Transgenerational analysis of H3K4me3 and H3K27me3 by ChIP-Seq links epigenetic inheritance to metabolism

正Histone methylation is a kind of important epigenetic modification which occurs on the lysine residue or arginine residue of histone tails(Zhang and Reinberg,2001).It takes part in multiple biological processes,including gene expression,genomic stability,stem cell maturity,genetic imprinting,mitosis and development(Fischle et al.,2005).Abnormal histone methylation pattern may     

Cree antidiabetic plant extracts display mechanism-based inactivation of CYP3A4

Seventeen Cree antidiabetic medicinal plants were studied to determine their potential to inhibit cytochrome P450 3A4 (CYP3A4) through mechanism-based inactivation (MBI). The ethanolic extracts of the medicinal plants were studied for their inhibition of CYP3A4 using the substrates testosterone and dibenzylfluorescein (DBF) in high pressure liquid chromatography (HPLC) and microtiter fluorometric assays, respectively. Using testosterone as a substrate, extracts of Alnus incana, Sarracenia purpurea, and Lycopodium clavatum were identified as potent CYP3A4 MBIs, while those from Abies balsamea, Picea mariana, Pinus banksiana, Rhododendron tomentosum, Kalmia angustifolia, and Picea glauca were identified as less potent inactivators. Not unexpectedly, the other substrate, DBF, showed a different profile of inhibition. Only A. balsamea was identified as a CYP3A4 MBI using DBF. Abies balsamea displayed both NADPH- and time-dependence of CYP3A4 inhibition using both substrates. Overall, several of the medicinal plants may markedly deplete CYP3A4 through MBI and, consequently, decrease the metabolism of CYP3A4 substrates including numerous medications used by diabetics.     

Individual blastomeres of 4- and 8-cell embryos have ability to develop into a full organism in mouse

正Following fertilization in mammals, the zygote initiates the developmental program, which has a transient capacity to generate cell types of both embryonic and extraembryonic lineages, which is defined as totipotency (Condic, 2014). In mice,only zygotes and blastomeres of 2-cell stage embryos are considered totipotent, since they have the ability to develop into a full     

Discovery of potent,low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment

A new series of C-phenyl d-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3?mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes.     

VCSRA: A fast and accurate multiple sequence alignment algorithm with a high degree of parallelism

正Multiple sequence alignment (MSA)is the alignment among more than two molecular biological sequences,which is a fundamental method to analyze evolutionary events such as mutations,insertions,deletions,and re-arrangements.In theory,a dynamic programming algorithm can be employed to produce the optimal     

Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators

This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5) induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric mechanism. The compounds were initially shown to induce CYP3A4/5 via the gold-standard induction assay measured in primary human hepatocytes. This was followed up by testing the compounds in a PXR assay which correlated well with the assay in primary cells. Further, one of the compounds was crystallized with PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with previously published PXR co-crystal structures, lead to modification ideas. The compounds synthesized based on these ideas were shown not to be CYP3A4/5 inducers. The mGluR2 activity of the resulting compounds was maintained.     

Generating a reporter mouse line marking medium spiny neurons in the developing striatum driven by Arpp21 cis-regulatory elements

正The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.     

Generation of rat-mouse chimeras by introducing single cells of rat inner cell masses into mouse blastocysts

正In the field of developmental biology and regenerative medicine,mammalian interspecific chimeras have been proved very useful for investigating early embryonic development and the immune system establishment,and extended to a promising potential for human organ generation(Rossant et al.,1982).In the early     

Control of flowering and inflorescence architecture in tomato by synergistic interactions between ALOG transcription factors

正Inflorescences are flower-bearing shoots that originate from pools of stem cells in shoot apical meristems (SAM).Inflorescence architecture is determined by a process of meristem maturation,during which stem cell fate switches from a vegetative to a reproductive growth program.A major factor in plant reproductive success in nature and yield in agriculture is the number of branches and flowers on inflorescences (Kobayashi and Weigel,2007;     

A behavioral paradigm to study the persistence of reward memory extinction in Drosophila

<正>Drosophila has been proven to be a powerful animal model to study genetic mechanisms underlying different behaviors and diseases (Sokolowski,2001;Bier,2005).Extinction is a process that repeated presentation of a conditioned stimulus without reinforcement results in decreased conditioned responses (Bouton,2004) and receives increasing attention for treating its related diseases such as post-traumatic stress disorder (PTSD) and addiction     

LncPipe: A Nextflow-based pipeline for identification and analysis of long non-coding RNAs from RNA-Seq data

正Long noncoding RNAs(lncRNAs)have been increasingly implicated in a variety of human diseases,including autoimmune disease(Wu et al.,2015),neurodegenerative diseases(Wapinski and Chang,2011)and cancer(Huarte,2015).Due to recent advances in next-generation sequencing technologies,tens of thousands of lnc RNAs have been identified and annotated,a number of them     

