan Zhang, Chuanju Dong, Junchang Feng, Junpeng Li, Shengjie Li, Jianxin Feng, Xiaodi Duan, Gaigai Sun, Peng Xu, Xuejun Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉HIFs〈/em〉 (Hypoxia inducible factors) are the main regulators of the expression change of oxygen-dependent genes, in addition, they also play important roles in immune regulation. 〈em〉HIFs〈/em〉 participate in infectious diseases and inflammatory responses, providing us a new therapeutic target for the treatment of diseases. In this study, 16 〈em〉HIFs〈/em〉 were identified in common carp genome database. Comparative genomics analysis showed large expansion of 〈em〉HIF〈/em〉 gene family and approved the four round whole genome duplication (WGD) event in common carp. To further understand the function of 〈em〉HIFs〈/em〉, the domain architectures were predicted. All HIF proteins had the conserved HLH-PAS domain, which were essential for them to form dimer and bind to the downstream targets. The differences in domain of HIFα and HIFβ might result in their different functions. Phylogenetic analysis revealed that all 〈em〉HIFs〈/em〉 were divided into two subfamilies and the 〈em〉HIFs〈/em〉 in common carp were clustered with their teleost counterparts indicating they are highly conservative during evolution. In addition, the tissue distribution was examined by RT-PCR showed that most of 〈em〉HIF〈/em〉 genes had a wide range of tissue distribution but exhibited tissue-specific expression patterns. The expression divergences were observed between the copy genes, for example, 〈em〉HIF1A-1〈/em〉, 〈em〉HIF2A-1〈/em〉, 〈em〉ARNT-〈/em〉2 had wide tissue distribution while their copies had limited tissue distribution, proving the function divergence of copies post the WGD event. In order to find an effective activation of 〈em〉HIFs〈/em〉 and apply to treatment of aquatic diseases, we investigate the dietary supplementation effects of different strains of 〈em〉Lactococcus lactis〈/em〉 on the expression of 〈em〉HIFα〈/em〉 subfamily members in kidney of common carp infected with 〈em〉A. hydrophila〈/em〉. In addition, all of the 〈em〉HIF〈/em〉 genes have a high expression in the early stages of infection, and decreased in the treatment time point of 48 h in common carp. This phenomenon confirms that as a switch, the main function of 〈em〉HIFs〈/em〉 is to regulate the production of immune response factors in early infection. So activation of the switch may be an effective method for infectious disease treatment. As expected, the treatment groups improved the expression of 〈em〉HIFs〈/em〉 compared with the control group, and the effects of the three strains are different. The strain1 of 〈em〉L. lactis〈/em〉 had a stronger induction on 〈em〉HIF〈/em〉 genes than strain2 and strain3, and it might be applied as a potential activation of 〈em〉HIF〈/em〉 genes for disease treatment. So, adding befitting 〈em〉L. lactis〈/em〉 maybe a well method to activate the 〈em〉HIF〈/em〉 genes to protect them from mycobacterial infection.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): K.A.S.N. Shanaka, M.D. Neranjan Tharuka, Thanthrige Thiunuwan Priyathilaka, Jehee Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Viperin, also known as RSAD2 (Radical S-adenosyl methionine domain containing 2), is an interferon-induced endoplasmic reticulum-associated antiviral protein. Previous studies have shown that viperin levels are elevated in the presence of viral RNA, but it has rarely been characterized in marine organisms. This study was designed to functionally characterize rockfish viperin (〈em〉SsVip〈/em〉), to examine the effects of different immune stimulants on its expression, and to determine its subcellular localization. SsVip is a 349 amino acid protein with a predicted molecular mass of 40.24 kDa. It contains an S-adenosyl 〈span〉l〈/span〉-methionine binding conserved domain with a CNYKCGFC sequence. Unchallenged tissue expression analysis using quantitative real time PCR (qPCR) revealed 〈em〉SsVip〈/em〉 expression to be the highest in the blood, followed by the spleen. When challenged with poly I:C, 〈em〉SsVip〈/em〉 was upregulated by approximately 60-fold in the blood after 24 h, and approximately 50-fold in the spleen after 12 h. Notable upregulation was detected throughout the poly I:C challenge experiment in both tissues. Significant expression of 〈em〉SsVip〈/em〉 was detected in the blood following 〈em〉Streptococcus iniae〈/em〉 and lipopolysaccharide challenge, and viral hemorrhagic septicemia virus (VHSV) gene transcription was significantly downregulated during SsVip overexpression. Furthermore, cell viability assay and virus titer quantification with the presence of SsVip revealed a significant reduction in virus replication. As with previously identified viperin counterparts, SsVip was localized in the endoplasmic reticulum. Our findings show that SsVip is an antiviral protein crucial to innate immune defense.