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Biased molecules

Zhibiao Mai, Chuanle Xiao, Jingjie Jin, Gong Zhang
Low-input RNA-seq is powerful to represent the gene expression profiles with limited number of cells, especially when single-cell variations are not the aim. However, pre-amplification-based and molecule index-based library construction methods boost bias or require higher throughput. Here we demonstrate a simple, low-cost, low-bias and low-input RNA-seq with ion torrent semiconductor sequencing (LIEA RNA-seq). We also developed highly accurate and error-tolerant spliced mapping algorithm FANSe2splice to accurately map the single-ended reads to the reference genome with better experimental verifiability than the previous spliced mappers...
April 21, 2017: Scientific Reports
Zhiqiang Yan, Jin Wang
Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN...
April 20, 2017: Nucleic Acids Research
Lindsey K Lepley, Timothy A Butterfield
Eccentric exercise is able to mechanically engage muscle, initiating strain-sensing molecules that promote muscle recovery by inducing beneficial adaptations in neural activity and muscle morphology, 2 critical components of muscle function that are negatively altered after injury. However, due to misinterpreted mathematic modeling and in situ and in vitro stretch protocols, a dogma that exposing muscle to eccentric exercise is associated with injury has been perpetuated in the literature. In response, clinicians have been biased toward using concentric exercise postinjury to improve the recovery of muscle function...
April 2017: Journal of Sport Rehabilitation
Robert Abel, Lingle Wang, David L Mobley, Rich A Friesner
Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We here briefly review a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically consider proper validation and effective use of these techniques...
April 14, 2017: Current Topics in Medicinal Chemistry
Anna S Rydhög, Filip Szczepankiewicz, Ronnie Wirestam, André Ahlgren, Carl-Fredrik Westin, Linda Knutsson, Ofer Pasternak
The assessment of the free water fraction in the brain provides important information about extracellular processes such as atrophy and neuroinflammation in various clinical conditions as well as in normal development and aging. Free water estimates from diffusion MRI are assumed to account for freely diffusing water molecules in the extracellular space, but may be biased by other pools of molecules in rapid random motion, such as the intravoxel incoherent motion (IVIM) of blood, where water molecules perfuse in the randomly oriented capillary network...
April 12, 2017: NeuroImage
Luxitaa Goenka, Melvin George, Maitrayee Sen
PURPOSE AND OBJECTIVE: Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis...
April 10, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Tracey A Ruhlman, Jin Zhang, John C Blazier, Jamal S M Sabir, Robert K Jansen
PREMISE OF THE STUDY: There is a misinterpretation in the literature regarding the variable orientation of the small single copy region of plastid genomes (plastomes). The common phenomenon of small and large single copy inversion, hypothesized to occur through intramolecular recombination between inverted repeats (IR) in a circular, single unit-genome, in fact, more likely occurs through recombination-dependent replication (RDR) of linear plastome templates. If RDR can be primed through both intra- and intermolecular recombination, then this mechanism could not only create inversion isomers of so-called single copy regions, but also an array of alternative sequence arrangements...
April 11, 2017: American Journal of Botany
Brittany W Schuck, Ryan MacArthur, James Inglese
Reporter-biased artifacts-i.e., compounds that interact directly with the reporter enzyme used in a high-throughput screening (HTS) assay and not the biological process or pharmacology being interrogated-are now widely recognized to reduce the efficiency and quality of HTS used for chemical probe and therapeutic development. Furthermore, narrow or single-concentration HTS perpetuates false negatives during primary screening campaigns. Titration-based HTS, or quantitative HTS (qHTS), and coincidence reporter technology can be employed to reduce false negatives and false positives, respectively, thereby increasing the quality and efficiency of primary screening efforts, where the number of compounds investigated can range from tens of thousands to millions...
