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https://www.readbyqxmd.com/read/28930678/dna-ligase-iv-guides-end-processing-choice-during-nonhomologous-end-joining
#1
Michael P Conlin, Dylan A Reid, George W Small, Howard H Chang, Go Watanabe, Michael R Lieber, Dale A Ramsden, Eli Rothenberg
Nonhomologous end joining (NHEJ) must adapt to diverse end structures during repair of chromosome breaks. Here, we investigate the mechanistic basis for this flexibility. DNA ends are aligned in a paired-end complex (PEC) by Ku, XLF, XRCC4, and DNA ligase IV (LIG4); we show by single-molecule analysis how terminal mispairs lead to mobilization of ends within PECs and consequent sampling of more end-alignment configurations. This remodeling is essential for direct ligation of damaged and mispaired ends during cellular NHEJ, since remodeling and ligation of such ends both require a LIG4-specific structural motif, insert1...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930581/biophysical-mechanisms-complementing-classical-cell-biology
#2
Richard H W Funk
This overview addresses phenomena in cell- and molecular biology which are puzzling by their fast and highly coordinated way of organization. Generally, it appears that informative processes probably involved are more on the biophysical than on the classical biochemical side. The coordination problem is explained within the first part of the review by the topic of endogenous electrical phenomena. These are found e.g. in fast tissue organization and reorganization processes like development, wound healing and regeneration...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28930551/uremic-toxins-are-conditional-danger-or-homeostasis-associated-molecular-patterns
#3
Yu Sun, Candice Johnson, Jun Zhou, Luqiao Wang, Ya-Feng Li, Yifan Lu, Gayani Nanayakkara, Hangfei Fu, Ying Shao, Claudette Sanchez, William Y Yang, Xin Wang, Eric T Choi, Rongshan Li, Hong Wang, Xiao-Feng Yang
We mined novel uremic toxin (UT) metabolomics/gene databases, and analyzed the expression changes of UT receptors and UT synthases in chronic kidney disease (CKD) and cardiovascular disease (CVD). We made the following observations: 1) UTs represent only 1/80(th) of human serum small-molecule metabolome; 2) Some UTs are increased in CKD and CVD; 3) UTs either induce or suppress the expression of inflammatory molecules; 4) The expression of UT genes is significantly modulated in CKD patients, and coronary artery disease (CAD) patients; 5) The expression of UT genes is upregulated by caspase-1 and TNF-alpha pathways but is inhibited in regulatory T cells...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28930490/tezacaftor-ivacaftor-in-subjects-with-cystic-fibrosis-and-f508del-f508del-cftr-or-f508del-g551d-cftr
#4
Scott H Donaldson, Joseph M Pilewski, Matthias Griese, Jon Cooke, Lakshmi Viswanathan, Elizabeth Tullis, Jane C Davies, Julie A Lekstrom-Himes, Linda T Wang
RATIONALE: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES: To evaluate safety and efficacy of tezacaftor monotherapy and tezacaftor/ivacaftor combination therapy in subjects with CF homozygous for F508del or compound heterozygous for F508del and G551D...
September 20, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28930435/new-triplet-sensitization-routes-for-photon-upconversion-thermally-activated-delayed-fluorescence-molecules-inorganic-nanocrystals-and-singlet-to-triplet-absorption
#5
Nobuhiro Yanai, Nobuo Kimizuka
Photon upconversion based on triplet-triplet annihilation (TTA-UC) has attracted much interest because of its possible applications to renewable energy production and biological fields. In particular, the UC of near-infrared (NIR) light to visible (vis) light is imperative to overcome the Shockley-Queisser limit of single-junction photovoltaic cells, and the efficiency of photocatalytic hydrogen production from water can also be improved with the aid of vis-to-ultraviolet (UV) UC. However, both processes have met limitations in the wavelength range, efficiency, and sensitivity for weak incident light...
September 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28930429/mapping-protein-targets-of-bioactive-small-molecules-using-lipid-based-chemical-proteomics
#6
Kenneth M Lum, Yoshiaki Sato, Brittney A Beyer, Warren C Plaisted, Justin L Anglin, Luke L Lairson, Benjamin F Cravatt
Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid-protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms...
