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https://www.readbyqxmd.com/read/29455659/receptor-tyrosine-kinases-and-downstream-pathways-as-druggable-targets-for-cancer-treatment-the-current-arsenal-of-inhibitors
#1
REVIEW
Wagner Ricardo Montor, Andrei Ronaldo Oliveira Silva Escartin Salas, Fabiana Henriques Machado de Melo
Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29452455/complex-hur-function-in-pancreatic-cancer-cells
#2
REVIEW
Jonathan R Brody, Dan A Dixon
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal patient outcomes. The underlying core genetic drivers of disease have been identified in human tumor specimens and described in genetically engineered mouse models. These genetic drivers of PDAC include KRAS signaling, TP53 mutations, and genetic loss of the SMAD4 tumor suppressor protein. Beyond the known mutational landscape of PDAC genomes, alternative disrupted targets that extend beyond conventional genetic mutations have been elusive and understudied in the context of PDAC cell therapeutic resistance and survival...
February 16, 2018: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/29450406/chemical-modification-of-the-sirna-seed-region-suppresses-off-target-effects-by-steric-hindrance-to-base-pairing-with-targets
#3
Hanna Iribe, Kengo Miyamoto, Tomoko Takahashi, Yoshiaki Kobayashi, Jastina Leo, Misako Aida, Kumiko Ui-Tei
Chemical modifications of 2'-O-methyl (2'-OMe) and locked nucleic acid (LNA) of the nucleotides in the seed region (positions 2-8) of the small interfering RNA (siRNA) guide strand significantly reduced seed-matched (SM) off-target effects. The siRNA with 2'-OMe modifications inhibited the expression of a completely-matched (CM) target gene, whereas that with LNA modifications did not inhibit the expression of the CM target. By computational predictions of conformational changes of siRNA by these modifications, we revealed that both modifications in the siRNA seed region reduce SM off-target effects by steric hindrance to base-pairing with target transcripts but LNA modifications also disturb the association of the siRNA guide strand with the Argonaute (AGO) protein by altering RNA conformation...
May 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/29447113/the-ago-proteins-an-overview
#4
Saife Niaz
Small RNAs govern almost every biological process in eukaryotes associating with the Argonaute proteins to form the RNA-induced silencing complex (mRISC). Argonaute proteins constitute the core of RISCs with different members having variety of protein binding partners and biochemical properties. This review focuses on the AGO subfamily of the Argonautes that are ubiquitously expressed and are associated with small RNAs. The structure, function and the role of the AGO proteins in the cell is discussed in detail...
November 27, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/29442909/synthetic-polysaccharides-as-drug-carriers-synthesis-of-polyglucose-amphotericin-b-conjugates-and-in-vitro-evaluation-of-their-anti-fungal-and-anti-leishmanial-activities
#5
Vasanthan Ravichandran, Gayathri P Kothandaraman, Christian Bories, Philippe M Loiseau, A Jayakrishnan
While many naturally occurring polysaccharides have been widely used as drug carriers, there are two main drawbacks in their use: the first is their physical properties such as molecular weight, branching, type of glycosidic linkages and solubility depend on their source and the method of isolation and purification, the second is many of them are contaminated with proteins and protein removal is essential for preventing immune reactions. Synthetic polysaccharides on the other hand can be tailor made from their respective monomers with consistent physical properties and are, free from protein contamination, both being significant advantages in their use...
