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Target tractability

Subhas Khajanchi, Sandip Banerjee
We present a mathematical model which describes the growth of malignant gliomas in presence of immune responses by considering the role of immunotherapeutic agent T11 target structure (T11TS). The model consider five populations, namely, glioma cells, macrophages, cytotoxic T-lymphocytes, TGF - β and IFN - γ. The model system has highly nonlinear terms with four discrete time lags, but remains tractable. The goal of this work is to better understand the effect of multiple delays on the interaction between gliomas and immune components in conjunction with an administration of T11 target structure...
June 13, 2018: Mathematical Biosciences
Sanduo Zheng, Lok-To Sham, Frederick A Rubino, Kelly P Brock, William P Robins, John J Mekalanos, Debora S Marks, Thomas G Bernhardt, Andrew C Kruse
The peptidoglycan cell wall provides an essential protective barrier in almost all bacteria, defining cellular morphology and conferring resistance to osmotic stress and other environmental hazards. The precursor to peptidoglycan, lipid II, is assembled on the inner leaflet of the plasma membrane. However, peptidoglycan polymerization occurs on the outer face of the plasma membrane, and lipid II must be flipped across the membrane by the MurJ protein before its use in peptidoglycan synthesis. Due to its central role in cell wall assembly, MurJ is of fundamental importance in microbial cell biology and is a prime target for novel antibiotic development...
June 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Benjamin Guy Trist, Dominic James Hare, Kay Lorraine Double
Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood...
May 16, 2018: Cell Chemical Biology
Frederick H Wilson, Katerina Politi
<b/> A patient with advanced lung adenocarcinoma harboring a CD74-NRG1 gene rearrangement, which promotes ERBB2-ERBB3 heterodimerization and activation of downstream signaling, had an exceptional therapeutic response to an experimental anti-ERBB3 antibody. This result illustrates how NRG1 rearrangements, which are observed at a low frequency in a variety of solid tumors, may represent tractable therapeutic targets. Cancer Discov; 8(6); 676-8. ©2018 AACR. See related article by Drilon et al., p. 686 .
June 2018: Cancer Discovery
Chen Chen, Paulus Jochems, Lucia Salz, Kerstin Schneeberger, Louis C Penning, Stan F J van de Graaf, Ulrich Beuers, Hans Clevers, Niels Geijsen, Rosalinde Masereeuw, Bart Spee
Investigation of diseases of the bile duct system and identification of potential therapeutic targets are hampered by the lack of tractable in vitro systems to model cholangiocyte biology. Here, we show a step-wise method for the differentiation of murine Lgr5+ liver stem cells (organoids) into cholangiocyte-like cells (CLCs) using a combination of growth factors and extracellular matrix components. Organoid-derived CLCs display key properties of primary cholangiocytes, such as expressing cholangiocyte markers, forming primary cilia, transporting small molecules and responding to farnesoid X receptor (FXR) agonist...
May 31, 2018: Biofabrication
Pengfei Kong, Maik J Lehmann, J Bernd Helms, Jos F Brouwers, Nishith Gupta
Successful inter-host transmission of most apicomplexan parasites requires the formation of infective sporozoites within the oocysts. Unlike all other infective stages that are strictly intracellular and depend on host resources, the sporozoite stage develops outside the host cells, but little is known about its self-governing metabolism. This study deployed Eimeria falciformis , a parasite infecting the mouse as its natural host, to investigate the process of phospholipid biogenesis in sporozoites. Lipidomic analyses demonstrated the occurrence of prototypical phospholipids along with abundant expression of at least two exclusive lipids, phosphatidylthreonine (PtdThr) and inositol phosphorylceramide with a phytosphingosine backbone, in sporozoites...
2018: Cell Discovery
Axel Dahlberg, Stephanie Wehner
Stabilizer states form an important class of states in quantum information, and are of central importance in quantum error correction. Here, we provide an algorithm for deciding whether one stabilizer (target) state can be obtained from another stabilizer (source) state by single-qubit Clifford operations (LC), single-qubit Pauli measurements (LPM) and classical communication (CC) between sites holding the individual qubits. What is more, we provide a recipe to obtain the sequence of LC+LPM+CC operations which prepare the desired target state from the source state, and show how these operations can be applied in parallel to reach the target state in constant time...