Identifying normal embryos from reciprocal translocation carriers by whole chromosome haplotyping

正Reciprocal translocation is a chromosomal structural abnormality that arises when two non-homologous chromosomes rearrange and attach with each other, an incidence that occurs in about 1/500to 1/625 newborns (Mackie and Scriven, 2002). This event typically does not lead to any significant loss of genetic material, thus reciprocal translocation carriers do not exhibit any severe abnormal     

The N6-adenine methylation in yeast genome profiled by single-molecule technology

正The most common and abundant DNA modification is 5-methylcytosine(5mC),which has been well-established as an epigenetic mark regulating gene expression in eukaryotes(Jones,2012).Another DNA modification N~6-methyldeoxyadenosine(6mA),previously reported as a widespread DNA methylation in prokaryotes,     

SERCA regulates collective cell migration by maintaining cytoplasmic Ca~(2+) homeostasis

<正>Characterized by multicellular migratory behavior and cooperative ability,collective cell migration plays critical roles in developmental,physiological and pathological processes,such as organogenesis,wound healing and tumor metastasis (Friedl and Gilmour,2009).Molecular features of collective cell migration including collective polarization,coordinated cytoskeletal activity,and guidance signaling have been recently investigated in a variety of in vivo and in vitro model systems (Scarpa and Mayor,2016),but many other aspects of regulatory mechanisms remain unexplored.     

Functional non-homologous end joining patterns triggered by CRISPR/Cas9 in human cells

正CRISPR/Cas9-mediated genome engineering technologies are now widely applied in various organisms,including mouse and human cells(Cong et al.,2013;Mali et al.,2013;Yang et al.,2013;Hsu et al.,2014).The most widely used customized CRISPR/Cas9(Sp Cas9)is derived from Streptococcus pyogenes(Cong et al.,2013).The CRISPR/Cas9 system creates site-specific double-     

Prosthetic groups for radioiodination and astatination of peptides and proteins: A comparative study of five potential bioorthogonal labeling strategies

¹²⁵I- and ²¹¹At-labeled azide and tetrazine based prosthetic groups for bioorthogonal conjugation were designed and tested in a comparative study of five bioorthogonal systems. All five bioconjugation reactions conducted on a model clickable peptide led to quantitative yields within less than a minute to several hours depending on the system used. Transferability to the labeling of an IgG was demonstrated with one of the bioorthogonal system. This study provides several new alternatives to the conventional and suboptimal approach currently in use for radioiodination and astatination of biomolecules and should accelerate the development of new probes with these radionuclides for applications in nuclear imaging and targeted alpha-therapy.     

Design and synthesis of a potent,highly selective,orally bioavailable,retinoic acid receptor alpha agonist

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.     

ZFN,TALEN and CRISPR-Cas9 mediated homology directed gene insertion in Arabidopsis: A disconnect between somatic and germinal cells

正Breakthroughs in the generation of programmable sequence-specific nucleases (SSNs), such as zinc finger nucleases (ZFNs),TAL effector nucleases (TALENs) and the RNA-directed nuclease CRISPR-associated protein 9 (Cas9), have greatly increased the ease of plant genome engineering (Voytas, 2013; Malzahn et al.,2017). Programmable SSNs introduce a DNA double-strand break     

The central active site arginine in sulfite oxidizing enzymes alters kinetic properties by controlling electron transfer and redox interactions

A central conserved arginine, first identified as a clinical mutation leading to sulfite oxidase deficiency, is essential for catalytic competency of sulfite oxidizing molybdoenzymes, but the molecular basis for its effects on turnover and substrate affinity have not been fully elucidated.We have used a bacterial sulfite dehydrogenase, SorT, which lacks an internal heme group, but transfers electrons to an external, electron accepting cytochrome, SorU, to investigate the molecular functions of this arginine residue (Arg78). Assay of the SorT Mo centre catalytic competency in the absence of SorU showed that substitutions in the central arginine (R78Q, R78K and R78M mutations) only moderately altered SorT catalytic properties, except for R78M which caused significant reduction in SorT activity. The substitutions also altered the Mo-centre redox potentials (Mo^VI/V potential lowered by ca. 60–80 mV). However, all Arg78 mutations significantly impaired the ability of SorT to transfer electrons to SorU, where activities were reduced 17 to 46-fold compared to SorT^WT, precluding determination of kinetic parameters. This was accompanied by the observation of conformational changes in both the introduced Gln and Lys residues in the crystal structure of the enzymes. Taking into account data collected by others on related SOE mutations we propose that the formation and maintenance of an electron transfer complex between the Mo centre and electron accepting heme groups is the main function of the central arginine, and that the reduced turnover and increases in K_Msulfite are caused by the inefficient operation of the oxidative half reaction of the catalytic cycle in enzymes carrying these mutations.