April 1, 2018: Journal of Nanoscience and Nanotechnology
https://www.readbyqxmd.com/read/29435920/target-mrna-driven-biogenesis-of-cognate-micrornas-in-vitro
#6
Mainak Bose, Suvendra N Bhattacharyya
miRNAs are 20-22 nucleotide long noncoding RNAs that act as post-transcriptional regulators of gene expression controlling more than half of protein coding genes in humans. Being the critical modulators of the mRNA translation process, biogenesis, function, and turnover of these small RNAs are tightly regulated in cells. We have reported that target mRNAs induce increased biogenesis of cognate miRNAs from pre-miRNAs by increased activity of Ago-associated Dicer endonuclease that processes precursor miRNAs to their mature form...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29434619/from-bioengineering-to-crispr-cas9-a-personal-retrospective-of-20-years-of-research-in-programmable-genome-targeting
#7
Albert Jeltsch
Genome targeting of restriction enzymes and DNA methyltransferases has many important applications including genome and epigenome editing. 15-20 years ago, my group was involved in the development of approaches for programmable genome targeting, aiming to connect enzymes with an oligodeoxynucleotide (ODN), which could form a sequence-specific triple helix at the genomic target site. Importantly, the target site of such enzyme-ODN conjugate could be varied simply by altering the ODN sequence promising great applicative values...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29431896/on-taking-the-sting-out-of-immune-activation
#8
REVIEW
Andra Banete, Kyle Seaver, Devyani Bakshi, Katrina Gee, Sameh Basta
Nearly a decade ago, an endoplasmic reticulum (ER) adaptor protein called stimulator of interferon genes (STING) was found to be critical in the induction of type I IFN production in response to DNA virus infection. STING functions by sensing cytoplasmic DNA and activates key transcription factors, including IFN regulatory factor (IRF)-3 and IRF7, to initiate type I IFN expression. Type I IFNs are vital in immunity against viral infections and can influence cancer cell proliferation, migration, and apoptosis...
February 12, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29427109/polyglutamine-independent-features-in-ataxin-3-aggregation-and-pathogenesis-of-machado-joseph-disease
#9
Ana Luisa Carvalho, Alexandra Silva, Sandra Macedo-Ribeiro
The expansion of a trinucleotide (CAG) repeat, translated into a polyglutamine expanded sequence in the protein encoded by the MJD gene, was identified over 20 years ago as the causative mutation in a severe neurodegenerative disorder originally diagnosed in individuals of Portuguese ancestry. This incapacitating disease, called Machado-Joseph disease or spinocebellar ataxia type 3, is integrated into a larger group of neurodegenerative disorders-the polyglutamine expansion disorders-caused by extension of a CAG repeat in the coding sequence of otherwise unrelated genes...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29427096/clinical-features-of-huntington-s-disease
#10
Rhia Ghosh, Sarah J Tabrizi
Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is devastating. The causative genetic mutation is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the protein...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29425824/salt-and-drought-stress-and-aba-responses-related-to-bzip-genes-from-v-radiata-and-v-angularis
#11
Lanfen Wang, Jifeng Zhu, Xiaoming Li, Shumin Wang, Jing Wu
Mung bean and adzuki bean are warm-season legumes widely cultivated in China. However, bean production in major producing regions is limited by biotic and abiotic stress, such as drought and salt stress. Basic leucine zipper (bZIP) genes play key roles in responses to various biotic and abiotic stresses. However, only several bZIP genes involved in drought and salt stress in legumes, especially Vigna radiata and Vigna angularis, have been identified. In this study, we identified 54 and 50 bZIP proteins from whole-genome sequences of V...
February 6, 2018: Gene
https://www.readbyqxmd.com/read/29418061/platelets-couple-inflammation-to-tumorigenesis-a-bridge-too-far
#12
Matthew J Flick, Joseph S Palumbo
Platelets were first implicated in the pathogenesis of cancer and inflammatory pathologies decades ago, but an understanding of the mechanisms coupling platelet function to cancer progression is still a work in progress. In their paper, Servais et al. push the field forward by illustrating that platelets represent a crucial link between inflammatory disease and tumorigenesis [1]. This interesting paper presents data showing that platelets promote intestinal tumorigenesis in the context of inflammatory colitis by supporting the recruitment and/or expansion of myeloid-derived suppressor cells (MDSCs)...