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Developmental Cell, Volume 50, Issue 1〈/p〉 〈p〉Author(s): Amir J. Bidhendi, Anja Geitmann〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Morphogenesis of wavy epidermal pavement cells in plants has fascinated researchers for decades. A mechanical mechanism had been proposed in which the anticlinal cell walls, forming the in-plane cell borders, feature contiguous stiff and soft zones that generate waves upon stretching. We replicated this model as designed and also expanded on it to test its validity for three-dimensional (3D) cell geometry. Our results suggest that both the assumptions going into and the predictions arising from this hypothesis do not stand closer scrutiny and may misguide experimentalists. Unlike what the published data seem to suggest, we observed that only waves of negligible magnitude can be formed by this anticlinal stretch model and that these are virtually eliminated when full 3D geometry of the cell is considered. Further, the model produces cell wall stresses that do not match the experimental evidence.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1534580719303727-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Developmental Cell, Volume 50, Issue 1〈/p〉 〈p〉Author(s): Avinash Thakur, Pamela A. Hoodless〈/p〉 〈div〉〈p〉To date, how epigenetic changes are regulated during liver regeneration remains unclear. In this issue of 〈em〉Developmental Cell〈/em〉, Wang and colleagues (2019) employed transcriptomic and epigenomic profiling to explore how 〈em〉Uhrf1〈/em〉, an epigenetic regulator of DNA methylation, functions in liver regeneration using a mouse model of partial hepatectomy.〈/p〉〈/div〉

Description: 〈p〉Publication date: 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Developmental Cell, Volume 50, Issue 1〈/p〉 〈p〉Author(s): Dongjie Zhou, Toru Suzuki, Maki Asami, Anthony C.F. Perry〈/p〉

Description: 〈p〉Publication date: 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Developmental Cell, Volume 50, Issue 1〈/p〉 〈p〉Author(s): Siti Nur Sarah Morris, James A. Olzmann〈/p〉 〈div〉〈p〉In this issue of 〈em〉Developmental Cell〈/em〉, Chorlay et al. (2019) provide evidence that asymmetric membrane surface tension determines the directionality of lipid droplet (LD) emergence. Furthermore, phospholipid synthesis “refills” the outer leaflet of the endoplasmic reticulum (ER) membrane to maintain cytosolic LD emergence and prevent disruptions to ER homeostasis.〈/p〉〈/div〉

Description: 〈p〉Publication date: 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Developmental Cell, Volume 50, Issue 1〈/p〉 〈p〉Author(s): Colin C. Conine, Fengyun Sun, Lina Song, Jaime A. Rivera-Pérez, Oliver J. Rando〈/p〉

Description: 〈p〉Publication date: Available online 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Metabolism〈/p〉 〈p〉Author(s): Kevin D. Hall〈/p〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Protein Expression and Purification, Volume 163〈/p〉 〈p〉Author(s): Vasiliki Paraskevopoulou, Verónica García Artiaga, Rachel Rowlinson, G. Sebastiaan Winkler, Paul Gellert, Snow Stolnik, Ross Overman, Franco H. Falcone〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Helicobacter pylori〈/em〉 is a pathogenic microorganism infecting approximately 50% of the global population, and establishes life-long colonization despite the hostile stomach environment. 