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https://www.readbyqxmd.com/read/29148755/novel-anti-tubercular-6-dialkylaminopyrimidine-carboxamides-from-phenotypic-whole-cell-high-throughput-screening-of-a-softfocus-library-structure-activity-relationship-and-target-identification-studies
#1
Colin R Wilson, Richard K Gessner, Atica Moosa, Ronnett Seldon, Digby F Warner, Valerie Mizrahi, Candice Soares de Melo, Sandile B Simelane, Aloysius T Nchinda, Efrem Abay, Dale Taylor, Mathew Njoroge, Christel Brunschwig, Nina Lawrence, Helena I M Boshoff, Clifton E Barry, Frederick A Sirgel, Paul van Helden, C John Harris, Richard Gordon, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Olalla Sanz, Gracia Santos, Maria José Rebollo-Lopez, Beatriz Urones, Carolyn Selenski, Maria Jose Lafuente-Monasterio, Matthew Axtman, Joël Lelièvre, Lluis Ballell, Rudolf Mueller, Leslie J Street, Sandeep R Ghorpade, Kelly Chibale
A BioFocus DPI SoftFocus library of ~35,000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with anti-tubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits which passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29148548/acrylate-based-materials-for-heart-valve-scaffold-engineering
#2
Rosaria Santoro, Seshasailam Venkateswaran, Francesco Amadeo, Rong Zhang, Maura Brioschi, Anthony Callanan, Marco Agrifoglio, Cristina Banfi, Mark Bradley, Maurizio Pesce
Calcific aortic valve disease (CAVD) is the most frequent cardiac valve pathology. Its standard treatment consists of surgical replacement either with mechanical (metal made) or biological (animal tissue made) valve prostheses, both of which have glaring deficiencies. In the search for novel materials to manufacture artificial valve tissue, we have conducted a high-throughput screening with subsequent up-scaling to identify non-degradable polymer substrates that promote valve interstitial cells (VICs) adherence/growth and, at the same time, prevent their evolution toward a pro-calcific phenotype...
November 17, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/29148434/the-cutting-away-of-potential-secondary-electron-tracks-explains-the-effects-of-beam-size-and-detector-wall-density-in-small-field-photon-dosimetry
#3
Hui Khee Looe, Bjoern Delfs, Daniela Poppinga, Ping Jiang, Dietrich Harder, Bjoern Poppe
The well-known field-size dependent overresponse in small-field photon-beam dosimetry of solid-state detectors equipped with very thin sensitive volumes, such as the PTW microDiamond, cannot be caused by the photon and electron interactions within these sensitive layers because they are only a few micrometers thick. The alternative explanation is that their overresponse is caused by the combination of two effects, the modification of the secondary electron fluence profile i) by a field size too small to warrant lateral secondary electron equilibrium and ii) by the density-dependent electron ranges in the structural detector materials placed in front of or backing the sensitive layer...
November 17, 2017: Physics in Medicine and Biology
https://www.readbyqxmd.com/read/29147782/common-functional-variants-of-the-glutamatergic-system-in-autism-spectrum-disorder-with-high-and-low-intellectual-abilities
#4
Andreas G Chiocchetti, Afsheen Yousaf, Hannah S Bour, Denise Haslinger, Regina Waltes, Eftichia Duketis, Tomas Jarczok, Michael Sachse, Monica Biscaldi, Franziska Degenhardt, Stefan Herms, Sven Cichon, Jörg Ackermann, Ina Koch, Sabine M Klauck, Christine M Freitag
The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups...
November 16, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29147671/distal-22q11-2-microduplication-case-report-and-review-of-the-literature
#5
Elana Pinchefsky, Laurence Laneuville, Myriam Srour
Distal chromosome 22q11.2 microduplications are associated with a wide range of phenotypes and unclear pathogenicity. The authors report on a 3-year-old girl with global developmental delay harboring a de novo 1.24 Mb distal chromosome 22q11.2 microduplication and a paternally inherited 0.25 Mb chromosome 4p14 microduplication. The authors review clinical features of 30 reported cases of distal 22q11.2 duplications. Common features include developmental delay (93%), neuropsychiatric features (26%), and nonspecific facial dysmorphisms (74%)...