April 10, 2017: Current Protocols in Neuroscience
Ji Hao, Bo Li, Hyun Young Jung, Fangze Liu, Sanghyun Hong, Yung Joon Jung, Swastik Kar
Designing ultrasensitive detectors often requires complex architectures, high-voltage operations, and sophisticated low-noise measurements. In this work, it is shown that simple low-bias two-terminal DC-conductance values of graphene and single-walled carbon nanotubes are extremely sensitive to ionized gas molecules. Incident ions form an electrode-free, dielectric- or electrolyte-free, bias-free vapor-phase top-gate that can efficiently modulate carrier densities up to ≈0.6 × 10(13) cm(-2) . Surprisingly, the resulting current changes are several orders of magnitude larger than that expected from conventional electrostatic gating, suggesting the possible role of a current-gain inducing mechanism similar to those seen in photodetectors...
April 10, 2017: Advanced Materials
João T S Coimbra, Pedro A Fernandes, Maria J Ramos
We discuss potential-of-mean force convergence issues involving the methods for generating starting structures of umbrella sampling simulations for the study of the water-bilayer permeation of drug-like compounds. We provide a proof of concept of the benefits of potential-energy modification methods, in particular the flooding technique, to enhance the sampling and improve the convergence of the potential-of-mean force. In addition, we also discuss how these potential modifiers could introduce the necessary bias to induce the correct description of other relevant internal degrees of freedom for the compounds, thus providing a more accurate description of the permeation process...
April 13, 2017: Journal of Chemical Theory and Computation
Zoran Rankovic
Understanding the "limits and boundaries" of the central nervous system (CNS) property space is a critical aspect of modern CNS drug design. Medicinal chemists are often guided by the physicochemical properties of marketed CNS drugs, which are heavily biased toward "traditional" aminergic targets and commonly described as small lipophilic amines. This miniperspective describes the statistical analysis of the calculated physicochemical properties for a diverse set of ligands for mostly "nontraditional" CNS targets and classified as either "brain penetrant" or "peripherally restricted" on the basis of the experimental mouse brain exposure...
April 7, 2017: Journal of Medicinal Chemistry
José Augusto Berrocal, R Helen Zha, Bas F M de Waal, Jody A M Lugger, Martin Lutz, E W Meijer
Block molecules belong to a rapidly growing research field in materials chemistry in which discrete macromolecular architectures bridge the gap between block copolymers (BCP) and liquid crystals (LCs). The merging of characteristics from both BCP and LCs is expected to result in exciting breakthroughs, such as the discovery of unexpected morphologies or significant shrinking of domain spacings in materials that possess the high definition of organic molecules and the processability of polymers. Here we report the bulk self-assembly of two families of monodisperse block molecules comprised of naphthalenediimides (NDIs) and oligodimethylsiloxanes (ODMS)...
April 7, 2017: ACS Nano
T J Ruckwardt, K M Morabito, E Bar-Haim, D Nair, B S Graham
The CD103(+) subset of lung-migratory dendritic cells (DCs) plays an important role in the generation of CD8(+) T cell responses following respiratory infection. Here, we demonstrate that the dependence on CD103(+) DCs for stimulation of RSV-specific T cells is both epitope and age-dependent. CD103(+) DCs in neonatal mice develop two phenotypically and functionally distinct populations following respiratory infection. Neonatal CD103(+) DCs expressing low levels of CD103 (CD103lo DCs) and other lineage and maturation markers including costimulatory molecules are phenotypically immature and functionally limited...
April 5, 2017: Mucosal Immunology
Ricardo Visini, Mahendra Awale, Jean-Louis Reymond
To better understand chemical space we recently enumerated the database GDB-17 containing 166.4 billion possible molecules up to 17 atoms of C, N, O, S and halogen following simple rules of chemical stability and synthetic feasibility. However due to the combinatorial explosion caused by systematic enumeration GDB-17 is strongly biased towards the largest, functionally and stereochemically most complex molecules and far too large for most virtual screening tools. Herein we selected a much smaller subset of GDB-17, called the fragment database FDB-17, which contains 10 million fragment-like molecules evenly covering a broad value range for molecular size, polarity and stereochemical complexity...
