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Computational Biology
Determining Glutathione Levels in Plants
Jul 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Sahoo S, Awasthi JP, Sunkar R, Panda SK
Determining Glutathione Levels in Plants
Jul 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Upon exposure to abiotic stresses, plants tend to accumulate excessive amounts of reactive oxygen species (ROS) that inturn react with cellular lipids, proteins, and DNA. Therefore, decreasing ROS accumulation is indispensible to survive under stress, which is accomplished by inducing enzymatic and nonenzymatic antioxidant defense pathways. Glutathione, particularly reduced glutathione (GSH), represents a principal anitioxidant that could decrease ROS through scavenging them directly or indirectly through ascorbate-glutathione cycle or GSH peroxidases. Glutathione content can be determined using HPLC or spectrophotometric assays. In this chapter, we provided detailed assays to determine total, reduced, and oxidized gluathione using spectrophotometric method.
Benchmarking density functional tight binding models for barrier heights and reaction energetics of organic molecules
Jul 24, 2017   Journal Of Computational Chemistry
Gruden M, Andjeklović L, Jissy AK, Stepanović S, Zlatar M, Cui Q, Elstner M
Benchmarking density functional tight binding models for barrier heights and reaction energetics of organic molecules
Jul 24, 2017
Journal Of Computational Chemistry
Density Functional Tight Binding (DFTB) models are two to three orders of magnitude faster than ab initio and Density Functional Theory (DFT) methods and therefore are particularly attractive in applications to large molecules and condensed phase systems. To establish the applicability of DFTB models to general chemical reactions, we conduct benchmark calculations for barrier heights and reaction energetics of organic molecules using existing databases and several new ones compiled in this study. Structures for the transition states and stable species have been fully optimized at the DFTB level, making it possible to characterize the reliability of DFTB models in a more thorough fashion compared to conducting single point energy calculations as done in previous benchmark studies. The encouraging results for the diverse sets of reactions studied here suggest that DFTB models, especially the most recent third-order version (DFTB3/3OB augmented with dispersion correction), in most cases provide satisfactory description of organic chemical reactions with accuracy almost comparable to popular DFT methods with large basis sets, although larger errors are also seen for certain cases. Therefore, DFTB models can be effective for mechanistic analysis (e.g., transition state search) of large (bio)molecules, especially when coupled with single point energy calculations at higher levels of theory. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
miR-26a/b Inhibit Tumor Growth and Angiogenesis by Targeting the HGF-VEGF Axis in Gastric Carcinoma
Jul 24, 2017   Cellular Physiology And Biochemistry : International Journal Of Experimental Cellular Physiology, Biochemistry, And Pharmacology
Si Y, Zhang H, Ning T, Bai M, Wang Y, Yang H, Wang X, Li J, Ying G, Ba Y
miR-26a/b Inhibit Tumor Growth and Angiogenesis by Targeting the HGF-VEGF Axis in Gastric Carcinoma
Jul 24, 2017
Cellular Physiology And Biochemistry : International Journal Of Experimental Cellular Physiology, Biochemistry, And Pharmacology
Abnormal expression of HGF is found in various cancers and correlates with tumor proliferation, metastasis and angiogenesis. However, the regulatory mechanism of the HGF-VEGF axis remains unclear. The expression characteristic of HGF in human gastric cancer tissues was shown by an immunohistochemistry assay, and the expression levels of target protein were detected by Western blot. The relative levels of miR-26a/b and target mRNA were examined by qRT-PCR. We used bioinformatics tools to search for miRNAs that can potentially target HGF. A luciferase assay was used to confirm direct targeting. Furthermore, the functions of miR-26a/b and HGF were evaluated by cell proliferation and migration assays in vitro and by the mouse xenograft tumor model in vivo. We found that the HGF protein was clearly increased while miR-26a/b were dramatically down-regulated in gastric cancer. miR-26a/b directly bind to the 3'-UTR of HGF mRNA at specific targeting sites. We demonstrated that the repression of the HGF-VEGF pathway by miR-26a/b overexpression suppressed gastric cancer cell proliferation and migration. Furthermore, miR-26a/b also showed an anti-tumor effect in the xenograft mouse model by suppressing tumor growth and angiogenesis. miR-26a/b could suppress tumor tumorigenesis and angiogenesis by targeting the HGF-VEGF axis and could serve as a potential treatment modality for targeted therapy in the clinical treatment of gastric cancer. © 2017 The Author(s). Published by S. Karger AG, Basel.
