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Jung Kim, Yongik Lee, Xiaodong Lu, Bing Song, Ka-Wing Fong, Qi Cao, Jonathan D Licht, Jonathan C Zhao, Jindan Yu
Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively...
December 4, 2018: Cell Reports
Arne Skerra, Mikhail Barkovskiy, Elena Ilyukhina, Martin Dauner, Andreas Eichinger
Colchicine is a toxic alkaloid prevalent in autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits polymerization of microtubules. Using combinatorial and rational protein design, we have developed an artificial binding protein based on the human lipocalin 2 that binds colchicine with a dissociation constant of 120 pM, i.e. 10 000-fold stronger than tubulin. Crystallographic analysis of the engineered lipocalin, dubbed Colchicalin, revealed major structural changes in the flexible loop region that forms the ligand pocket at one end of the eight-stranded β-barrel, resulting in a lid-like structure over the deeply buried colchicine...
December 1, 2018: Biological Chemistry
Stefan Harth, Andre Ten Haaf, Christian Loew, Christian Frisch, Achim Knappik
Anti-idiotypic antibodies play an important role in pre-clinical and clinical development of therapeutic antibodies, where they are used for pharmacokinetic studies and for the development of immunogenicity assays. By using an antibody phage display library in combination with guided in vitro selection against various marketed drugs, we generated antibodies that recognize the drug only when bound to its target. We have named such specificities Type 3, to distinguish them from the anti-idiotypic antibodies that specifically detect free antibody drug or total drug...
December 5, 2018: MAbs
Erik W J Mollen, Jonathan Ient, Vivianne C G Tjan-Heijnen, Liesbeth J Boersma, Lucio Miele, Marjolein L Smidt, Marc A G G Vooijs
Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers...
2018: Frontiers in Oncology
Ki-Hye Jung, Ji-Ae Park, Jung Young Kim, Mi Hyun Kim, Seyoung Oh, Hee-Kyung Kim, Eun-Ji Choi, Han-Jun Kim, Sun Hee Do, Kyo Chul Lee, Kyeong Min Kim, Yong Jin Lee, Yongmin Chang
Gadolinium-neutron capture therapy (Gd-NCT) is based on the nuclear capture reaction that occurs when 157 Gd is irradiated with low energy thermal neutrons to primarily produce gamma photons. Herein, we investigated the effect of neutron capture therapy (NCT) using a small molecular gadolinium complex, Gd-DO3A-benzothiazole (Gd-DO3A-BTA), which could be a good candidate for use as an NCT drug due to its ability to enter the intracellular nuclei of tumor cells. Furthermore, MRI images of Gd-DO3A-BTA showed a clear signal enhancement in the tumor, and the images also played a key role in planning NCT by providing accurate information on the in vivo uptake time and duration of Gd-DO3A-BTA...
2018: Contrast Media & Molecular Imaging
Dipendra Jha, Logan Ward, Arindam Paul, Wei-Keng Liao, Alok Choudhary, Chris Wolverton, Ankit Agrawal
Conventional machine learning approaches for predicting material properties from elemental compositions have emphasized the importance of leveraging domain knowledge when designing model inputs. Here, we demonstrate that by using a deep learning approach, we can bypass such manual feature engineering requiring domain knowledge and achieve much better results, even with only a few thousand training samples. We present the design and implementation of a deep neural network model referred to as ElemNet; it automatically captures the physical and chemical interactions and similarities between different elements using artificial intelligence which allows it to predict the materials properties with better accuracy and speed...
December 4, 2018: Scientific Reports
Wazeer Varsally, Suzana Hadjur
A recent study in Nature Genetics (Oudelaar et al., 2018) has developed a new method to study multi-way chromatin interactions at the allelic level from regulatory elements with high sensitivity and resolution. The method, termed 'Tri-C' is used to explore the combinatorial interactions between multiple regulatory elements underlying precise gene regulation of the globin locus.
December 3, 2018: Developmental Cell
Bing Song, Su-Hong Park, Jonathan C Zhao, Ka-Wing Fong, Shangze Li, Yongik Lee, Yeqing A Yang, Subhasree Sridhar, Xiaodong Lu, Sarki A Abdulkadir, Robert L Vessella, Colm Morrissey, Timothy M Kuzel, William J Catalona, Ximing J Yang, Jindan Yu
Prostate cancer (PCa) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation anti-androgen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiation. Here, we demonstrate that FOXA1 loss leads to remarkable up-regulation of transforming growth factor beta 3 (TGFB3), which encodes a ligand of TGF-β pathway...