〈em〉H. pylori〈/em〉 employs a wide range of outer membrane proteins (adhesins) for epithelial attachment, which specifically bind to glycans or non-carbohydrate structures expressed on the gastric epithelium. A recently described adhesin from 〈em〉H. pylori〈/em〉 is LabA, named after its ability to bind to a disaccharide present in gastric mucus (LacdiNAc-specific adhesin). Here, we describe the recombinant expression of LabA from 〈em〉H. pylori〈/em〉 strains J99 and 26695 in 〈em〉E. coli〈/em〉. High yields of recombinant LabA were obtained using periplasmic expression. We found that the addition of a C-terminal hexalysine (6K) tag enhanced the thermal stability of LabA without affecting its secondary structure, using differential scanning fluorimetry and circular dichroism spectroscopy. In contrast to our previous report for another 〈em〉H. pylori〈/em〉 adhesin (BabA), the 6K tag did not enhance recombinant protein yield or solubility. Both versions of LabA, with or without the 6K tag, were expressed and isolated from the periplasmic space of 〈em〉Escherichia coli〈/em〉, with a surprisingly high yield of at least 40 mg/L for each independent preparation, following a two-step purification protocol. The proteins were analyzed with mass spectrometry (MS). Unlike its reported effect on stability of BabA, the 6K tag did not appear to protect the N-term of recombinant LabA from partial periplasmic degradation.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computer Methods and Programs in Biomedicine, Volume 178〈/p〉 〈p〉Author(s): Kao-Shang Shih, Chi-Pin Hsu, Che-Wei Liu, Lu-Lin Wang, Sheng-Mou Hou, Shang-Chih Lin〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background and objectives〈/h6〉 〈p〉The statistical shape model (SSM) of numerous bones has been used to determine the anatomical representative of the population- or race-specific design for periarticular implants. Whether to include size- and profile-mismatched bones in the SSM calculation is debatable. Therefore, the objective of this study was to characterize the screening strategies for the mismatched bones to improve the SSM calculation.〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉The bone database used in this study consisted of 20 pelvises. A systematic four-staged SSM calculation was used to evaluate the accuracy of the predicted SSM shape among the four size- and profile-screening strategies. Additionally, the surface-smoothing effects on the SSM results were investigated. Two comparison indices were used in terms of profile difference and surface smoothness.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉Significant variations in size and profile existed for the collected bones. By normalizing the aspect ratio of all bones, exclusion of the size-mismatched bones reduced the maximum and root mean square (RMS) error values of the profile difference by 18.9% and 17.5%, respectively. After further excluding the profile-improper bones, normalization reduced the RMS profile difference by 24.1% compared with the non-normalized strategy. Exclusion of the size-improper bones for non-normalized strategy would have reduced the RMS profile difference by 15.4%. After smoothness, the RMS profile difference of SSM was only 6.1% higher than that of the non-smoothness SSM.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusions〈/h6〉 〈p〉The four-stage calculation showed that the most favorable strategy was to normalize bones to the same aspect ratio and exclude improperly shaped bones. The model permitted inclusion of the original characteristics of the bones and preserved their shapes and excluded only significantly improper bones. After SSM calculation, the smoothed process provided satisfaction in quality with a statistically insignificant loss in bone morphology for population- or race-specific designs of implants.〈/p〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 217〈/p〉 〈p〉Author(s): Xiao-Juan Wang, Gao-Feng Shu, Xiao-Ling Xu, Chen-Han Peng, Chen-Ying Lu, Xing-Yao Cheng, Xiang-Chao Luo, Jie Li, Jing Qi, Xu-Qi Kang, Fei-Yang Jin, Min-Jiang Chen, Xiao-Ying Ying, Jian You, Yong-Zhong Du, Jian-Song Ji〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Spinal cord injury (SCI) leads to immediate disruption of neuronal membranes and loss of neurons, followed by extensive secondary injury process. Treatment of SCI still remains a tremendous challenge clinically. Minocycline could target comprehensive secondary injury via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Polyethylene glycol (PEG), a known sealing agent, is able to seal the damaged cell membranes and reduce calcium influx, thereby exerting neuroprotective capacity. Here, an E-selectin-targeting sialic acid - polyethylene glycol – poly (lactic-co-glycolic acid) (SAPP) copolymer was designed for delivering hydrophobic minocycline to achieve combinational therapy of SCI. The obtained SAPP copolymer could self-assemble into micelles with critical micelle concentration being of 13.40 μg/mL, and effectively encapsulate hydrophobic minocycline. The prepared drug-loaded micelles (SAPPM) displayed sustained drug release over 72 h, which could stop microglia activation and exhibited excellent neuroprotective capacity 〈em〉in vitro〈/em〉. The SAPP micelles were efficiently accumulated in the lesion site of SCI rats via the specific binding between sialic acid and E-selectin. Due to the targeting distribution and combinational effect between PEG and minocycline, SAPPM could obviously reduce the area of lesion cavity, and realize more survival of axons and myelin sheaths from the injury, thus distinctly improving hindlimb functional recovery of SCI rats and conferring superior therapeutic effect in coparison with other groups. Our work presented an effective and safe strategy for SCI targeting therapy. Besides, neuroprotective capacity of PEG deserves further investigation on other central nervous system diseases.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961219304259-fx1.jpg" width="312" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Current Opinion in Neurobiology, Volume 58〈/p〉 〈p〉Author(s): Li Zhaoping〈/p〉 〈div〉〈p〉Visual attention selects only a tiny fraction of visual input information for further processing. Selection starts in the primary visual cortex (V1), which creates a bottom-up saliency map to guide the fovea to selected visual locations via gaze shifts. This motivates a new framework that views vision as consisting of encoding, selection, and decoding stages, placing selection on center stage. It suggests a massive loss of non-selected information from V1 downstream along the visual pathway. Hence, feedback from downstream visual cortical areas to V1 for better decoding (recognition), through analysis-by-synthesis, should query for additional information and be mainly directed at the foveal region. Accordingly, non-foveal vision is not only poorer in spatial resolution, but also more susceptible to many illusions.〈/p〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 217〈/p〉 〈p〉Author(s): Dandan Zhang, Liewei Wen, Ru Huang, Huanhuan Wang, Xianglong Hu, Da Xing〈/p〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 218〈/p〉 〈p〉Author(s): Shao-Kai Sun, Jian-Cheng Wu, Haoyu Wang, Li Zhou, Cai Zhang, Ran Cheng, Di Kan, Xuejun Zhang, Chunshui Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Bioavailable persistent luminescence material is an ideal internal light source for long-term photodynamic therapy, but inevitably suffers from low utilization efficiency and weak persistent luminescence due to corrosion and screening processes. Herein, we show a facile and smart “turning solid into gel” strategy to fabricate persistent luminescence hydrogel for high-efficient persistent luminescence-sensitized photodynamic therapy. The homogeneous persistent luminescence hydrogel was synthesized via dispersing high-temperature calcined persistent luminescence material without corrosion and screening into a biocompatible alginate-Ca〈sup〉2+〈/sup〉 hydrogel. The simple synthesis strategy allows 100% of utilization efficiency and intact persistent luminescence of persistent luminescence material. The persistent luminescence hydrogel possesses favorable biocompatibility, bright persistent luminescence, red light renewability, good syringeability, and strong fixing ability in tumors. The persistent luminescence hydrogel can be easily injected in vivo as a powerful localized light source for superior persistent luminescence-sensitized photodynamic therapy of tumors. The “turning solid into gel” strategy enables taking full advantages of persistent luminescence for biological applications, and shows great potential in utilizing diverse theranostic agents regardless of hydrophilicity and hydrophobicity.