A preliminary study on the effects of lanthanum (III) on plant vitronectin-like protein and its toxicological basis
Jul 24, 2017   Ecotoxicology And Environmental Safety
Wang L, He J, Yang Q, Li X, Wei H, Chen DDY, Huang X
A preliminary study on the effects of lanthanum (III) on plant vitronectin-like protein and its toxicological basis
Jul 24, 2017
Ecotoxicology And Environmental Safety
Vitronectin-like protein (VN) is widely found outside plant plasma membranes. The VN molecular surface contains a large number of active groups that combine strongly with rare earth elements (REEs), which means that VN is a preferential binding target for REEs exhibiting their toxic effects, but the toxicological mechanism remains unknown. This study used transmission electron microscopy, circular dichroism, fluorescence spectrometry, ultraviolet-visible spectroscopy, X-ray photoelectron spectroscopy, and calculational chemistry (homology modeling, molecular dynamics simulation and quantum chemical calculation) to preliminarily investigate the effect of lanthanum [La(III)] as an REE, on the structure of VN and its toxicological mechanism. The results showed that low-concentration La(III) could cause micro-interference to the VN molecular structure through weak interactions, such as electrostatic attraction. High-concentration La(III) formed stable complexes with VN, which changed the average binding energy and electron cloud density of VN, loosened the molecular structure and increased the disorder of VN molecule. The results of building a 3D model of VN and simulating the interaction between La(III) and VN using calculational chemistry showed that La(H2O)73+ in solution could coordinately bind to the carboxyl-/carbonyl-O groups in the negatively charged areas on the VN molecular surface. Furthermore, one or more strong H-bonds were formed to enhance the stability of the La(H2O)73+-VN complexes. In summary, low La(III) concentrations could cause micro-interference to the VN molecular structure, whereas high La(III) concentrations could coordinately bind to VN to form stable La-VN complexes, which destroyed the molecular structure of VN; thus the toxicological basis by which La(III) exhibits its toxic effects is its binding to VN. Copyright © 2017 Elsevier Inc. All rights reserved.
Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport
Jul 24, 2017   JAMA Neurology
Kunkle BW, Vardarajan BN, Naj AC, Whitehead PL, Rolati S,   . . . . . .   , Beecham GW, Martin ER, Schellenberg GD, Mayeux RP, Pericak-Vance MA
Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport
Jul 24, 2017
JAMA Neurology
Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. To search for rare variants contributing to the risk for EOAD. In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset 65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129). The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.
Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center
Jul 24, 2017   PloS One
McDonnell SL, Baggerly KA, Baggerly CA, Aliano JL, French CB, Baggerly LL, Ebeling MD, Rittenberg CS, Goodier CG, Mateus Niño JF, Wineland RJ, Newman RB, Hollis BW, Wagner CL
Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center
Jul 24, 2017
PloS One
Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new standard of care for pregnant women to receive vitamin D testing and supplementation. To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population. Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016. During this time, a protocol that included 25(OH)D testing at first prenatal visit with recommended follow-up testing was initiated. Free vitamin D supplements were offered and the treatment goal was ≥40 ng/mL. PTB rates (
ARID1A-mutated ovarian cancers depend on HDAC6 activity
Jul 24, 2017   Nature Cell Biology Add nature.com free-link Cancel
Bitler BG, Wu S, Park PH, Hai Y, Aird KM,   . . . . . .   , Huntsman DG, Conejo-Garcia JR, Cho KR, Christianson DW, Zhang R
ARID1A-mutated ovarian cancers depend on HDAC6 activity
Jul 24, 2017
Nature Cell Biology
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
Angular Rate Sensing with GyroWheel Using Genetic Algorithm Optimized Neural Networks
Jul 24, 2017   Sensors (Basel, Switzerland)
Zhao Y, Zhao H, Huo X, Yao Y
Angular Rate Sensing with GyroWheel Using Genetic Algorithm Optimized Neural Networks
Jul 24, 2017
Sensors (Basel, Switzerland)
GyroWheel is an integrated device that can provide three-axis control torques and two-axis angular rate sensing for small spacecrafts. Large tilt angle of its rotor and de-tuned spin rate lead to a complex and non-linear dynamics as well as difficulties in measuring angular rates. In this paper, the problem of angular rate sensing with the GyroWheel is investigated. Firstly, a simplified rate sensing equation is introduced, and the error characteristics of the method are analyzed. According to the analysis results, a rate sensing principle based on torque balance theory is developed, and a practical way to estimate the angular rates within the whole operating range of GyroWheel is provided by using explicit genetic algorithm optimized neural networks. The angular rates can be determined by the measurable values of the GyroWheel (including tilt angles, spin rate and torque coil currents), the weights and the biases of the neural networks. Finally, the simulation results are presented to illustrate the effectiveness of the proposed angular rate sensing method with GyroWheel.