February 8, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29418058/evolutionary-conservation-of-the-allosteric-activation-of-factor-viia-by-tissue-factor-in-lamprey
#13
D L Beeler, W C Aird, M A Grant
BACKGROUND: Previous studies have provided insight into the molecular basis of human tissue factor (TF) activation of activated factor VII (FVIIa). TF-induced allosteric networks of FVIIa activation have been rationalized through analysis of the dynamic changes and residue connectivities in the human soluble TF (sTF)/FVIIa complex structure during molecular dynamics (MD) simulation. Evolutionary conservation of the molecular mechanisms for TF-induced allosteric FVIIa activation between human and extant vertebrate jawless fish (lamprey), where blood coagulation emerged more than 500 million years ago, is unknown and of considerable interest...
February 8, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29415504/fundamental-molecules-and-mechanisms-for-forming-and-maintaining-neuromuscular-synapses
#14
REVIEW
Steven J Burden, Maartje G Huijbers, Leonor Remedio
The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse...
February 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29413524/mu-opioid-pharmacology-40-years-to-the-promised-land
#15
Gavril W Pasternak
Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29411671/mirna-biogenesis-pathway-is-differentially-regulated-during-adipose-derived-stromal-stem-cell-differentiation
#16
E C Martin, A T Qureshi, C B Llamas, M E Burow, A G King, O C Lee, V Dasa, M A Freitas, J A Forsberg, E A Elster, T A Davis, J M Gimble
Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood...
February 7, 2018: Adipocyte
https://www.readbyqxmd.com/read/29410531/mechanisms-of-clathrin-mediated-endocytosis
#17
REVIEW
Marko Kaksonen, Aurélien Roux
Clathrin-mediated endocytosis is a key process in vesicular trafficking that transports a wide range of cargo molecules from the cell surface to the interior. Clathrin-mediated endocytosis was first described over 5 decades ago. Since its discovery, over 50 proteins have been shown to be part of the molecular machinery that generates the clathrin-coated endocytic vesicles. These proteins and the different steps of the endocytic process that they mediate have been studied in detail. However, we still lack a good understanding of how all these different components work together in a highly coordinated manner to drive vesicle formation...
February 7, 2018: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/29408277/molecular-organization-and-mechanical-properties-of-the-hyaluronan-matrix-surrounding-the-mammalian-oocyte
#18
REVIEW
Antonietta Salustri, Luisa Campagnolo, Francesca Gioia Klinger, Antonella Camaioni
Successful ovulation and oocyte fertilization are essential prerequisites for the beginning of life in sexually reproducing animals. In mammalian fertilization, the relevance of the protein coat surrounding the oocyte plasma membrane, known as zona pellucida, has been widely recognized, while, until not too long ago, the general belief was that the cumulus oophorus, consisting of follicle cells embedded in a hyaluronan rich extracellular matrix, was not essential. This opinion was based on in vitro fertilization procedures, in which a large number of sperms are normally utilized and the oocyte can be fertilized even if depleted of cumulus cells...
February 2, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29408232/transactivator-a-new-face-of-arabidopsis-ago1
#19
Claudia Castillo-González, Xiuren Zhang
Argonaute (AGO) proteins execute RNA-induced transcriptional and post-transcriptional gene silencing. In this issue of Developmental Cell, Liu et al. (2018) uncover a nuclear function for Arabidopsis AGO1 in positively regulating gene expression. AGO1, guided by small RNAs, binds to chromatin to induce target gene transcription in response to environmental stimuli.
February 5, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29407228/double-silencing-of-relevant-genes-suggests-the-existence-of-the-direct-link-between-dna-replication-repair-and-central-carbon-metabolism-in-human-fibroblasts
#20
Aneta Wieczorek, Karolina Fornalewicz, Łukasz Mocarski, Robert Łyżeń, Grzegorz Węgrzyn
Genetics evidence for a link between DNA replication and glycolysis has been demonstrated a decade ago in Bacillus subtilis, where temperature-sensitive mutations in genes coding for replication proteins could be suppressed by mutations in genes of glycolytic enzymes. Then, a strong influence of dysfunctions of particular enzymes from the central carbon metabolism (CCM) on DNA replication and repair in Escherichia coli was reported. Therefore, we asked if such a link occurs only in bacteria or it is a more general phenomenon...
January 30, 2018: Gene
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