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Meng Liu, Shiyang Shen, Di Wen, Mengru Li, Teng Li, Xiaojie Chen, Zhen Gu, Ran Mo
Protein therapeutics hold increasing interest with promise of revolutionizing the cancer treatment by virtue of potent specific activity and reduced adverse effect. Nonetheless, the therapeutic efficacy of anticancer proteins is highly compromised by multiple successive physiological barriers to protein delivery. Concurrent elimination of bulk tumor cells and highly-tumorigenic cancer stem-like cells (CSCs) has been evidenced as a promising strategy to improve cancer therapy. Here we show that a hierarchically-assembled nanocomposite can self-adaptively transform its particulate property in response to endogenous tumor-associated signals to overcome the sequential barriers and achieve enhanced antitumor efficacy by killing CSCs and bulk tumor cells synchronously...
March 16, 2018: Nano Letters
Liping Qian, Yibo Zuo, Wenjun Deng, Ying Miao, Jin Liu, Yukang Yuan, Tingting Guo, Liting Zhang, Jun Jin, Jun Wang, Hui Zheng
Type-I interferons (IFN-I) are widely used for antiviral immunotherapy in clinic. Therefore, identification of the regulators of IFN-I antiviral activity is important for developing novel targets for IFN-based antiviral therapy. Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) is critical for cellular inflammatory responses. However, the roles of MCPIP1 in interferons (IFNs)-mediated antiviral immunity are unexplored. In this study, we demonstrate for the first time that MCPIP1 is an important positive regulator of IFNs antiviral activity...
March 12, 2018: Biochemical and Biophysical Research Communications
Laurène Bastet, Pierre Turcotte, Joseph T Wade, Daniel A Lafontaine
Riboswitches are RNA regulators that control gene expression by modulating their structure in response to metabolite binding. The study of mechanisms by which riboswitches modulate gene expression is crucial to understand how riboswitches are involved in maintaining cellular homeostasis. Previous reports indicate that riboswitches can control gene expression at the level of translation, transcription or mRNA decay. However, there are very few described examples where riboswitches regulate multiple steps in gene expression...
March 14, 2018: RNA Biology
Tomoya Maeda, Yuya Tanaka, Masayuki Inui
The Corynebacterium glutamicum R grtA (cgR_2936), grtB (cgR_2934), and grtC (cgR_2933) genes were identified as paralogs encoding glutamine-rich toxic proteins. We also identified a new antisense small RNA AsgR (antisense sRNA for grtA) that overlaps the 3' end of the grtA gene. Single over-expressions of grtA, grtB, and grtC resulted in complete inhibition of Escherichia coli cell growth. This growth was rescued by co-expression of AsgR. Similar effects were observed in C. glutamicum, although the toxicities of these proteins were moderate...
March 14, 2018: Molecular Microbiology
Rintaro Iwata Hara, Yuki Hisada, Yusuke Maeda, Takanori Yokota, Takeshi Wada
Heteroduplex oligonucleotides (HDOs), composed of a DNA/LNA gapmer and its complementary RNA, are a novel, promising candidates for antisense drugs. We previously reported oligodiaminogalactoses (ODAGals), designed to bind to A-type nucleic acid duplexes such as DNA/RNA and RNA/RNA duplexes. In this paper, we report oligodiguanidinogalactoses (ODGGals) as novel A-type duplex binding molecules. We aimed to study in detail applicability of ODAGals and ODGGals for additives to HDOs as an antisense drug. The effect of ODAGal4 (ODAGal 4mer) and ODGGal3 (ODGGal 3mer) on an HDO were evaluated by UV melting analyses, RNA degradation study by ribonuclease A (RNase A), and ribonuclease H (RNase H)...
March 12, 2018: Scientific Reports
Alvaro Orell, Vanessa Tripp, Victor Aliaga-Tobar, Sonja-Verena Albers, Vinicius Maracaja-Coutinho, Lennart Randau
Non-coding RNAs (ncRNA) are involved in essential biological processes in all three domains of life. The regulatory potential of ncRNAs in Archaea is, however, not fully explored. In this study, RNA-seq analyses identified a set of 29 ncRNA transcripts in the hyperthermophilic archaeon Sulfolobus acidocaldarius that were differentially expressed in response to biofilm formation. The most abundant ncRNA of this set was found to be resistant to RNase R treatment (RNase R resistant RNA, RrrR(+)) due to duplex formation with a reverse complementary RNA (RrrR(-))...
