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     

PIK-75 promotes homology-directed DNA repair

Homo!ogy-directed repair(HDR)is one of two major DNA repair pathways to mend the double-strand breaks(DSBs)formed in the genome(Liang et al.,1998;Pardo et al.,2009).Although less efficient compared with another DNA repair pathway,nonhomologous end joining(NHEJ),HDR is a type of precise repair to restore DNA damage and sustain genomic stability(Pardo et al.,2009;Ceccaldi et al.,2016).By contrast,NHEJ usually introduces mutations into the repaired site,thus probably harming the genomic integrity(Lieber et al.,2003).The error-free property enables HDR to be harnessed to correct a faulty mutation for therapeutic purpose in cells or in the body(Wu et al.,2013).In add让ion,HDR possesses great potential in the generation of genome-edited animals with precise genetic modifications,such as point mutation,DNA replacement,and DNA insertion in a specific genomic site(Wang et al.,2013).However,the low repair frequency mediated by HDR significantly limits让s application for efficient gene correction or establishment of various genetically modified animal models.Currently,multiple site-specific endonucleases have emerged as highly efficient tools to create targeted DSBs and markedly promote subsequent DNA repair either via HDR or NHEJ(Gaj et al.,2013).Nonetheless,the HDR-mediated modifications following the cleavage of engineering nucleases are still inefficient,usually with an efficiency less than 20%in cultured mammalian cells and embryos(Mali et al..2013;Wang et al.,2013;Yang et al.,2013).     

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.     

Performance evaluation measures for protein complex prediction

Protein complexes play a dominant role in cellular organization and function. Prediction of protein complexes from the network of physical interactions between proteins (PPI networks) has thus become one of the important research areas. Recently, many computational approaches have been developed to identify these complexes. Various performance assessment measures have been proposed for evaluating the efficiency of these methods. However, there are many inconsistencies in the definitions and usage of the measures across the literature. To address this issue, we have gathered and presented the most important performance evaluation measures and developed a tool, named CompEvaluator, to critically assess the protein complex prediction methods. The tool and documentation are publicly available at https://sourceforge.net/projects/compevaluator/files/.     

Design,synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC₅₀?=?0.527?μM, ACC2 IC₅₀?=?0.397?μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC₅₀ values of 1.92?μM, 0.38?μM, 1.22?μM, 2.05?μM and 5.42?μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.     

Structure-based design and biological evaluation of inhibitors of the pseudomonas aeruginosa heme oxygenase (pa-HemO)

1. Download high-res image (149KB)
2. Download full-size image

     

Amelioration of mechanism-based inactivation of CYP3A4 by a H-PGDS inhibitor

This work describes the rational amelioration of mechanism-based inactivation (MBI) of Cytochrome P450 (CYP) 3A4 in a human hematopoietic prostaglandin D synthase (hH-PGDS) inhibitor (cpd 1). We utilized metabolism reports in order to check if patterns in the metabolism of 1 and similar compounds by CYP3A4 could be deciphered. Then we used structure based design, first modifying the CYP3A4 crystal structure (pdb code: 4NY4) by adding an oxyferryl moiety to the heme, followed by validating the modified structure to obtain the 1′ and 4 position oxidation products of midazolam and then recapitulating the metabolism patterns deciphered previously for 1 and analogs. We checked if the pattern deciphered could lead to a putative reactive moiety. Finally we used the docking pose of 1 into this model of the modified CYP3A4 crystal structure to guide transformation of 1 into MBI-free H-PGDS inhibitors.     

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.     

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-     

Elongator—a tRNA modifying complex that promotes efficient translational decoding

Naturally occurring modifications of the nucleosides in the anticodon region of tRNAs influence their translational decoding properties. Uridines present at the wobble position in eukaryotic cytoplasmic tRNAs often contain a 5-carbamoylmethyl (ncm⁵) or 5-methoxycarbonylmethyl (mcm⁵) side-chain and sometimes also a 2-thio or 2′-O-methyl group. The first step in the formation of the ncm⁵ and mcm⁵ side-chains requires the conserved six-subunit Elongator complex. Although Elongator has been implicated in several different cellular processes, accumulating evidence suggests that its primary, and possibly only, cellular function is to promote modification of tRNAs. In this review, we discuss the biosynthesis and function of modified wobble uridines in eukaryotic cytoplasmic tRNAs, focusing on the in vivo role of Elongator-dependent modifications in Saccharomyces cerevisiae. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena.     

Recent advances in extracellular vesicle research for urological cancers: From technology to application

Urological malignancies, including prostate cancer, bladder cancer and kidney cancer, are major causes of morbidity and mortality worldwide. Because of the high incidence, diversity in biology, and especially direct interaction with urine, urological cancers are an important resource for both scientists and clinicians for novel diagnostic and therapeutic discovery. Extracellular vesicles (EVs) are lipid bilayer encapsulated particles released by cells into the extracellular space. Since EVs work as a safe way to transport important biological information through the whole body, they are now recognized as an important mechanism of cell–cell communication and have opened a new window for us to gain a better understanding of cancer biology, novel diagnostics, and therapeutic options. In recent years, numerous evolutions in EV technologies and novel biological and clinical findings continue to be reported in the research field of urological cancers. This comprehensive review aims to give an update of recent advances in EV technologies and summarize the state-of-the-art knowledge of EVs related to prostate cancer, bladder cancer and kidney cancer, particularly focusing on the potential of EV as biomarkers and their biological roles in promoting cancer and metastasis.     

The blastema and epimorphic regeneration in mammals

Studying regeneration in animals where and when it occurs is inherently interesting and a challenging research topic within developmental biology. Historically, vertebrate regeneration has been investigated in animals that display enhanced regenerative abilities and we have learned much from studying organ regeneration in amphibians and fish. From an applied perspective, while regeneration biologists will undoubtedly continue to study poikilothermic animals (i.e., amphibians and fish), studies focused on homeotherms (i.e., mammals and birds) are also necessary to advance regeneration biology. Emerging mammalian models of epimorphic regeneration are poised to help link regenerative biology and regenerative medicine. The regenerating rodent digit tip, which parallels human fingertip regeneration, and the regeneration of large circular defects through the ear pinna in spiny mice and rabbits, provide tractable, experimental systems where complex tissue structures are regrown through blastema formation and morphogenesis. Using these models as examples, we detail similarities and differences between the mammalian blastema and its classical counterpart to arrive at a broad working definition of a vertebrate regeneration blastema. This comparison leads us to conclude that regenerative failure is not related to the availability of regeneration-competent progenitor cells, but is most likely a function of the cellular response to the microenvironment that forms following traumatic injury. Recent studies demonstrating that targeted modification of this microenvironment can restrict or enhance regenerative capabilities in mammals helps provide a roadmap for eventually pushing the limits of human regeneration.     

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     

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     

The rational design of multiple molecular module-based assemblies for simultaneously improving rice yield and grain quality

正Rice is one of the most important staple food for over half of the world's population,and a substantial increase in productivity and quality of rice grain will be required to feed a growing human population.Grain size and shape are the two important components contributing to grain yield and quality,because they impact both yield potential and end-use quality.Over the past 50 years,the