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1865, Issue 10〈/p〉 〈p〉Author(s): Mabrouka Salem, Mohammed-Amine El Azreq, Julie Pelletier, Bernard Robaye, Fawzi Aoudjit, Jean Sévigny〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Extracellular nucleotides are released as constitutive danger signals by various cell types and activate nucleotide (P2) receptors such as P2Y〈sub〉6〈/sub〉 receptor. P2Y〈sub〉6〈/sub〉 activation on monocytes induces the secretion of the chemokine CXCL8 which may propagate intestinal inflammation. Also, P2Y〈sub〉6〈/sub〉 expression is increased in infiltrating T cells of Crohn's disease patients. As inflammatory bowel disease (IBD) is associated with immune cell recruitment, we hypothesised that P2Y〈sub〉6〈/sub〉 would participate to the establishment of inflammation in this disease. To address this, we used P2Y〈sub〉6〈/sub〉 deficient (〈em〉P2ry6〈/em〉〈sup〉‐〈/sup〉〈sup〉−〈/sup〉〈sup〉/〈/sup〉〈sup〉−〈/sup〉) mice in the dextran sodium sulfate (DSS) murine model of IBD. In disagreement with our hypothesis, P2Y〈sub〉6〈/sub〉 deficient mice were more susceptible to inflammation induced by DSS than WT mice. DSS treated-〈em〉P2ry6〈/em〉〈sup〉−〈/sup〉〈sup〉/〈/sup〉〈sup〉−〈/sup〉 mice showed increased histological damage and increased neutrophil and macrophage infiltration that correlated with increased mRNA levels of the chemokines KC and MCP-1. DSS treated-〈em〉P2ry6〈/em〉〈sup〉−〈/sup〉〈sup〉/〈/sup〉〈sup〉−〈/sup〉 mice exhibited also higher levels of Th17/Th1 lymphocytes in their colon which correlated with increased levels of IFN-γ and IL-17A in the sera as well as increased mRNA levels of IFN-γ, IL-17A, IL-6, IL-23 and IL-1β in 〈em〉P2ry6〈/em〉〈sup〉−〈/sup〉〈sup〉/〈/sup〉〈sup〉−〈/sup〉 colons. This inflammation was also accompanied by a decreased cell proliferation and goblet cell number. Importantly, injection of anti-IL-17 intraperitoneally partially protected 〈em〉P2ry6〈/em〉〈sup〉−〈/sup〉〈sup〉/〈/sup〉〈sup〉−〈/sup〉 mice from DSS-induced colitis. Taken together, in the absence of P2Y〈sub〉6〈/sub〉, an exacerbated intestinal inflammation to DSS was observed which correlated with increased recruitment of Th17/Th1 lymphocytes. These data suggest a protective role of P2Y〈sub〉6〈/sub〉 expressed on leukocytes in intestinal inflammation.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms〈/p〉 〈p〉Author(s): Samuel Hamilton, Rafael de Cabo, Michel Bernier〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Maternally Expressed Gene 3 (MEG3) is a long noncoding RNA (lncRNA) that coordinates a diverse array of cellular processes requiring epigenetic regulation of genes and interactions with key signaling proteins and by acting as a competitive endogenous (ce)RNA. Epigenetic modifications driven by in utero nutrition affect MEG3 expression and its role in the development of multiple metabolic disorders. This review examines how epigenetic modification of MEG3 expression can confer adaptedness to different metabolic environments. To this end, we discuss how nutritional status that leads to an increase of MEG3 expression can protect against cancer and metabolic dysfunctions, while interventions that promote MEG3 downregulation minimize the pleiotropic costs associated with its expression. Lastly, we identify research directions that would further shed light on the role of MEG3 in metabolic regulation and in functional imprinted gene networks. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 218〈/p〉 〈p〉Author(s): Shijie Zhen, Xiaoqing Yi, Zujin Zhao, Xiaoding Lou, Fan Xia, Ben Zhong Tang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The combination of photodynamic therapy (PDT) and chemotherapy (CT) offers a promising approach for the tumor eradication for overcoming multidrug resistance (MDR), which is a major obstacle to effective cancer treatment. However, for PDT, simultaneously achieving near-infrared (NIR) emission and efficient reactive oxygen species (ROS) generation with low dark toxicity is urgently needed but remains challenging. Herein, a series of novel fluorophores with strong NIR emission, hybridized local and charge transfer characteristics, good two-photon absorption, high photostability, low dark cytotoxicity and excellent ROS generation ability are developed. By encapsulating the NIR fluorophore (DEB-BDTO) as a photosensitizer along with a drug resistance inhibitor tariquidar (TQR) within a polymeric prodrug (PMP), a reduction-sensitive drug co-delivery system (DEB/TQR@PMP micelles) is constructed. The DEB/TQR@PMP micelles exhibit a prominent synergistic lethal effect of PDT and CT on SKOV-3 cells and SKOV-3/MDR cells, and can apparently enhance the inhibition of tumor growth compared with sole PDT or CT in the tumor-bearing mouse model. Both in vitro and in vivo experiments prove that the new NIR fluorophores are excellent photosensitizers and can furnish an efficient combination therapy of image-guided PDT and CT within drug delivery micelles, which is particularly useful for eradicating multidrug resistance cancer.