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Biased molecules

R De Vecchis, C Ariano, G Di Biase, M Noutsias
BACKGROUND: Sacubitril, a neprilysin inhibitor in the combination molecule sacubitril/valsartan, slows down degradation of endogenous natriuretic peptides, thereby enhancing their beneficial cardiovascular effects. However, sacubitril might also promote neuronal dysfunction and cognitive impairment in patients with chronic heart failure (CHF) treated with sacubitril/valsartan, due to possible neprilysin inhibition at the level of Central Nervous System. METHODS: A retrospective cohort study was undertaken to detect the effects exerted by sacubitril/valsartan on cognitive function in CHF patients...
February 15, 2018: Herz
Fabrice Gritti
A stochastic model of transcolumn eddy dispersion along packed beds was derived. It was based on the calculation of the mean travel time of a single analyte molecule from one radial position to another. The exchange mechanism between two radial positions was governed by the transverse dispersion of the analyte across the column. The radial velocity distribution was obtained by flow simulations in a focused-ion-beam scanning electron microscopy (FIB-SEM) based 3D reconstruction from a 2.1 mm × 50 mm column packed with 2 μm BEH-C 18 particles...
February 9, 2018: Journal of Chromatography. A
Omer Markovitch, Natalio Krasnogor
An intriguing question in evolution is what would happen if one could "replay" life's tape. Here, we explore the following hypothesis: when replaying the tape, the details ("decorations") of the outcomes would vary but certain "invariants" might emerge across different life-tapes sharing similar initial conditions. We use large-scale simulations of an in silico model of pre-biotic evolution called GARD (Graded Autocatalysis Replication Domain) to test this hypothesis. GARD models the temporal evolution of molecular assemblies, governed by a rates matrix (i...
2018: PloS One
Ruzanna Shkhyan, Ben Van Handel, Jacob Bogdanov, Siyoung Lee, Yifan Yu, Mila Scheinberg, Nicholas W Banks, Sean Limfat, Arthur Chernostrik, Carlos Eduardo Franciozi, Mohammad Parvez Alam, Varghese John, Ling Wu, Gabriel B Ferguson, Ali Nsair, Frank A Petrigliano, C Thomas Vangsness, Kanagasabai Vadivel, Paul Bajaj, Liming Wang, Nancy Q Liu, Denis Evseenko
OBJECTIVE: Human adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL-6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs...
February 7, 2018: Annals of the Rheumatic Diseases
Joseph F Cartwright, Karin Anderson, Joseph Longworth, Philip Lobb, David C James
High-fidelity replication of biologic-encoding recombinant DNA sequences by engineered mammalian cell cultures is an essential pre-requisite for the development of stable cell lines for the production of biotherapeutics. However, immortalized mammalian cells characteristically exhibit an increased point mutation frequency compared to mammalian cells in vivo, both across their genomes and at specific loci (hotspots). Thus unforeseen mutations in recombinant DNA sequences can arise and be maintained within producer cell populations...
February 10, 2018: Biotechnology and Bioengineering
Atanas Kaykov, Paul Nurse
DNA combing enables the quantitative analysis of DNA replication, DNA recombination, DNA-protein interaction, and DNA methylation along genomic single DNA molecules at 1 kb resolution. However, DNA combing has been restricted to short 200-500 kb long DNA fragments, which introduces significant bias in data analysis. An improved DNA combing methodology that allows to routinely image Mb-scale single DNA molecules and occasionally up to full-length fission yeast chromosomes is presented in this chapter. DNA combing of Mb-scale single DNA molecules can be applied to accurately measure the dynamic properties of DNA replication such as the rate of origin firing, replication fork velocity, fork directionality and the frequency of fork blockage...