February 26, 2018: Nucleic Acids Research
Purushottam R Lomate, Bryony C Bonning
Management of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), an invasive, agricultural pest in the United States, has presented significant challenges. This polyphagous insect uses both extra-oral and gut-based digestion thwarting protein- or nucleotide-based control strategies. The objective of this study was to biochemically characterize the digestive enzymes (proteases and nucleases) from the saliva, salivary gland and the gut of H. halys. Enzyme profiles for the two tissues and saliva radically differ: The pH optimum for proteases in the gut was six, with cysteine proteases predominant...
March 12, 2018: Archives of Insect Biochemistry and Physiology
Archana Singh, Deepti Jain, Chetna Tyagi, Sujata Singh, Sumit Kumar, Indrakant K Singh
Plants are endowed with an innate immune system, which enables them to protect themselves from pest and pathogen. The participation of pathogenesis-related (PR) proteins is one of the most crucial events of inducible plant defense response. Herein, we report the characterization of CaHaPR-4, a Helicoverpa-inducible class II PR-4 protein from chickpea. Bioinformatic analysis of CaHaPR-4 protein indicated the presence of a signal peptide, barwin domain but it lacks the chitin-binding site/hevein domain. The recombinant CaHaPR-4 is bestowed with RNase and bivalent ion-dependent DNase activity...
March 7, 2018: International Journal of Biological Macromolecules
Jessica B Lee, Albert J Keung
Chromatin immunoprecipitation (ChIP) is an invaluable method to characterize interactions between proteins and genomic DNA, such as the genomic localization of transcription factors and posttranslational modification of histones. DNA and proteins are reversibly and covalently crosslinked using formaldehyde. Then the cells are lysed to release the chromatin. The chromatin is fragmented into smaller sizes either by micrococcal nuclease (MNase) or sonication and then purified from other cellular components. The protein-DNA complexes are enriched by immunoprecipitation (IP) with antibodies that target the epitope of interest...
2018: Methods in Molecular Biology
Qiuju Chen, Dong Meng, Zhaoyu Gu, Wei Li, Hui Yuan, Xuwei Duan, Qing Yang, Yang Li, Tianzhong Li
It has been proved that the gametophytic self-incompatibility (GSI), mainly exists in Rosaceae and Solanaceae, is controlled by S genes, which are two tightly linked genes located at highly polymorphic S -locus: the S-RNase for pistil specificity and the F-box gene ( SFB/SLF ) for pollen specificity, respectively. However, the roles of those genes in SI of peach are still a subject of extensive debate. In our study, we selected 37 representative varieties according to the evolution route of peach and identified their S genotypes...
2018: Frontiers in Plant Science
Marcelo Echeverri, Amparo Alvarez-Valdés, Francisco Navas, Josefina Perles, Isabel Sánchez-Pérez, A G Quiroga
Three platinum complexes with cis and trans configuration cis -[Pt(TCEP)2 Cl2 ], cis -[Pt(tmTCEP)2 Cl2 ] and trans -[Pt(TCEP)2 Cl2 ], where TCEP is tris(2-carboxyethyl)phosphine, have been synthesized and fully characterized by usual techniques including single-crystal X-ray diffraction for trans -[Pt(TCEP)2 Cl2 ] and cis -[Pt(tmTCEP)2 Cl2 ]. Here, we also report on an esterification process of TCEP, which takes place in the presence of alcohols, leading to a platinum complex coordinated to an ester tmTCEP (2-methoxycarbonylethyl phosphine) ligand...
February 2018: Royal Society Open Science
Shiyu Wang, Nickolas Allen, Timothy A Vickers, Alexey S Revenko, Hong Sun, Xue-Hai Liang, Stanley T Crooke
Chemically modified antisense oligonucleotides (ASOs) with phosphorothioate (PS) linkages have been extensively studied as research and therapeutic agents. PS-ASOs can enter the cell and trigger cleavage of complementary RNA by RNase H1 even in the absence of transfection reagent. A number of cell surface proteins have been identified that bind PS-ASOs and mediate their cellular uptake; however, the mechanisms that lead to productive internalization of PS-ASOs are not well understood. Here, we characterized the interaction between PS-ASOs and epidermal growth factor receptor (EGFR)...
March 5, 2018: Nucleic Acids Research
Sandra Jordaan, Olusiji A Akinrinmade, Thomas Nachreiner, Christian Cremer, Krupa Naran, Shivan Chetty, Stefan Barth
Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate...
March 5, 2018: Biomedicines
Guanzhong Mao, Abhishek S Srivastava, Shiying Wu, David Kosek, Magnus Lindell, Leif A Kirsebom
The natural trans-acting ribozyme RNase P RNA (RPR) is composed of two domains in which the catalytic (C-) domain mediates cleavage of various substrates. The C-domain alone, after removal of the second specificity (S-) domain, catalyzes this reaction as well, albeit with reduced efficiency. Here we provide experimental evidence indicating that efficient cleavage mediated by the Escherichia coli C-domain (Eco CP RPR) with and without the C5 protein likely depends on an interaction referred to as the "P6-mimic"...