September 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28930353/interplay-between-bulk-self-assembly-interfacial-and-foaming-properties-in-a-catanionic-surfactant-mixture-of-varying-composition
#7
José Ferreira, Alesya Mikhailovskaya, Alexis Chenneviere, Frédéric Restagno, Fabrice Cousin, François Muller, Jéril Degrouard, Anniina Salonen, Eduardo F Marques
The self-aggregation, surface properties and foamability of the catanionic surfactant mixture cetyltrimethylammonium bromide (CTAB)/sodium octyl sulfonate (SOSo) have been investigated to obtain insight on the relation between bulk nanostructures, surfactant packing, and foam stability and aging. Light microscopy, SANS, cryo-TEM, DLS, surface tension, rheometry and direct photography were used to characterize mixtures with varying CTAB molar fraction, xCTAB. In the bulk, self-assembly is richer in the excess CTAB region than in the excess SOSo one...
September 20, 2017: Soft Matter
https://www.readbyqxmd.com/read/28930051/addiction-and-the-role-of-circadian-genes
#8
Laura A Forde, Gursharan Kalsi
OBJECTIVE: In mammals, intimate interactions exist between the circadian system and other molecular systems, and mounting evidence is suggesting that these relationships may affect substance use disorders. Research in preclinical models supports the role of circadian genes as risk factors for addiction. Here, we explore the evidence and review human genetic studies testing the association between specific circadian genes and substance use disorders. METHOD: A literature search was conducted in PubMed for studies testing variants in eight circadian genes known to be central to the functioning of the master clock in the brain...
September 2017: Journal of Studies on Alcohol and Drugs
https://www.readbyqxmd.com/read/28929458/backbone-resonance-assignment-of-the-bcl6-btb-poz-domain
#9
Li-Ying Lin, S E Evans, L Fairall, John W R Schwabe, Simon D Wagner, Frederick W Muskett
BCL6 is a transcriptional repressor. Two domains of the protein, the N-terminal BTB-POZ domain and the RD2 domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ domains, including BCL6 have been determined. The BTB-POZ domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR...
September 19, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28929263/melt-extrusion-of-high-dose-co-amorphous-drug-drug-combinations
#10
Lærke Arnfast, Md Kamruzzaman, Korbinian Löbmann, Johanna Aho, Stefania Baldursdottir, Thomas Rades, Jukka Rantanen
PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry...
September 19, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28929194/adapting-secretory-proteostasis-and-function-through-the-unfolded-protein-response
#11
Madeline Y Wong, Andrew S DiChiara, Patreece H Suen, Kenny Chen, Ngoc-Duc Doan, Matthew D Shoulders
Cells address challenges to protein folding in the secretory pathway by engaging endoplasmic reticulum (ER)-localized protective mechanisms that are collectively termed the unfolded protein response (UPR). By the action of the transmembrane signal transducers IRE1, PERK, and ATF6, the UPR induces networks of genes whose products alleviate the burden of protein misfolding. The UPR also plays instructive roles in cell differentiation and development, aids in the response to pathogens, and coordinates the output of professional secretory cells...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28929193/immune-regulation-by-ubiquitin-tagging-as-checkpoint-code
#12
Peng Zeng, Jieyu Ma, Runqing Yang, Yun-Cai Liu
The immune system is equipped with effective machinery to mobilize its activation to defend invading microorganisms, and at the same time, to refrain from attacking its own tissues to maintain immune tolerance. The balance of activation and tolerance is tightly controlled by diverse mechanisms, since breakdown of tolerance could result in disastrous consequences such as the development of autoimmune diseases. One of the mechanisms is by the means of protein ubiquitination, which involves the process of tagging a small peptide ubiquitin to protein substrates...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28929162/interactions-and-stabilisation-of-acetone-sulfur-dioxide-and-water-with-1-octyl-3-methylimidazolium-tetrafluoroborate-omim-bf4-at-low-temperatures
#13
Matthew Buckley, Karen L Syres, Robert G Jones
The interactions between three small molecules, water (H2O), sulfur dioxide (SO2) and acetone ((CH3)2CO), with the ionic liquid (IL) 1-octyl-3-methylimidazolium tetrafluoroborate, [OMIM][BF4], have been determined using line of sight temperature programmed desorption (LOSTPD) from a gold surface. Multilayers of the IL were deposited by physical vapour deposition with multilayers of the small molecular species (adsorbed from the gas phase) at 90 K. LOSTPD was then carried out with the small molecular species desorbing first from the mixed multilayer, followed at higher temperatures by desorption of the IL from the gold surface...