2018: Methods in Molecular Biology
Linas Urnavicius, Clinton K Lau, Mohamed M Elshenawy, Edgar Morales-Rios, Carina Motz, Ahmet Yildiz, Andrew P Carter
Dynein and its cofactor dynactin form a highly processive microtubule motor in the presence of an activating adaptor, such as BICD2. Different adaptors link dynein and dynactin to distinct cargoes. Here we use electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein to dynactin. Whereas BICD2 is biased towards recruiting a single dynein, the adaptors BICDR1 and HOOK3 predominantly recruit two dyneins. We find that the shift towards a double dynein complex increases both the force and speed of the microtubule motor...
February 7, 2018: Nature
Manon Réau, Florent Langenfeld, Jean-François Zagury, Nathalie Lagarde, Matthieu Montes
Virtual Screening (VS) is designed to prospectively help identifying potential hits, i.e., compounds capable of interacting with a given target and potentially modulate its activity, out of large compound collections. Among the variety of methodologies, it is crucial to select the protocol that is the most adapted to the query/target system under study and that yields the most reliable output. To this aim, the performance of VS methods is commonly evaluated and compared by computing their ability to retrieve active compounds in benchmarking datasets...
2018: Frontiers in Pharmacology
Woo Sik Kim, Jong-Seok Kim, Min-Kyoung Shin, Sung Jae Shin
Mycobacterium avium subspecies paratuberculosis (MAP) is the causative pathogen of Johne's disease in ruminants, characterized by chronic granulomatous enteritis; it also has zoonotic potential and is associated with Crohn's disease in humans. A better understanding of the mycobacterial antigens and their roles in the host immune response may facilitate the rational design of control strategies, including the development of effective vaccines and diagnostic tools. However, the functional roles of a large proportion of MAP antigens involved in modulating the host immune response remain unknown...
February 2, 2018: Cytokine
Nihit Pokhrel, Lutz Maibaum
Understanding how different classes of molecules move across biological membranes is a prerequisite to predicting a solute's permeation rate, which is a critical factor in the fields of drug design and pharmacology. We use biased Molecular Dynamics computer simulations to calculate and compare the free energy profiles of translocation of several small molecules across 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayers as a first step towards determining the most efficient method for free energy calculations...
February 6, 2018: Journal of Chemical Theory and Computation
Sandro Pasquali, Andreas V Hadjinicolaou, Vanna Chiarion Sileni, Carlo Riccardo Rossi, Simone Mocellin
BACKGROUND: The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000. OBJECTIVES: To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma...
February 6, 2018: Cochrane Database of Systematic Reviews
Simon Ardui, Adam Ameur, Joris R Vermeesch, Matthew S Hestand
Short read massive parallel sequencing has emerged as a standard diagnostic tool in the medical setting. However, short read technologies have inherent limitations such as GC bias, difficulties mapping to repetitive elements, trouble discriminating paralogous sequences, and difficulties in phasing alleles. Long read single molecule sequencers resolve these obstacles. Moreover, they offer higher consensus accuracies and can detect epigenetic modifications from native DNA. The first commercially available long read single molecule platform was the RS system based on PacBio's single molecule real-time (SMRT) sequencing technology, which has since evolved into their RSII and Sequel systems...
February 1, 2018: Nucleic Acids Research
Takaumi Morita, Marko Damjanović, Keiichi Katoh, Yasutaka Kitagawa, Nobuhiro Yasuda, Yanhua Lan, Wolfgang Wernsdorfer, Brian K Breedlove, Markus Enders, Masahiro Yamashita
Herein we report the synthesis and characterization of a dinuclear TbIII single-molecule magnet (SMM) with two [TbPc2]0 units connected via a fused-phthalocyaninato ligand. The stable and robust complex [(obPc)Tb(Fused-Pc)Tb(obPc)] (1) was characterized by using synchrotron radiation measurements and other spectroscopic techniques (ESI-MS, FT-IR, UV). The magnetic couplings between the TbIII ions and the two π radicals present in 1 were explored by means of density functional theory (DFT). Direct- and alternating current magnetic susceptibility measurements were conducted on magnetically diluted and non-diluted samples of 1, indicating this compound to be an SMM with improved properties compared to those of the well-known [TbPc2]-/0/+ and the axially symmetric dinuclear TbIII phthalocyaninato triple-decker complex (Tb2(obPc)3)...