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961219304296-fx1.jpg" width="500" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Methods〈/p〉 〈p〉Author(s): Melissa Spence, Mario Banuelos, Roummel F. Marcia, Suzanne Sindi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Structural variants (SVs) are a class of genomic variation shared by members of the same species. Though relatively rare, they represent an increasingly important class of variation, as SVs have been associated with diseases and susceptibility to some types of cancer. Common approaches to SV detection require the sequencing and mapping of fragments from a test genome to a high-quality reference genome. Candidate SVs correspond to fragments with discordant mapped configurations. However, because errors in the sequencing and mapping will also create discordant arrangements, many of these predictions will be spurious. When sequencing coverage is low, distinguishing true SVs from errors is even more challenging. In recent work, we have developed SV detection methods that exploit genome information of closely related individuals – parents and children. Our previous approaches were based on the assumption that any SV present in a child’s genome must have come from one of their parents. However, using this strict restriction may have resulted in failing to predict any rare but novel variants present only in the child. In this work, we generalize our previous approaches to allow the child to carry novel variants. We consider a constrained optimization approach where variants in the child are of two types either inherited - and therefore must be present in a parent – or novel. For simplicity, we consider only a single parent and single child each of which have a haploid genome. However, even in this restricted case, our approach has the power to improve variant prediction. We present results on both simulated candidate variant regions, parent-child trios from the 1000 Genomes Project, and a subset of the 17 Platinum Genomes.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Shu-Yi Hao, Shi-Liang Feng, Xing-Rong Wang, Zhichao Wang, Shi-Wu Chen, Ling Hui〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of conjugates of podophyllotoxin and coumarin were prepared using the click reaction, and their cytotoxicities against A549, HepG2, HeLa, and LoVo cells were evaluated. Among them, compound 〈strong〉14e〈/strong〉 exhibited the strongest cytotoxicities against these cancer cells with IC〈sub〉50〈/sub〉 values of 4.9–17.5 μM. Furthermore, 〈strong〉14e〈/strong〉 disrupted microtubules and induced cell cycle arrest at G1 phase by regulating P21 and Cyclin D1 in LoVo cells. In addition, 〈strong〉14e〈/strong〉 bond CT DNA and selectively inhibited Topo IIβ over Topo IIα. Molecular docking model showed that 〈strong〉14e〈/strong〉 appeared to form stable hydrogen bonds with several DNA bases and residue Gln778. Taken together, these conjugates have the potential to be developed as anti-tumor drugs.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉The conjugates of podophyllotoxin and coumarin disrupt the microtubules, induce cell cycle arrest in G1 phase, bind to CT DNA, and inhibit Topo-Ⅱβ in LoVo cells.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304457-ga1.jpg" width="429" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Seminars in Cell & Developmental Biology〈/p〉 〈p〉Author(s): Tânia Capelôa, Zohra Benyahia, Luca X. Zampieri, Marine C.N.M. Blackman, Pierre Sonveaux〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types in the clinics, either alone or, most often, in combination therapies. While their cardiotoxicity is well known, the emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of permeability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthracyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide biosynthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype.〈/p〉〈/div〉