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Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48.

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Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48.

Nat Commun. 2018 Jun 11;9(1):2280

Authors: Velimezi G, Robinson-Garcia L, Muñoz-Martínez F, Wiegant WW, Ferreira da Silva J, Owusu M, Moder M, Wiedner M, Rosenthal SB, Fisch KM, Moffat J, Menche J, van Attikum H, Jackson SP, Loizou JI

Abstract
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). Thus, as compared to FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.

PMID: 29891926 [PubMed - in process]



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The budding yeast RSC complex maintains ploidy by promoting spindle pole body insertion.

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The budding yeast RSC complex maintains ploidy by promoting spindle pole body insertion.

J Cell Biol. 2018 Jun 06;:

Authors: Sing TL, Hung MP, Ohnuki S, Suzuki G, San Luis BJ, McClain M, Unruh JR, Yu Z, Ou J, Marshall-Sheppard J, Huh WK, Costanzo M, Boone C, Ohya Y, Jaspersen SL, Brown GW

Abstract
Ploidy is tightly regulated in eukaryotic cells and is critical for cell function and survival. Cells coordinate multiple pathways to ensure replicated DNA is segregated accurately to prevent abnormal changes in chromosome number. In this study, we characterize an unanticipated role for the Saccharomyces cerevisiae "remodels the structure of chromatin" (RSC) complex in ploidy maintenance. We show that deletion of any of six nonessential RSC genes causes a rapid transition from haploid to diploid DNA content because of nondisjunction events. Diploidization is accompanied by diagnostic changes in cell morphology and is stably maintained without further ploidy increases. We find that RSC promotes chromosome segregation by facilitating spindle pole body (SPB) duplication. More specifically, RSC plays a role in distributing two SPB insertion factors, Nbp1 and Ndc1, to the new SPB. Thus, we provide insight into a role for a SWI/SNF family complex in SPB duplication and ploidy maintenance.

PMID: 29875260 [PubMed - as supplied by publisher]



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Transfer learning for biomedical named entity recognition with neural networks.

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Transfer learning for biomedical named entity recognition with neural networks.

Bioinformatics. 2018 Jun 01;:

Authors: Giorgi JM, Bader GD

Abstract
Motivation: The explosive increase of biomedical literature has made information extraction an increasingly important tool for biomedical research. A fundamental task is the recognition of biomedical named entities in text (BNER) such as genes/proteins, diseases, and species. Recently, a domain-independent method based on deep learning and statistical word embeddings, called long short-term memory network-conditional random field (LSTM-CRF), has been shown to outperform state-of-the-art entity-specific BNER tools. However, this method is dependent on gold-standard corpora (GSCs) consisting of hand-labeled entities, which tend to be small but highly reliable. An alternative to GSCs are silver-standard corpora (SSCs), which are generated by harmonizing the annotations made by several automatic annotation systems. SSCs typically contain more noise than GSCs but have the advantage of containing many more training examples. Ideally, these corpora could be combined to achieve the benefits of both, which is an opportunity for transfer learning. In this work, we analyze to what extent transfer learning improves upon state-of-the-art results for BNER.
Results: We demonstrate that transferring a deep neural network (DNN) trained on a large, noisy SSC to a smaller, but more reliable GSC significantly improves upon state-of-the-art results for BNER. Compared to a state-of-the-art baseline evaluated on 23 GSCs covering four different entity classes, transfer learning results in an average reduction in error of approximately 11%. We found transfer learning to be especially beneficial for target data sets with a small number of labels (approximately 6000 or less).
Availability and implementation: Source code for the LSTM-CRF is available athttps://github.com/Franck-Dernoncourt/NeuroNER/ and links to the corpora are available athttps://github.com/BaderLab/Transfer-Learning-BNER-Bioinformatics-2018/.
Contact: john.giorgi@utoronto.ca.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29868832 [PubMed - as supplied by publisher]



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Modulating cell state to enhance suspension expansion of human pluripotent stem cells.

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Modulating cell state to enhance suspension expansion of human pluripotent stem cells.

Proc Natl Acad Sci U S A. 2018 Jun 04;:

Authors: Lipsitz YY, Woodford C, Yin T, Hanna JH, Zandstra PW

Abstract
The development of cell-based therapies to replace missing or damaged tissues within the body or generate cells with a unique biological activity requires a reliable and accessible source of cells. Human pluripotent stem cells (hPSC) have emerged as a strong candidate cell source capable of extended propagation in vitro and differentiation to clinically relevant cell types. However, the application of hPSC in cell-based therapies requires overcoming yield limitations in large-scale hPSC manufacturing. We explored methods to convert hPSC to alternative states of pluripotency with advantageous bioprocessing properties, identifying a suspension-based small-molecule and cytokine combination that supports increased single-cell survival efficiency, faster growth rates, higher densities, and greater expansion than control hPSC cultures. ERK inhibition was found to be essential for conversion to this altered state, but once converted, ERK inhibition led to a loss of pluripotent phenotype in suspension. The resulting suspension medium formulation enabled hPSC suspension yields 5.7 ± 0.2-fold greater than conventional hPSC in 6 d, for at least five passages. Treated cells remained pluripotent, karyotypically normal, and capable of differentiating into all germ layers. Treated cells could also be integrated into directed differentiated strategies as demonstrated by the generation of pancreatic progenitors (NKX6.1+/PDX1+ cells). Enhanced suspension-yield hPSC displayed higher oxidative metabolism and altered expression of adhesion-related genes. The enhanced bioprocess properties of this alternative pluripotent state provide a strategy to overcome cell manufacturing limitations of hPSC.