2018: PloS One
Amir Abbas Mokhtarieh, Jieun Lee, Semi Kim, Myung Kyu Lee
Previously a scalable and extrusion-free method has been developed for efficient liposomal encapsulation of DNA by twice stepwise mixing of lipids in ethanol and DNA solution using T-shape mixing chamber. In this study, we prepared nanoliposomes encapsulating siRNA by simply discontinuous mixing of lipids in ethanol/ether/water mixture and acidic siRNA solution without use of special equipment. The simple mixing siRNA/liposomal particles (siRNA/SMLs) prepared using ethanol/ether/water (3:1:1) mixture showed 120...
February 28, 2018: Biochimica et Biophysica Acta
Kefeng Wu, Changbei Ma, Zhiyi Deng, Ning Fang, Zhenwei Tang, Xingxing Zhu, Kemin Wang
In this paper, we describe a novel, label-free and nicking enzyme-assisted fluorescence signal amplification strategy that demonstrates to be cost efficient, sensitive, and unique for assaying the RNase H activity and inhibition based on G-quadruplex formation using a thioflavin T (ThT) dye. This novel assay method is able to detect RNase H with a detection limit of 0.03 U /mL and further exhibits a good linearity R2 = 0.9923 at a concentration range of 0.03-1 U/mL under optimized conditions. Moreover, the inhibition effect of gentamycin on the RNase H activity is also studied...
May 15, 2018: Talanta
Andreas Dieckmann, Peter H Hagedorn, Yvonne Burki, Christine Brügmann, Marco Berrera, Martin Ebeling, Thomas Singer, Franz Schuler
The successful development of high-affinity gapmer antisense oligonucleotide (ASO) therapeutics containing locked nucleic acid (LNA) or constrained ethyl (cEt) substitutions has been hampered by the risk of hepatotoxicity. Here, we present an in vitro approach using transfected mouse fibroblasts to predict the potential hepatic liabilities of LNA-modified ASOs (LNA-ASOs), validated by assessing 236 different LNA-ASOs with known hepatotoxic potential. This in vitro assay accurately reflects in vivo findings and relates hepatotoxicity to RNase H1 activity, off-target RNA downregulation, and LNA-ASO-binding affinity...
March 2, 2018: Molecular Therapy. Nucleic Acids
Amin S M Salehi, Seung-Ook Yang, Conner C Earl, Miriam J Shakalli Tang, J Porter Hunt, Mark T Smith, David W Wood, Bradley C Bundy
Many diseases and disorders are linked to exposure to endocrine disrupting chemicals (EDCs) that mimic the function of natural estrogen hormones. Here we present a Rapid Adaptable Portable In-vitro Detection biosensor platform (RAPID) for detecting chemicals that interact with the human estrogen receptor β (hERβ). This biosensor consists of an allosteric fusion protein, which is expressed using cell-free protein synthesis technology and is directly assayed by a colorimetric response. The resultant biosensor successfully detected known EDCs of hERβ (BPA, E2, and DPN) at similar or better detection range than an analogous cell-based biosensor, but in a fraction of time...
February 27, 2018: Toxicology and Applied Pharmacology
Dhruv Kumar Shakyawar, Bhattiprolu Muralikrishna, Vegesna Radha
C3G (RapGEF1), essential for mammalian embryonic development, is ubiquitously expressed and undergoes regulated nucleo-cytoplasmic exchange. Here we show that C3G localizes to SC35 positive nuclear speckles, and regulates splicing activity. Reversible association of C3G with speckles was seen upon inhibition of transcription and splicing. C3G shows partial colocalization with SC35, and is recruited to a chromatin and RNase sensitive fraction of speckles. Its presence in speckles is dependent on intact cellular actin cytoskeleton, and is lost upon expression of the kinase, Clk1...
March 1, 2018: Molecular Biology of the Cell
Stefano Misino, Diego Bonetti, Sarah Luke-Glaser, Brian Luke
Cancer cells activate telomere maintenance mechanisms (TMMs) to bypass replicative senescence and achieve immortality by either upregulating telomerase or promoting homology-directed repair (HDR) at chromosome ends to maintain telomere length, the latter being referred to as ALT (Alternative Lengthening of Telomeres). In yeast telomerase mutants, the HDR-based repair of telomeres leads to the generation of 'survivors' that escape senescence and divide indefinitely. So far, yeast has proven to provide an accurate model to study the generation and maintenance of telomeres via HDR...
February 16, 2018: Differentiation; Research in Biological Diversity
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