January 2017: Child neurology open
https://www.readbyqxmd.com/read/29147652/identification-of-potent-chloride-intracellular-channel-protein-1-inhibitors-from-traditional-chinese-medicine-through-structure-based-virtual-screening-and-molecular-dynamics-analysis
#6
Wei Wang, Minghui Wan, Dongjiang Liao, Guilin Peng, Xin Xu, Weiqiang Yin, Guixin Guo, Funeng Jiang, Weide Zhong, Jianxing He
Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29146047/maternal-immune-activation-delays-excitatory-to-inhibitory-gamma-aminobutyric-acid-switch-in-offspring
#7
Irene Corradini, Elisa Focchi, Marco Rasile, Raffaella Morini, Genni Desiato, Romana Tomasoni, Michela Lizier, Elsa Ghirardini, Riccardo Fesce, Diego Morone, Isabella Barajon, Flavia Antonucci, Davide Pozzi, Michela Matteoli
BACKGROUND: The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. METHODS: Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. RESULTS: Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na(+)-K(+)-2Cl(-) cotransporter 1 and the K(+)-Cl(-) cotransporter 2 (KCC2)...
November 14, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29145966/outcome-evaluation-of-staged-treatment-for-bicondylar-tibial-plateau-fractures
#8
Vincenzo Giordano, Ney Pecegueiro do Amaral, Hilton A Koch, Rodrigo Pires E Albuquerque, Felipe Serrão de Souza, José Félix Dos Santos Neto
BACKGROUND: The universal accepted strategy for treating high-energy tibial plateau fractures remains a topic of ongoing debate. The challenge for the practicing orthopaedic trauma surgeon is to provide anatomical articular fracture reduction, with successfully managing the complex soft-tissue injury that is commonly present at patient admission. The primary aim of the actual study was to evaluate the results of a staged protocol for the treatment of high-energy bicondylar tibial plateau fractures...
October 2017: Injury
https://www.readbyqxmd.com/read/29145430/de-novo-sequencing-and-analysis-of-the-transcriptome-during-the-browning-of-fresh-cut-luffa-cylindrica-fusi-3-fruits
#9
Haisheng Zhu, Jianting Liu, Qingfang Wen, Mindong Chen, Bin Wang, Qianrong Zhang, Zhuzheng Xue
Fresh-cut luffa (Luffa cylindrica) fruits commonly undergo browning. However, little is known about the molecular mechanisms regulating this process. We used the RNA-seq technique to analyze the transcriptomic changes occurring during the browning of fresh-cut fruits from luffa cultivar 'Fusi-3'. Over 90 million high-quality reads were assembled into 58,073 Unigenes, and 60.86% of these were annotated based on sequences in four public databases. We detected 35,282 Unigenes with significant hits to sequences in the NCBInr database, and 24,427 Unigenes encoded proteins with sequences that were similar to those of known proteins in the Swiss-Prot database...
2017: PloS One
https://www.readbyqxmd.com/read/29145373/quick-hits
#10
Yasemin Saplakoglu
No abstract text is available yet for this article.
November 14, 2017: Scientific American
https://www.readbyqxmd.com/read/29144848/watching-the-evolution-of-the-american-family-amazon-s-transparent-ecological-systems-theory-and-the-changing-dynamics-of-public-opinion
#11
Amy B Becker, Maureen E Todd
Using Bronfenbrenner's (1979) ecological systems theory as an organizing framework, the research closely examines the text of the Amazon Studios hit show, Transparent, and by extension the evolution of public opinion towards transgender individuals. By examining the Pfefferman family in detail and their related microsystem and macrosystem, we are able to closely unpack the transition of Jeffrey Tambor's character from Mort to Maura and the show's connections with broader developments in the Los Angeles LGBT community and the Jewish diaspora in postwar and contemporary Los Angeles...
November 16, 2017: Journal of Homosexuality
https://www.readbyqxmd.com/read/29144001/biological-evaluation-and-energetic-analyses-of-novel-gsk-3%C3%AE-inhibitors
#12
Denan Zhang, Lei Liu, Lin Pang, Qing Jin, Kehui Ke, Ming Hu, Jingbo Yang, Weifang Ma, Hongbo Xie, Xiujie Chen
Glycogen synthase kinase-3 beta (GSK-3β) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3β activity have been implicated in diabetes, heart disease, Parkinson disease and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3β were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29143719/microbial-protein-targets-towards-understanding-and-intervention
#13
Paul W Denny
The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burdens caused by near untreatable microbial pathogens, there is an urgent need to identify new antimicrobials. Central to this is the elucidation of new, robustly validated, drug targets. Informed by industrial practice and concerns, the use of both biological and chemical tools in validation is key...
November 16, 2017: Parasitology
https://www.readbyqxmd.com/read/29143468/predictive-qsar-modeling-study-on-berberine-derivatives-with-hypolipidemic-activity
#14
Pan Yu, Dongdong Li, Junjun Ni, Linguo Zhao, Gang Ding, Zhenzhong Wang, Wei Xiao
Berberine (BBR) isolated from a Chinese herb, is identified as a new cholesterol-lowering small molecule, and hundreds of berberine derivatives have been obtained for optimization of their hypolipidemic activities in recent years. However, so far there is no available quantitative structure-activity relationship (QSAR) model used for the development of novel BBR analogs with hypolipidemic activities, mainly due to lack of lipid-lowering molecular mechanisms and target identification of BBR. In this paper, the tactics using ligand efficiency indices instead of pIC50 as the activity could be adopted for the development of BBR QSAR models...