PMID: 29866848 [PubMed - as supplied by publisher]



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The role of biomaterials in overcoming barriers to regeneration in the central nervous system.

The role of biomaterials in overcoming barriers to regeneration in the central nervous system.

Biomed Mater. 2018 Jun 04;13(5):050201

Authors: Führmann T, Shoichet MS

PMID: 29864020 [PubMed - in process]



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Patient Similarity Networks for Precision Medicine.

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Patient Similarity Networks for Precision Medicine.

J Mol Biol. 2018 May 31;:

Authors: Pai S, Bader GD

Abstract
Clinical research and practice in the 21st century is poised to be transformed by analysis of computable electronic medical records and population-level genome-scale patient profiles. Genomic data captures genetic and environmental state, providing information about heterogeneity in disease and treatment outcome, but genomic-based clinical risk scores are limited. Achieving the goal of routine precision medicine that takes advantage of this rich genomics data will require computational methods that support heterogeneous data, have excellent predictive performance, and ideally, provide biologically-interpretable results. Traditional machine-learning approaches excel at performance, but often have limited interpretability. Patient similarity networks are an emerging paradigm for precision medicine, in which patients are clustered or classified based on their similarities in various features, including genomic profiles. This strategy is analogous to standard medical diagnosis, has excellent performance, is interpretable, and can preserve patient privacy. We review new methods based on patient similarity networks, including Similarity Network Fusion for patient clustering and netDx for patient classification. While these methods are already useful, much work is required to improve their scalability for contemporary genetic cohorts, optimize parameters, and incorporate a wide range of genomics and clinical data. The coming five years will provide an opportunity to assess the utility of network-based algorithms for precision medicine.

PMID: 29860027 [PubMed - as supplied by publisher]



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Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells.

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Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells.

Mol Ther Nucleic Acids. 2018 Jun 01;11:518-527

Authors: Arnold AE, Malek-Adamian E, Le PU, Meng A, Martínez-Montero S, Petrecca K, Damha MJ, Shoichet MS

Abstract
Glioblastoma stem cells (GSCs) are invasive, treatment-resistant brain cancer cells that express downregulated in renal cell carcinoma (DRR), also called FAM107A, a genetic driver of GSC invasion. We developed antibody-antisense oligonucleotide (AON) conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the GSCs, such as CD44 and EphA2, conjugated to chemically modified AONs against DRR/FAM107A, which were designed as chimeras of DNA and 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) for increased nuclease stability and mRNA affinity. We demonstrate that these therapeutic conjugates successfully internalize, accumulate, and reduce DRR/FAM107A expression in patient-derived GSCs. This is the first example of an antibody-antisense strategy against cancer stem cells.

PMID: 29858087 [PubMed]



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Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials.

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Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials.

NPJ Prim Care Respir Med. 2018 May 24;28(1):18

Authors: D'Urzo A, Bader G, Shen S, Goyal P, Altman P

Abstract
Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George's Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.

PMID: 29795478 [PubMed - in process]



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Construction of Synthetic Phage Displayed Fab Library with Tailored Diversity.

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Construction of Synthetic Phage Displayed Fab Library with Tailored Diversity.

J Vis Exp. 2018 May 01;(135):

Authors: Huang G, Zhong Z, Miersch S, Sidhu SS, Hou SC, Wu D

Abstract
Demand for monoclonal antibodies (mAbs) in basic research and medicine is increasing yearly. Hybridoma technology has been the dominant method for mAb development since its first report in 1975. As an alternative technology, phage display methods for mAb development are increasingly attractive since Humira, the first phage-derived antibody and one of the best-selling mAbs, was approved for clinical treatment of rheumatoid arthritis in 2002. As a non-animal based mAb development technology, phage display bypasses antigen immunogenicity, humanization, and animal maintenance that are required from traditional hybridoma technology based antibody development. In this protocol, we describe a method for construction of synthetic phage-displayed Fab libraries with diversities of 109-1010 obtainable with a single electroporation. This protocol consists of: 1) high-efficiency electro-competent cell preparation; 2) extraction of uracil-containing single-stranded DNA (dU-ssDNA); 3) Kunkel's method based oligonucleotide-directed mutagenesis; 4) electroporation and calculation of library size; 5) protein A/L-based enzyme-linked immunosorbent assay (ELISA) for folding and functional diversity evaluation; and 6) DNA sequence analysis of diversity.

PMID: 29782009 [PubMed - in process]



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Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies.

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Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies.

J Mol Biol. 2018 May 17;:

Authors: Nelson B, Adams J, Kuglstatter A, Li Z, Harris SF, Liu Y, Bohini S, Ma H, Klumpp K, Gao J, Sidhu SS

Abstract
Hepatitis C viral infection is the major cause of chronic hepatitis that affects as many as 71 million people worldwide. Rather than target the rapidly shifting viruses and their numerous serotypes, four independent antibodies were made to target the host antigen CD81 and were shown to block Hepatitis C viral entry. The single-chain variable fragment of each antibody was crystallized in complex with the CD81 large extracellular loop (LEL) in order to guide affinity maturation of two distinct antibodies by phage display. Affinity maturation of antibodies using phage display has proven to be critical to therapeutic antibody development and typically involves modification of the paratope for increased affinity, improved specificity, enhanced stability or a combination of these traits. One antibody was engineered for increased affinity for human CD81 LEL that equated to increased efficacy while the second antibody was engineered for cross-reactivity with cynomolgus CD81 to facilitate animal model testing. The use of structures to guide affinity maturation library design demonstrates the utility of combining structural analysis with phage display technologies.

PMID: 29778602 [PubMed - as supplied by publisher]



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