September 20, 2017: Faraday Discussions
https://www.readbyqxmd.com/read/28929152/size-dependent-targeted-delivery-of-gold-nanoparticles-modified-with-the-il-6r-specific-aptamer-air-3a-to-il-6r-carrying-cells
#14
Lisa Prisner, Nadine Bohn, Ulrich Hahn, Alf Mews
The delivery of gold nanoparticles (AuNPs) to specific cells strongly depends on the properties e.g. the size of the particles and is of great interest for a large variety of biomedical applications. Here we investigated the size dependence of the receptor-ligand mediated AuNP delivery to cells by comparing very small "molecular" Au-clusters of only 2 nm to larger 7 nm and 36 nm AuNPs with a distinct surface plasmon resonance. Since the molecular weight in this range changes by almost three orders of magnitude, we show how the amount of gold relates to the number of delivered AuNPs...
September 20, 2017: Nanoscale
https://www.readbyqxmd.com/read/28928965/recent-advances-in-understanding-and-managing-cardiomyopathy
#15
REVIEW
Paulino Alvarez, Wh Wilson Tang
Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Currently, cardiomyopathy is the leading diagnosis of heart transplant patients worldwide. Incorporation of next-generation sequencing strategies will likely revolutionize genetic testing in cardiomyopathy. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing has opened a new avenue for precision medicine in cardiomyopathy...
2017: F1000Research
https://www.readbyqxmd.com/read/28928884/anti-melanoma-activities-of-haspin-inhibitor-chr-6494-deployed-as-a-single-agent-or-in-a-synergistic-combination-with-mek-inhibitor
#16
Lili Han, Peiling Wang, Yang Sun, Sijing Liu, Jun Dai
Background: Melanoma is a heterogeneous malignancy that presents an immense challenge in therapeutic development. Recent approaches targeting the oncogenic MAP kinase pathways have shown tremendous improvement in the overall survival of patients with advanced melanoma. However, there is still an urgent need for identification of new strategies to overcome drug resistances and to improve therapeutic efficacy. Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) belongs to a selected group of mitotic kinases and is required for normal mitosis progression...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28928403/dimerization-regulates-both-deaminase-dependent-and-deaminase-independent-hiv-1-restriction-by-apobec3g
#17
Michael Morse, Ran Huo, Yuqing Feng, Ioulia Rouzina, Linda Chelico, Mark C Williams
APOBEC3G (A3G) is a human enzyme that inhibits human immunodeficiency virus type 1 (HIV-1) infectivity, in the absence of the viral infectivity factor Vif, through deoxycytidine deamination and a deamination-independent mechanism. A3G converts from a fast to a slow binding state through oligomerization, which suggests that large A3G oligomers could block HIV-1 reverse transcriptase-mediated DNA synthesis, thereby inhibiting HIV-1 replication. However, it is unclear how the small number of A3G molecules found in the virus could form large oligomers...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28928392/mucosa-associated-lymphoid-tissue-lymphoma-translocation-1-as-a-novel-therapeutic-target-for-rheumatoid-arthritis
#18
Chang Hoon Lee, Su Jeong Bae, Miok Kim
Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-targeting inhibitory small molecule, MALT1 selective inhibitor 2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1H-1,2,4-triazol-1-yl]phenylacetamide (MI-2) strongly suppresses the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine tumour necrosis factor α...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28928246/exploiting-mitochondrial-and-oxidative-vulnerabilities-with-a-synthetic-analog-of-pancratistatin-in-combination-with-piperlongumine-for-cancer-therapy
#19
Dennis Ma, Tyler Gilbert, Christopher Pignanelli, Daniel Tarade, Megan Noel, Fadi Mansour, Manika Gupta, Sabrina Ma, Jesse Ropat, Colin Curran, Sergey Vshyvenko, Tomas Hudlicky, Siyaram Pandey
Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitochondria, it induced the release of apoptogenic factors...
September 19, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28928160/quantitative-and-mechanistic-understanding-of-azd1775-penetration-across-human-blood-brain-barrier-in-glioblastoma-patients-using-an-ivive-pbpk-modeling-approach
#20
Jing Li, Jianmei Wu, Xun Bao, Norissa Honea, Youming Xie, Seongho Kim, Alex Sparreboom, Nader Sanai
PURPOSE: AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). EXPERIMENTAL DESIGN: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems...
September 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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