April 4, 2017: Journal of Chemical Information and Modeling
Kurt V Mikkelsen, Mogens Brøndsted Nielsen, Mark A Ratner, Thorsten Hansen, Stine T Olsen
Molecular photoswitches incorporated in molecular junctions yield the possibility of light-controlled switching of conductance due to the electronic difference of the photoisomers. Another isomerization mechanism, dark-photoswitching, promoted by a voltage stimulus rather than by light can be operative in the Coulomb-blockade regime.Here we elucidate theoretically the mechanistic and thermodynamic restrictions for this dark-photoswitching for donor-acceptor substituted 4n and 4n+2 π-electron open-chain oligoenes by considering the molecular energies and orbitals of the molecules placed in a junction...
March 30, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Nuria Vilaboa, Alba Boré, Francisco Martin-Saavedra, Melanie Bayford, Natalie Winfield, Stuart Firth-Clark, Stewart B Kirton, Richard Voellmy
Comparative modeling of the DNA-binding domain of human HSF1 facilitated the prediction of possible binding pockets for small molecules and definition of corresponding pharmacophores. In silico screening of a large library of lead-like compounds identified a set of compounds that satisfied the pharmacophoric criteria, a selection of which compounds was purchased to populate a biased sublibrary. A discriminating cell-based screening assay identified compound 001, which was subjected to systematic analysis of structure-activity relationships, resulting in the development of compound 115 (IHSF115)...
March 21, 2017: Nucleic Acids Research
Kazuma Nakano, Akino Shiroma, Makiko Shimoji, Hinako Tamotsu, Noriko Ashimine, Shun Ohki, Misuzu Shinzato, Maiko Minami, Tetsuhiro Nakanishi, Kuniko Teruya, Kazuhito Satou, Takashi Hirano
PacBio RS II is the first commercialized third-generation DNA sequencer able to sequence a single molecule DNA in real-time without amplification. PacBio RS II's sequencing technology is novel and unique, enabling the direct observation of DNA synthesis by DNA polymerase. PacBio RS II confers four major advantages compared to other sequencing technologies: long read lengths, high consensus accuracy, a low degree of bias, and simultaneous capability of epigenetic characterization. These advantages surmount the obstacle of sequencing genomic regions such as high/low G+C, tandem repeat, and interspersed repeat regions...
March 31, 2017: Human Cell
Claire E Olingy, Cheryl L San Emeterio, Molly E Ogle, Jack R Krieger, Anthony C Bruce, David D Pfau, Brett T Jordan, Shayn M Peirce, Edward A Botchwey
Successful tissue repair requires the activities of myeloid cells such as monocytes and macrophages that guide the progression of inflammation and healing outcome. Immunoregenerative materials leverage the function of endogenous immune cells to orchestrate complex mechanisms of repair; however, a deeper understanding of innate immune cell function in inflamed tissues and their subsequent interactions with implanted materials is necessary to guide the design of these materials. Blood monocytes exist in two primary subpopulations, characterized as classical inflammatory or non-classical...
March 27, 2017: Scientific Reports
Yuji Shimizu, Masaharu Nakayama
Lysophosphatidic acid (LPA) activates the G-protein-coupled receptor LPA1, which regulates various cellular processes, including cell proliferation and migration. Although LPA1 transduces cellular responses via Gq, Gi, and G12/13, associations between these signaling molecules and cellular phenotypes remain poorly characterized due to the lack of signal-specific pharmacological tools. Here, we characterized novel signal-biased modulators using multiple assays, including label-free impedance assays. LPA caused dramatic changes in cellular impedance in LPA1-expressing recombinant cells, which were susceptible to G-protein and protein kinase inhibitors...
February 1, 2017: SLAS Discovery
Timothy A Su, Haixing Li, Rebekka S Klausen, Nathaniel T Kim, Madhav Neupane, James L Leighton, Michael L Steigerwald, Latha Venkataraman, Colin Nuckolls
This Account provides an overview of our recent efforts to uncover the fundamental charge transport properties of Si-Si and Ge-Ge single bonds and introduce useful functions into group 14 molecular wires. We utilize the tools of chemical synthesis and a scanning tunneling microscopy-based break-junction technique to study the mechanism of charge transport in these molecular systems. We evaluated the fundamental ability of silicon, germanium, and carbon molecular wires to transport charge by comparing conductances within families of well-defined structures, the members of which differ only in the number of Si (or Ge or C) atoms in the wire...
March 27, 2017: Accounts of Chemical Research
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