February 5, 2018: Journal of the American Chemical Society
Guan-Jhong Lin, Tien-Jung Chen, Jhao-Ting Wu, Jin-Jei Wu
A stable low-pretilt molecular configuration (SLPMC) is successfully developed in optically compensated bend (OCB) liquid crystal (LC) devices by simultaneously employing the curing voltage and surface-anchored crosslinking monomer during the polymerization process. For the SLPMC OCB cell with the low-bend state, the warm-up voltage making the LC molecules reorient from the splay to the bend state is annihilated, and the transient twist state occurring as the driven LC molecules recover from the bend to the splay state is also eliminated...
February 1, 2018: Optics Letters
Francesco Greco, Antonino Inferrera, Roberto La Rocca, Michele Navarra, Marco Casciaro, Gaetano Grosso, Sebastiano Gangemi, Vincenzo Ficarra, Vincenzo Mirone
CONTEXT: Benign prostate hyperplasia (BPH) is one of the most common urologic diseases. However, the molecular and cellular mechanisms involving the stromal and epithelial components of the prostate that lead to BPH remain unclear. OBJECTIVE: To review and evaluate the evidence implicating microRNAs (miRNAs) in the pathogenesis of BPH. EVIDENCE ACQUISITION: A systematic search of the PubMed and Embase databases was performed using the terms "benign prostate hypertrophy and miRNA" or ("benign prostate hypertrophy and microRNAs" or "miRNA" or "miR") on July 31, 2017...
February 2, 2018: European Urology Focus
Isidro Ferrer, Meritxell Aguiló García, Irene López González, Daniela Diaz Lucena, Aina Roig Villalonga, Margarita Carmona Tech, Franc Llorens, Paula Garcia-Esparcia, Alejandra Martinez-Maldonado, Margalida Frau Mendez, Benjamín Torrejón Escribano, Joan Josep Bech Serra, Eduard Sabido, Carolina de la Torre Gómez, José Antonio Del Rio
Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421...
February 3, 2018: Brain Pathology
Ira W Deveson, Marion E Brunck, James Blackburn, Elizabeth Tseng, Ting Hon, Tyson A Clark, Michael B Clark, Joanna Crawford, Marcel E Dinger, Lars K Nielsen, John S Mattick, Tim R Mercer
The human transcriptome is so large, diverse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed targeted single-molecule and short-read RNA-seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome, identifying a fundamental distinction between protein-coding and noncoding gene content: almost every noncoding exon undergoes alternative splicing, producing a seemingly limitless variety of isoforms...
January 2, 2018: Cell Systems
Yachao Zhang
A clear insight into the electrical manipulation of molecular spins at interface is crucial to the design of molecule-based spintronic devices. Here we report on the electrically driven spin transition in manganocene physisorbed on a metallic surface in two different adsorption configurations predicted by ab initio techniques, including a Hubbard-U correction at the manganese site and accounting for the long-range van der Waals interactions. We show that the application of an electric field at the interface induces a high-spin to low-spin transition in the flat-lying manganocene, while it could hardly alter the high-spin ground state of the standing-up molecule...
January 28, 2018: Journal of Chemical Physics
John C Hackett
Cytochrome P450 3A4 (CYP3A4) is the dominant xenobiotic-metabolizing enzyme in the liver and intestine and is involved in the disposition of more than 50% of drugs. Owing to its ability to bind multiple substrates, its reaction kinetics are complex, and its association with the microsomal membrane confounds our understanding of how this enzyme recognizes and recruits diverse substrates. Testosterone (TST) hydroxylation is the prototypical CYP3A4 reaction, displaying positive homotropic cooperativity with three binding sites...
January 30, 2018: Journal of Biological Chemistry
Nicholas J W Rattray, Nicole C Deziel, Joshua D Wallach, Sajid A Khan, Vasilis Vasiliou, John P A Ioannidis, Caroline H Johnson
BACKGROUND: Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample...
January 26, 2018: Human Genomics
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