July 13, 2018: Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences
C H Williams-Gray, R S Wijeyekoon, K M Scott, S Hayat, R A Barker, J L Jones
BACKGROUND: A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing...
May 28, 2018: Journal of Neuroinflammation
Sandor Vajda, Dmitri Beglov, Amanda E Wakefield, Megan Egbert, Adrian Whitty
Many proteins in their unbound structures lack surface pockets appropriately sized for drug binding. Hence, a variety of experimental and computational tools have been developed for the identification of cryptic sites that are not evident in the unbound protein but form upon ligand binding, and can provide tractable drug target sites. The goal of this review is to discuss the definition, detection, and druggability of such sites, and their potential value for drug discovery. Novel methods based on molecular dynamics simulations are particularly promising and yield a large number of transient pockets, but it has been shown that only a minority of such sites are generally capable of binding ligands with substantial affinity...
May 22, 2018: Current Opinion in Chemical Biology
M Gluza, M Kliesch, J Eisert, L Aolita
The experimental interest and developments in quantum spin-1/2 chains has increased uninterruptedly over the past decade. In many instances, the target quantum simulation belongs to the broader class of noninteracting fermionic models, constituting an important benchmark. In spite of this class being analytically efficiently tractable, no direct certification tool has yet been reported for it. In fact, in experiments, certification has almost exclusively relied on notions of quantum state tomography scaling very unfavorably with the system size...
May 11, 2018: Physical Review Letters
Maria Bhatti, Thomas Ippolito, Cory Mavis, Juan Gu, Mitchell S Cairo, Megan S Lim, Francisco Hernandez-Ilizaliturri, Matthew J Barth
Though outcomes for pediatric Burkitt lymphoma (BL) have improved significantly in recent decades with intensive multi-agent chemotherapy and the addition of rituximab, chemotherapy resistance remains a significant impediment to cure following relapse. Activation of the PI3K/AKT pathway has been implicated in Burkitt lymphomagenesis and increased PI3K/AKT activation has been associated with worse outcomes in adults with aggressive B-cell non-Hodgkin lymphoma (B-NHL). Inhibitors of the PI3K/AKT pathway have been approved for the treatment of refractory indolent B-NHL and continue to be investigated for treatment of aggressive B-NHLs...
April 24, 2018: Oncotarget
Fernando Montaño, Sergio Grinstein, Roni Levin
This chapter describes methods to induce and quantify phagocytosis in primary macrophages and in myeloid cell lines. To this end, we initially detail the isolation of primary human monocytes and their differentiation into macrophages. Because primary cells are comparatively refractory to molecular manipulation, we also describe the culture of RAW 264.7 cells-an immortalized monocyte/macrophage cell line, which is more tractable. The chapter also includes methods for preparation of phagocytic targets, specifically sheep erythrocytes opsonized with immunoglobulin G (IgG), as well as means of distinguishing bound from internalized targets, using fluorescently labeled secondary antibodies...
2018: Methods in Molecular Biology
Gavin Hackett, Kevin Moore, David Burgin, Fraser Hornby, Bryony Gray, Mark Elliott, Imran Mir, Matthew Beard
We have purified and characterized recombinant botulinum neurotoxin serotype FA (BoNT/FA). This protein has also been named as a new serotype (serotype H), but the classification has been controversial. A lack of well-characterized, highly pure material has been a roadblock to study. Here we report purification and characterization of enzymatically active, and of inactive nontoxic, recombinant forms of BoNT/FA as tractable alternatives to purifying this neurotoxin from native Clostridium botulinum . BoNT/FA cleaves the same intracellular target proteins as BoNT/F1 and other F serotype BoNTs; the intracellular targets are vesicle associated membrane proteins (VAMP) 1, 2 and 3...
May 11, 2018: Toxins
Sophie K Herbst, Lorenz Fiedler, Jonas Obleser
Human observers automatically extract temporal contingencies from the environment and predict the onset of future events. Temporal predictions are modeled by the hazard function, which describes the instantaneous probability for an event to occur given it has not occurred yet. Here, we tackle the question of whether and how the human brain tracks continuous temporal hazard on a moment-to-moment basis, and how flexibly it adjusts to strictly implicit variations in the hazard function. We applied an encoding-model approach to human electroencephalographic data recorded during a pitch-discrimination task, in which we implicitly manipulated temporal predictability of the target tones by varying the interval between cue and target tone (i...
