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A Tiwari, H Luo, X Chen, P Singh, I Bhattacharya, P Jasper, J E Tolsma, H M Jones, A Zutshi, A K Abraham
Understanding pharmacological target coverage is fundamental in drug discovery and development as it helps establish a sequence of research activities, from laboratory objectives to clinical doses. To this end, we evaluated the impact of tissue target concentration data on the level of confidence in tissue coverage predictions using a site of action (SoA) model for antibodies. By fitting the model to increasing amounts of synthetic tissue data and comparing the uncertainty in SoA coverage predictions, we confirmed that, in general, uncertainty decreases with longitudinal tissue data...
October 22, 2016: CPT: Pharmacometrics & Systems Pharmacology
L C Perkin, E N Elpidina, B Oppert
Tribolium castaneum is a major agriculture pest damaging stored grains and cereal products. The T. castaneum genome contains 26 cysteine peptidase genes, mostly cathepsins L and B, and seven have a major role in digestion. We targeted the expression of the most highly expressed cathepsin L gene on chromosome 10, TC011001, by RNA interference (RNAi), using double-stranded RNA (dsRNA) constructs of different regions of the gene (3', middle, 5' and entire coding regions). RNA sequencing and quantitation (RNA-seq) was used to evaluate knockdown and specificity amongst the treatments...
October 22, 2016: Insect Molecular Biology
Hasup Lee, Minkyung Baek, Gyu Rie Lee, Sangwoo Park, Chaok Seok
Many proteins function as homo- or hetero-oligomers; therefore, attempts to understand and regulate protein functions require knowledge of protein oligomer structures. The number of available experimental protein structures is increasing, and oligomer structures can be predicted using the experimental structures of related proteins as templates. However, template-based models may have errors due to sequence differences between the target and template proteins, which can lead to functional differences. Such structural differences may be predicted by loop modeling of local regions or refinement of the overall structure...
October 22, 2016: Proteins
Christian Parisod
Taking transposable elements into consideration in surveys of genetic and epigenetic variation remains challenging in species lacking a high-quality reference genome. Here, molecular techniques reducing genome complexity and specifically targeting restructuring and methylation changes in TE genome fractions are described. In particular, methyl-sensitive transposon display (MSTD) uses isoschizomers and PCR amplifications to assess the methylation environment of TE insertions. MSTD offers reliable insights into genome-wide epigenetic changes associated with TEs, especially when used together with similar techniques tracking random sequences...
2017: Methods in Molecular Biology
Clement Chung
PURPOSE: Current strategies for managing neuroendocrine tumors (NETs) in adult patients are reviewed, with a focus on medication safety concerns. SUMMARY: NETs usually originate in the gastrointestinal or bronchopulmonary tract. Symptoms due to hormonal hypersecretion often occur in patients with foregut or midgut NETs or liver metastases. Surgical resection is recommended for most localized NETs, while systemic cytotoxic chemotherapy is typically used for high-grade and pancreatic tumors...
November 1, 2016: American Journal of Health-system Pharmacy: AJHP
Isaac Garrido-Benavent, Sergio Pérez-Ortega, Asunción de Los Ríos
Symbiotic associations between green algae (Chlorophyta) and fungi give rise to morphologically and eco-physiologically distinct entities, or so-called, lichens. In one of the most peculiar of these associations, the partners are species of the macroscopic genus Prasiola (Trebouxiophyceae) and the ascomycete Mastodia tessellata (Verrucariaceae). This is the only known case of a lichen symbiosis involving a foliose green alga. Despite intense research targeted at understanding the biology of this particular association, little is known about the genetic variability of its symbionts...
October 18, 2016: Molecular Phylogenetics and Evolution
J Chee, B W S R Robinson, R A Holt, J Creaney
Harnessing the immune system to fight cancer is an exciting advancement in lung cancer therapy. Anti-tumor immunity can be augmented by checkpoint blockade therapy, which removes the inhibition/brakes imposed on the immune system by the tumor. Checkpoint blockade therapy with anti-PD1/anti-PDL1 antibodies causes tumor regression in around 25% of lung cancer patients. In another approach, the immune system is forced or accelerated to attack the tumour, via augmentation of the anti-tumour response against mutations carried by each lung tumour...
October 18, 2016: Chest
Shara I Feld, Sarah E Tevis, Alexander G Cobian, Mark W Craven, Gregory D Kennedy
BACKGROUND: Many studies have evaluated predictors of postoperative complications, yet little is known about the development of multiple complications. The goal of this study was to assess complication timing in cascades of multiple complications and the risk of future complications given a patient's first complication. METHODS: This study includes 30-day, postoperative complications from the American College of Surgeons National Surgical Quality Improvement Program for all patients who underwent major inpatient and outpatient operative procedures from 2005-2013...
October 18, 2016: Surgery
Franziska Hopfner, Dietrich Haubenberger, Wendy R Galpern, Katrina Gwinn, Ashlee Van't Veer, Samantha White, Kailash Bhatia, Charles H Adler, David Eidelberg, William Ondo, Glenn T Stebbins, Caroline M Tanner, Rick C Helmich, Fred A Lenz, Roy V Sillitoe, David Vaillancourt, Jerrold L Vitek, Elan D Louis, Holly A Shill, Matthew P Frosch, Tatiana Foroud, Gregor Kuhlenbäumer, Andrew Singleton, Claudia M Testa, Mark Hallett, Rodger Elble, Günther Deuschl
Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics...