Diffuse large B cell lymphoma cell of origin by digital expression profiling in the REAL07 Phase 1-2 study
Jul 24, 2017   British Journal Of Haematology
Cascione L, Rinaldi A, Chiappella A, Kwee I, Ciccone G, Altenbuchinger M, Kohler C, Vitolo U, Inghirami G, Bertoni F
Bioinformatics Analysis in Menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells
Jul 24, 2017   Cell Biology International
Li C, Wang Y, Luan H, Zhang H, Xu Y
Bioinformatics Analysis in Menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells
Jul 24, 2017
Cell Biology International
We read with great interest the recent report by Semeghini et al., "Menopause transition promotes distinct modulation of mRNAs and miRNAs expression in calvaria and bone marrow osteoblastic cells," which appeared on 24 May 2017 in Cell Biology International. The results of the report are very helpful for us, however, from our perspective, the author's methods in bioinformatics analysis is inappropriate: Student's t-tests is an inappropriate statistical method for detecting differentially expressed mRNA or miRNA in osteoblastic cells from calvaria of ovariectomized rats compared to control or in osteoblastic cells from bone marrow of ovariectomized rats compared to control. This article is protected by copyright. All rights reserved.
Natural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival
Jul 24, 2017   Nature Communications
Buscher K, Ehinger E, Gupta P, Pramod AB, Wolf D, Tweet G, Pan C, Mills CD, Lusis AJ, Ley K
Natural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival
Jul 24, 2017
Nature Communications
Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12β and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings.
Genetic variants in HSD17B3, SMAD3, and IPO11 impact circulating lipids in response to fenofibrate in individuals with type 2 diabetes
Jul 24, 2017   Clinical Pharmacology And Therapeutics
Rotroff DM, Pijut SS, Marvel SW, Jack JR, Havener TM,   . . . . . .   , McLeod HL, Buse JB, Wagner MJ, Motsinger-Reif AA, ACCORD/ACCORDion Investigators.
Genetic variants in HSD17B3, SMAD3, and IPO11 impact circulating lipids in response to fenofibrate in individuals with type 2 diabetes
Jul 24, 2017
Clinical Pharmacology And Therapeutics
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated T2D patients, we examined lipid changes in response to fenofibrate therapy using genome-wide association(GWA). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects(p
Feedback-Driven Sensory Mapping Adaptation for Robust Speech Activity Detection
Jul 24, 2017   IEEE/ACM Transactions On Audio, Speech, And Language Processing
Bellur A, Elhilali M
Feedback-Driven Sensory Mapping Adaptation for Robust Speech Activity Detection
Jul 24, 2017
IEEE/ACM Transactions On Audio, Speech, And Language Processing
Parsing natural acoustic scenes using computational methodologies poses many challenges. Given the rich and complex nature of the acoustic environment, data mismatch between train and test conditions is a major hurdle in data-driven audio processing systems. In contrast, the brain exhibits a remarkable ability at segmenting acoustic scenes with relative ease. When tackling challenging listening conditions that are often faced in everyday life, the biological system relies on a number of principles that allow it to effortlessly parse its rich soundscape. In the current study, we leverage a key principle employed by the auditory system: its ability to adapt the neural representation of its sensory input in a high-dimensional space. We propose a framework that mimics this process in a computational model for robust speech activity detection. The system employs a 2-D Gabor filter bank whose parameters are retuned offline to improve the separability between the feature representation of speech and nonspeech sounds. This retuning process, driven by feedback from statistical models of speech and nonspeech classes, attempts to minimize the misclassification risk of mismatched data, with respect to the original statistical models. We hypothesize that this risk minimization procedure results in an emphasis of unique speech and nonspeech modulations in the high-dimensional space. We show that such an adapted system is indeed robust to other novel conditions, with a marked reduction in equal error rates for a variety of databases with additive and convolutive noise distortions. We discuss the lessons learned from biology with regard to adapting to an ever-changing acoustic environment and the impact on building truly intelligent audio processing systems.