March 2018: ENeuro
Payal Sanadhya, Patricia Bucki, Orna Liarzi, David Ezra, Abraham Gamliel, Sigal Braun Miyara
The bionematicidal effect of a synthetic volatile mixture (SVM) of four volatile organic compounds (VOCs) emitted by the endophytic fungus Daldinia cf. concentrica against the devastating plant-parasitic root-knot nematode Meloidogyne javanica has been recently demonstrated in both in vitro and greenhouse experiments. However, the mode of action governing the observed irreversible paralysis of J2 larvae upon exposure to SVM is unknown. To unravel the mechanism underlying the anthelmintic and nematicidal activities, we used the tractable model worm Caenorhabditis elegans...
2018: PloS One
Chizue Hiruta, Keiichi Kakui, Knut E Tollefsen, Taisen Iguchi
The microcrustacean Daphnia pulex is an important model for environmental, ecological, evolutionary and developmental genomics because its adaptive life history displays plasticity in response to environmental changes. Even though the whole-genome sequence is available and omics data have actively accumulated for this species, the available tools for analyzing gene function have thus far been limited to RNAi (RNA interference) and TALEN (the transcription activator-like effector nuclease) systems. The development of the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) system is thus expected to further increase the genetic tractability of D...
May 2, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Alexander Chamessian, Michael Young, Yawar Qadri, Temugin Berta, Ru-Rong Ji, Thomas Van de Ven
The spinal dorsal horn (SDH) is comprised of distinct neuronal populations that process different somatosensory modalities. Somatostatin (SST)-expressing interneurons in the SDH have been implicated specifically in mediating mechanical pain. Identifying the transcriptomic profile of SST neurons could elucidate the unique genetic features of this population and enable selective analgesic targeting. To that end, we combined the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) method and Fluorescence Activated Nuclei Sorting (FANS) to capture tagged SST nuclei in the SDH of adult male mice...
May 1, 2018: Scientific Reports
Amrita Banerjee, Eliot T McKinley, Jakob von Moltke, Robert J Coffey, Ken S Lau
Intestinal tuft cells are a morphologically unique cell type, best characterized by striking microvilli that form an apical tuft. These cells represent approximately 0.5% of gut epithelial cells depending on location. While they are known to express chemosensory receptors, their function has remained unclear. Recently, numerous groups have revealed startling insights into intestinal tuft cell biology. Here, we review the latest developments in understanding this peculiar cell type's structure and function. Recent advances in volumetric microscopy have begun to elucidate tuft cell ultrastructure with respect to its cellular neighbors...
May 1, 2018: Journal of Clinical Investigation
Abid Qureshi, Vaqar Gani Tantray, Altaf Rehman Kirmani, Abdul Ghani Ahangar
Viral diseases like influenza, AIDS, hepatitis, and Ebola cause severe epidemics worldwide. Along with their resistant strains, new pathogenic viruses continue to be discovered so creating an ongoing need for new antiviral treatments. RNA interference is a cellular gene-silencing phenomenon in which sequence-specific degradation of target mRNA is achieved by means of complementary short interfering RNA (siRNA) molecules. Short interfering RNA technology affords a potential tractable strategy to combat viral pathogenesis because siRNAs are specific, easy to design, and can be directed against multiple strains of a virus by targeting their conserved gene regions...
April 15, 2018: Reviews in Medical Virology
Markus Gastauer, Pedro Walfir Martins Souza Filho, Silvio Junio Ramos, Cecílio Frois Caldeira, Joyce Reis Silva, José Oswaldo Siqueira, Antonio Eduardo Furtini Neto
Environmental legislation in many countries demands the rehabilitation of degraded areas to minimize environmental impacts. Brazilian laws require the restitution of self-sustaining ecosystems to historical conditions but ignore the emergence of novel ecosystems due to large-scale changes, such as species invasions, extinctions, and land-use or climate changes, although these novel ecosystems might fulfill ecosystem services in similar ways as historic ecosystems. Thorough discussions of rehabilitation goals, target ecosystems, applied methods, and approaches to achieving mine land rehabilitation, as well as dialogues about the advantages and risks of chemical inputs or non-native, non-invasive species that include all political, economic, social, and academic stakeholders are necessary to achieve biological feasibility, sociocultural acceptance, economic viability, and institutional tractability during environmental rehabilitation...
April 11, 2018: Ambio
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