December 4, 2018: Journal of Clinical Investigation
Matilda S Newton, Dana J Morrone, Kun-Hwa Lee, Burckhard Seelig
The universal genetic code of 20 amino acids is the product of evolution. It is believed that earlier versions of the code comprised fewer residues. Many theories for the order in which amino acids were integrated into the code have been proposed, considering factors ranging from prebiotic chemistry to codon capture. Several meta-analyses combined these theories to yield a feasible consensus chronology of the genetic code's evolution, but there is a dearth of experimental data to test the hypothesised order...
December 3, 2018: Chembiochem: a European Journal of Chemical Biology
Veronica Estrada, Julia Krebbers, Christian Voss, Nicole Brazda, Heinrich Blazyca, Jennifer Illgen, Klaus Seide, Christian Jürgens, Jörg Müller, Rudolf Martini, Hoc Khiem Trieu, Hans Werner Müller
Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection...
2018: Communications biology
Alison L Gould, Vivian Zhang, Lisa Lamberti, Eric W Jones, Benjamin Obadia, Nikolaos Korasidis, Alex Gavryushkin, Jean M Carlson, Niko Beerenwinkel, William B Ludington
Gut bacteria can affect key aspects of host fitness, such as development, fecundity, and lifespan, while the host, in turn, shapes the gut microbiome. However, it is unclear to what extent individual species versus community interactions within the microbiome are linked to host fitness. Here, we combinatorially dissect the natural microbiome of Drosophila melanogaster and reveal that interactions between bacteria shape host fitness through life history tradeoffs. Empirically, we made germ-free flies colonized with each possible combination of the five core species of fly gut bacteria...
December 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mohammad Mehdi Movahedi, Alireza Mehdizadeh, Fereshteh Koosha, Neda Eslahi, Vahid Pirhajati Mahabadi, Habib Ghaznavi, Ali Shakeri-Zadeh
In this article, we report a targeted cancer treatment strategy using nano-photo-thermal therapy (NPTT) and radiotherapy (RT) methods. Gold nanorods (AuNRs) without and with folic acid (FA) conjugation were firstly synthesized and then characterized. Cytotoxicity of various methods; NPTT (nanoparticles; 808 nm laser; 2 W/cm2 ) or RT (6 MV X-ray; 2 Gy) or combination of NPTT and RT; was separately investigated on KB nasopharyngeal carcinoma cells. The effects of different treatments were studies using MTT assay, inductively coupled plasma-mass spectrometry (ICP-MS) and transmission electron microscopy (TEM)...
December 2018: Photodiagnosis and Photodynamic Therapy
Gualberto Ruano, Jonathan A Kost
BACKGROUND: A major challenge for effective pharmacotherapy in pain management is to provide the drug best suited to the patient's innate characteristics. OBJECTIVE: The article illustrates pharmacogenetic principles to optimize treatments for patients and increase the likelihood of pain relief without dependence. Genetic variances are particularly relevant to opioid drugs used in pain control, and can now be harvested for predictive clinical decision support. STUDY DESIGN: Clinically actionable polymorphisms in CYP2D6 (cytochrome p450 2D6) and OPRM1 (mu 1 opioid receptor), the most important gene coding, respectively, for a metabolizing enzyme and receptor for opioids are reviewed, and functional effects described...
November 2018: Pain Physician
Jialong Shi, Qingfu Zhang, Jianyong Sun
Pareto local search (PLS) is a basic building block in many metaheuristics for a multiobjective combinatorial optimization problem. In this paper, an enhanced PLS variant called parallel PLS based on decomposition (PPLS/D) is proposed. PPLS/D improves the efficiency of PLS using the techniques of parallel computation and problem decomposition. It decomposes the original search space into L subregions and executes L parallel processes searching in these subregions simultaneously. Inside each subregion, the PPLS/D process is guided by a unique scalar objective function...