October 4, 2016: Parkinsonism & related Disorders
C Franklin, E Livingstone, A Roesch, B Schilling, D Schadendorf
Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma...
September 2, 2016: European Journal of Surgical Oncology
M Moradi, N Sattarahmady, A Rahi, G R Hatam, S M Rezayat Sorkhabadi, H Heli
Detection of leishmaniasis is important in clinical diagnoses. In the present study, identification of Leishmania parasites was performed by a label-free, PCR-free and signal-on ultrasensitive electrochemical DNA biosensor. Gold nanoleaves were firstly electrodeposited by an electrodeposition method using spermidine as a shape directing agent. The biosensor was fabricated by immobilization of a Leishmania major specific DNA probe onto gold nanoleaves, and methylene blue was employed as a marker. Hybridization of the complementary single stranded DNA sequence with the biosensor under the selected conditions was then investigated...
December 1, 2016: Talanta
Sittiporn Pattaradilokrat, Vorthon Sawaswong, Phumin Simpalipan, Morakot Kaewthamasorn, Napaporn Siripoon, Pongchai Harnyuttanakorn
BACKGROUND: An effective malaria vaccine is an urgently needed tool to fight against human malaria, the most deadly parasitic disease of humans. One promising candidate is the merozoite surface protein-3 (MSP-3) of Plasmodium falciparum. This antigenic protein, encoded by the merozoite surface protein (msp-3) gene, is polymorphic and classified according to size into the two allelic types of K1 and 3D7. A recent study revealed that both the K1 and 3D7 alleles co-circulated within P. falciparum populations in Thailand, but the extent of the sequence diversity and variation within each allelic type remains largely unknown...
October 21, 2016: Malaria Journal
Chaoyun Hao, Zhiqiang Xia, Rui Fan, Lehe Tan, Lisong Hu, Baoduo Wu, Huasong Wu
BACKGROUND: Piper nigrum L., or "black pepper", is an economically important spice crop in tropical regions. Black pepper production is markedly affected by foot rot disease caused by Phytophthora capsici, and genetic improvement of black pepper is essential for combating foot rot diseases. However, little is known about the mechanism of anti- P. capsici in black pepper. The molecular mechanisms underlying foot rot susceptibility were studied by comparing transcriptome analysis between resistant (Piper flaviflorum) and susceptible (Piper nigrum cv...
October 21, 2016: BMC Genomics
Elizabeth E Hjort, Weiqi Huang, Liping Hu, Elizabeth A Eklund
Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5...
October 19, 2016: Oncotarget
Na Li, Yunhuan Yan, Angke Zhang, Jiming Gao, Chong Zhang, Xue Wang, Gaopeng Hou, Gaiping Zhang, Jinbu Jia, En-Min Zhou, Shuqi Xiao
Many viruses encode microRNAs (miRNAs) that are small non-coding single-stranded RNAs which play critical roles in virus-host interactions. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically impactful viruses in the swine industry. The present study sought to determine whether PRRSV encodes miRNAs that could regulate PRRSV replication. Four viral small RNAs (vsRNAs) were mapped to the stem-loop structures in the ORF1a, ORF1b and GP2a regions of the PRRSV genome by bioinformatics prediction and experimental verification...
October 17, 2016: Oncotarget
Anna Chung-Kwan Tse, Jing-Woei Li, Simon Yuan Wang, Ting-Fung Chan, Keng Po Lai, Rudolf Shiu-Sun Wu
Hypoxia is a global environmental concern and poses a significant threat to aquatic ecosystems, including the sustainability of natural fish populations. The deleterious effects of hypoxia on fish reproductive fitness, as mediated by disruption of sex hormones and gene expression along the Brain-Pituitary-Gonad axis, have been well documented. Recently, we further demonstrated that the observed disruption of steroidogenesis in the ovary of marine medaka Oryzias melastigma is mediated through microRNAs (miRNAs)...
October 8, 2016: Aquatic Toxicology
Yi Lin, Eiichiro Mori, Masato Kato, Siheng Xiang, Leeju Wu, Ilmin Kwon, Steven L McKnight
Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent...
October 20, 2016: Cell
Johan Kreuger, Paul O'Callaghan
Here we report on a technical difficulty we encountered while optimizing genotyping strategies to identify mice derived from Exoc3l2tm1a(KOMP)Wtsi embryonic stem cells obtained from the Knockout Mouse Project Repository. The Exoc3l2tm1a(KOMP)Wtsi construct encodes a "knockout-first" design with loxP sites that confer conditional potential (KO1st). We designed primers that targeted wild-type sequences flanking the most downstream element of the construct, an 80 base pair synthetic loxP region, which BLAST alignment analysis reveals is an element common to over 10,000 conditional gene-targeting mouse models...
2016: PloS One
Philippe Hermand, Annick Vandercammen, Emmanuel Mertens, Emmanuel Di Paolo, Vincent Verlant, Philippe Denoël, Fabrice Godfroid
The use of protein antigens able to protect against the majority of Streptococcus pneumoniae serotypes is envisaged as stand-alone and/or complement to the current capsular polysaccharide-based pneumococcal vaccines. Pneumolysin (Ply) is a key virulence factor that is highly conserved in amino acid sequence across pneumococcal serotypes, and therefore may be considered as a vaccine target. However, native Ply cannot be used in vaccines due to its intrinsic cytolytic activity. In the present work a completely, irreversibly detoxified pneumolysin (dPly) has been generated using an optimized formaldehyde treatment...
October 21, 2016: Human Vaccines & Immunotherapeutics
Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
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