Optimization of 5-arylidene barbiturates as potent,selective, reversible LSD1 inhibitors for the treatment of acute promyelocytic leukemia

Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 12a exhibited reversible and potent inhibition (IC₅₀?=?0.41?μM) and high selectivity over the MAO-A and MAO-B. Notably, 12a strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4). Our findings indicate that 5-arylidene barbiturate may represent a new skeleton of LSD1 inhibitors and 12a deserve as a promising agent for the further research.     

高通量质谱法用于小鼠脑部神经肽的鉴定

神经肽在参与调控人体各种生理功能上发挥着重要的作用,如痛觉、睡眠、情绪、学习与记忆等生理活动都受到神经肽的影响。神经肽主要存在于机体的神经组织内,其他体液和器官中也有少量的分布。目前对全脑组织神经肽高通量鉴定的研究仍不足,高通量检测这些神经肽对了解神经肽的组成和功能具有重要的意义。本研究通过对小鼠全脑组织内源性肽段的萃取,运用液相串联质谱(LC-MS/MS)技术对全脑组织的神经肽进行检测,共鉴定到1 830条内源性肽段和99条预测神经肽肽段。这些内源性肽段的鉴定在疾病的治疗和机制研究以及药物的研发方面提供了参考价值,也为研究新的神经肽及其功能奠定了基础。     

Neurotoxic,cytotoxic, apoptotic and antiproliferative effects of some marine algae extracts on the NA2B cell line

Oxidative stress contributes to cancer pathologies and to apoptosis. Marine algae exhibit cytotoxic, antiproliferative and apoptotic effects; their metabolites have been used to treat many types of cancer. We investigated in culture extracts of Petalonia fascia, Jania longifurca and Halimeda tuna to determine their effects on mouse neuroblastoma cell line, NA2B. NA2B cells were treated with algae extracts, and the survival and proliferation of NA2B cells were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of algae extracts on oxidative stress in NA2B cells also were investigated using nitric oxide synthase (NOS) immunocytochemistry and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling. We observed significant neurite inhibition with moderate damage by the neurotoxicity-screening test (NST) at IC₅₀ dilutions of the extracts. MTT demonstrated that J. longifurca extracts were more toxic than P. fascia and H. tuna extracts. We found an increase of endothelial and inducible NOS immunostaining for oxidative stress and TUNEL analysis revealed increased apoptosis after application of extract. Our findings suggest that the algae we tested may have potential use for treatment of cancer.     

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

1. Download high-res image (284KB)
2. Download full-size image

     

Single-Cell Droplet Microfluidic Screening for Antibodies Specifically Binding to Target Cells

1. Download high-res image (180KB)
2. Download full-size image

     

Pot size affects expression of Mn efficiency in barley

Mn efficiency is defined here as an ability of a genotype to grow and yield well in a soil which is limiting in available Mn for a standard genotype (Graham, 1984). Screening for Mn efficiency in soil-based pot testing had been producing inconsistent results, and thus improvement of pot screening became an objective. One possible factor, pot size was examined as the cause, using two sizes of pot. In large pots, the expectation of higher dry matter and shoot Mn concentration in a Mn-efficient genotype compared to a Mn-inefficient genotype was realised over a wide range of Mn supply, whereas in small pots, the genotypic differences were expressed at only one, low rate of Mn supply (10 mg kg soil^-1). Plants in the small pots strongly responded to root restriction by decreasing yields and increasing root/shoot ratios and Mn concentrations of shoots. The critical value of Mn concentration for shoot growth was not affected by the small pots, but the Mn mobilization by plants might be affected in the small pots. The practical outcome of these results is that using an adequate size of pot and measuring the Mn concentration of shoots, soil-based pot screening for Mn efficiency can be improved.     

Isolation and characterization of cDNA clones corresponding to the genes expressed preferentially in floral organs of Arabidopsis thaliana

Seventeen cDNA clones of genes corresponding to mRNAs expressed preferentially in floral organs of Arabidopsis thaliana were obtained by differential screening of a flower bud cDNA library, and classified into five groups (1A, 17A, 1B, 4B and 5B) by cross-hybridization and restriction analysis. Sequence analysis revealed that the 1A-1 and 17A-1 clones encode vegetative storage proteins (VSPs). The VSP mRNAs were detected in a small amount in leaves and increased to a limited level by wounding. Both 1B-1 and 5B-1 clones were homologous to transmembrane protein cDNAs. The protein encoded by 4B-1 clone contained a proline-rich region, but no homologous proteins were found in databases.     

Identification of a set of RFLP probes for subspecies differentiation in Oryza sativa L.

Sixty-eight indica-japonica tester-differentiating RFLP probes were tested in seven indica and seven japonica varieties of rice (Oryza sativa L.) with four enzyme digestions (EcoRI, EcoRV, HindIII and DraI). Twenty-one DNA clones were isolated as indica-japonica subspecies-differentiating probes. A set of 13 probes was established as core probes for subspecies differentiation and a pooled blotting analysis was carried out to facilitate the application of RFLP in rice genetics and breeding practice. A dendrogram of 12 wide-compatibility varieties was constructed based on RFLPs detected by 13 core probes with single enzyme digestions. It was speculated that most RFLPs of indica-japonica differentiating probes were generated by insertions/deletions, which may be of great significance for the origin and differentiation of subspecies in Oryza sativa L.     

Life cycle and host specificity ofEutinobothrus sp. (Col.: curculionidae) an agent for biological control ofSida acuta (malvaceae) in the northern territory,Australia

The biology of an undescribed weevil,Eutinobothrus sp., and its specificity toSida acuta, a serious weed in northern Australia, were studied in a quarantine facility in Australia. Sixty-eight plant species were screened and onlyS. acuta andS. rhombifolia could sustain populations ofEutinobothrus sp. Adults feed externally on the stems and oviposit in feeding scars. Larvae feed internally and pupate in the stem. Prepupae and pupae may aestivate in the stem and adults emerge with the onset of the wet season when new growth is evident.Eutinobothrus sp. was released in January, 1994 in the Northern Territory and has established.