November 29, 2018: IEEE Transactions on Cybernetics
Pawel Bialk, Yichen Wang, Kelly Banas, Eric B Kmiec
Recent studies point to the evolution of drug resistance in lung cancer as being centered, at least in part, on the upregulation of various genes involved in controlling efflux or drug inactivation. Among the most important of these genes is Nuclear Factor Erythroid 2-Related Factor ( NRF2 ), considered the master regulator of 100-200 target genes involved in cellular responses to oxidative and/or electrophilic stress. With increased focus on the development of combinatorial approaches for cancer treatment, we utilized CRISPR/Cas9 to disable the NRF2 gene in lung cancer cells by disrupting the NRF2 nuclear export signal (NES) domain; phenotypically, the protein is largely blocked from transiting into the nucleus after translation...
December 21, 2018: Molecular Therapy Oncolytics
Lisa D Urness, Xiaofen Wang, Huy Doan, Nathan Shumway, C Albert Noyes, Edgar Gutierrez-Magana, Ree Lu, Suzanne L Mansour
Morphogenesis of the inner ear epithelium requires coordinated deployment of several signaling pathways, and disruptions cause abnormalities of hearing and/or balance. The FGFR2b ligands, FGF3 and FGF10, are expressed throughout otic development and are required individually for normal morphogenesis, but their prior and redundant roles in otic placode induction complicates investigation of subsequent combinatorial functions in morphogenesis. To interrogate these roles and identify new effectors of FGF3 and FGF10 signaling at the earliest stages of otic morphogenesis, we used conditional gene ablation after otic placode induction, and temporal inhibition of signaling with a secreted, dominant-negative FGFR2b ectodomain...
November 30, 2018: Development
Tobias J Hauke, Georg Höfner, Klaus T Wanner
The γ-aminobutyric acid (GABA) transporter mGAT4 represents a promising drug target for the treatment of epilepsy and other neurological disorders; however, the lack of highly potent and selective inhibitors for mGAT4 still retards its pharmacological elucidation. Herein, the generation and screening of pseudostatic combinatorial hydrazone libraries at the murine GABA transporter mGAT4 for the search of novel GABA uptake inhibitors is described. The hydrazone libraries contained more than 1100 compounds derived from nipecotic acid derivatives substituted at the 5-position instead, as common, at the 1-position of the core structure...
November 22, 2018: Bioorganic & Medicinal Chemistry
Tanu Kaushal, Gaurava Srivastava, Ashok Sharma, Arvind Singh Negi
Quinoxalines are benzopyrazines containing benzene and pyrazine rings fused together. In the recent past, quinoxalines have attracted Medicinal Chemists considerably for their syntheses and chemistry due to their distinct pharmacological activities. Diverse synthetic protocols have been developed via multicomponent reactions, single pot synthesis and combinatorial approach using efficient catalysts, reagents, and nano-composites etc. Further, the versatility of the quinoxaline core and its reasonable chemical simplicity devise it extremely promising source of bioactive compounds...
November 15, 2018: Bioorganic & Medicinal Chemistry
Raquel Dos Santos, Carina Figueiredo, Aline Canani Viecinski, Ana Sofia Pina, Arménio J M Barbosa, A Cecília A Roque
Human serum albumin (HSA) in an important therapeutic agent and disease biomarker, with an increasing market demand. By proteins and drugs that bind to HSA as inspiration, a combinatorial library of 64 triazine-based ligands was rationally designed and screened for HSA binding at physiological conditions. Two triazine-based lead ligands (A3A2 and A6A5), presenting more than 50% HSA bound and high enrichment factors, were selected for further studies. Binding and elution conditions for HSA purification from human plasma were optimized for both ligands...
November 16, 2018: Journal of Chromatography. A
Eduardo Anitua, Paquita Nurden, Roberto Prado, Alan T Nurden, Sabino Padilla
The healing of vascularized mammalian tissue injuries initiate with hemostasis and clotting as part of biological defense system leading to the formation of a fibrin clot in which activated platelets are trapped to quickly stop bleeding and destroy microbials. In order to harness the therapeutic potential of biomolecules secreted by platelets and stemmed from plasma, blood deconstruction has allowed to yield autologous platelet-and plasma-derived protein fibrin scaffold. The autologous growth factors and microparticles stemmed from platelets and plasma, interact with fibrin, extracellular matrix, and tissue cells in a combinatorial, synergistic, and multidirectional way on mechanisms governing tissue repair...
November 21, 2018: Biomaterials
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