November 16, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29143030/quantitative-chemoproteomic-profiling-reveals-multiple-target-interactions-of-spongiolactone-derivatives-in-leukemia-cells
#15
M H Wright, Y Tao, J Drechsel, J Krysiak, S Chamni, A Weigert-Munoz, N L Harvey, D Romo, S A Sieber
The spongiolactones are marine natural products with an unusual rearranged spongiane skeleton and a fused β-lactone ring. These compounds have potential anticancer properties but their mode of action has yet to be explored. Here we employ activity-based protein profiling to identify the targets of a more potent spongiolactone derivative in live cancer cells, and compare these to the targets of a simpler β-lactone. These hits provide the first insights into the covalent mechanism of action of this natural product class...
November 16, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29140675/identification-of-novel-allosteric-modulators-of-glutamate-transporter-eaat2
#16
Sandhya Kortagere, Ole Valente Mortensen, Jingsheng Xia, William Lester, Yuhong Fang, Yellamelli V V Srikanth, Joseph M Salvino, Andreia Cristina Karklin Fontana
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsyand neurodegenerative diseases among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain...
November 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29140481/excessive-burden-of-lysosomal-storage-disorder-gene-variants-in-parkinson-s-disease
#17
Laurie A Robak, Iris E Jansen, Jeroen van Rooij, André G Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M Shulman
Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk...
November 13, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29140130/the-effects-of-hydrogen-peroxide-and-lipopolysaccharide-on-rat-alveolar-l2-cells
#18
Eun Kyeong Kang, Han Suk Kim
PURPOSE: This study aimed to investigate differential cell responses of alveolar epithelial cells (AECs) after treatments with lipopolysaccharide (LPS) and hydrogen peroxide (H2O2) to mimic the exposure to inflammation and oxidative stress and the mechanisms of a double-hit model of apoptosis. MATERIALS AND METHODS: AECs were cultured and treated with combinations of 1 μg/mL of LPS and 500 μM H2O2 as follows: LPS-only at 0 h, LPS at 0 h with H2O2 at 6 h (LPS + H2O2), H2O2-only at 0 h, H2O2 at 0 h with LPS at 6 h (H2O2 + LPS), and control...
October 2017: Experimental Lung Research
https://www.readbyqxmd.com/read/29138965/molecular-dynamics-and-integrated-pharmacophore-based-identification-of-dual-formula-see-text-inhibitors
#19
Maninder Kaur, Pankaj Kumar Singh, Manjinder Singh, Renu Bahadur, Om Silakari
Despite increase in the understanding of the pathogenesis of rheumatoid arthritis (RA), it remains a tough challenge. The advent of kinases involved in key intracellular pathways in pathogenesis of RA may provide a new phase of drug discovery for RA. The present study is aimed to identify dual JAK3/[Formula: see text] inhibitors by developing an optimum pharmacophore model integrating the information revealed by ligand-based pharmacophore models and structure-based pharmacophore models (SBPMs). For JAK3 inhibitors, the addition of an aromatic ring feature and for [Formula: see text] the addition of a hydrophobic feature proposed by SBPMs lead to five-point pharmacophore (i...
November 14, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/29138493/suppression-of-srcap-chromatin-remodelling-complex-and-restriction-of-lymphoid-lineage-commitment-by-pcid2
#20
Buqing Ye, Benyu Liu, Liuliu Yang, Guanling Huang, Lu Hao, Pengyan Xia, Shuo Wang, Ying Du, Xiwen Qin, Pingping Zhu, Jiayi Wu, Nobuo Sakaguchi, Junyan Zhang, Zusen Fan
Lymphoid lineage commitment is an important process in haematopoiesis, which forms the immune system to protect the host from pathogen invasion. However, how multipotent progenitors (MPP) switch into common lymphoid progenitors (CLP) or common myeloid progenitors (CMP) during this process remains elusive. Here we show that PCI domain-containing protein 2 (Pcid2) is highly expressed in MPPs. Pcid2 deletion in the haematopoietic system causes skewed lymphoid lineage specification. In MPPs, Pcid2 interacts with the Zinc finger HIT-type containing 1 (ZNHIT1) to block Snf2-related CREBBP activator protein (SRCAP) activity and prevents the deposition of histone variant H2A...
November 15, 2017: Nature Communications
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