Microsphere-Based Assessment of DNA Methylation for AML Prognosis
Jul 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Wertheim GBW, Luskin MR, Carroll M, Master SR
Microsphere-Based Assessment of DNA Methylation for AML Prognosis
Jul 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Epigenetic dysregulation, including aberrant methylation of cytosine residues in DNA, is a hallmark of cancer and clearly results in oncogenic cellular alterations such as transcriptional attenuation of tumor suppressors and genomic instability. A number of studies have examined DNA methylation alterations in patients with acute myeloid leukemia (AML) and have shown that analysis of multilocus methylation patterns can identify biologically distinct AML subclasses and can predict patient prognosis. In order to utilize the prognostic capability of methylation analysis in a clinical setting, we have developed a microsphere-based HpaII tiny fragment enrichment by ligation-mediated PCR (xMELP) assay to interrogate the methylation state of genomic multiple loci along with a random forest-based classification algorithm that correlates DNA methylation status with patient prognosis. These tools can be easily implemented in a clinical molecular pathology laboratory and can be utilized for more accurate risk stratification of AML patients.
Detection theory for accurate and non-invasive skin cancer diagnosis using dynamic thermal imaging
Jul 24, 2017   Biomedical Optics Express
Godoy SE, Hayat MM, Ramirez DA, Myers SA, Padilla RS, Krishna S
Detection theory for accurate and non-invasive skin cancer diagnosis using dynamic thermal imaging
Jul 24, 2017
Biomedical Optics Express
Skin cancer is the most common cancer in the United States with over 3.5M annual cases. Presently, visual inspection by a dermatologist has good sensitivity (> 90%) but poor specificity (< 10%), especially for melanoma, which leads to a high number of unnecessary biopsies. Here we use dynamic thermal imaging (DTI) to demonstrate a rapid, accurate and non-invasive imaging system for detection of skin cancer. In DTI, the lesion is cooled down and the thermal recovery is recorded using infrared imaging. The thermal recovery curves of the suspected lesions are then utilized in the context of continuous-time detection theory in order to define an optimal statistical decision rule such that the sensitivity of the algorithm is guaranteed to be at a maximum for every prescribed false-alarm probability. The proposed methodology was tested in a pilot study including 140 human subjects demonstrating a sensitivity in excess of 99% for a prescribed specificity in excess of 99% for detection of skin cancer. To the best of our knowledge, this is the highest reported accuracy for any non-invasive skin cancer diagnosis method.
Handheld optical coherence tomography angiography
Jul 24, 2017   Biomedical Optics Express
Yang J, Liu L, Campbell JP, Huang D, Liu G
Handheld optical coherence tomography angiography
Jul 24, 2017
Biomedical Optics Express
We developed a handheld optical coherence tomography angiography (OCTA) system using a 100-kHz swept-source laser. The handheld probe weighs 0.4 kg and measures 20.6 × 12.8 × 4.6 cm3. The system has dedicated features for handheld operation. The probe is equipped with a mini iris camera for easy alignment. Real-time display of the en face OCT and cross-sectional OCT images in the system allows accurately locating the imaging target. Fast automatic focusing was achieved by an electrically tunable lens controlled by a golden-section search algorithm. An extended axial imaging range of 6 mm allows easy alignment. A registration algorithm using cross-correlation to register adjacent OCT B-frames with propagation from the central frame was used to effectively minimize motion artifacts in volumetric OCTA images captured in relatively short durations of 1 and 2.1 seconds. 2.5 × 2.5 mm (200 × 200 pixels) and 3.5 × 3.5 mm (300 × 300 pixels) retinal angiograms were demonstrated on two awake adult human subjects without the use of any mydriatic eye drops.
Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells
Jul 24, 2017   Frontiers In Immunology
Zayoud M, Marcu-Malina V, Vax E, Jacob-Hirsch J, Elad-Sfadia G, Barshack I, Kloog Y, Goldstein I
Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells
Jul 24, 2017
Frontiers In Immunology
The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti-rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven in vivo induction of Th17 and IL-17/IFN-γ producing "double positive" as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4+ T cells from CFA-immunized rats, re-stimulated in vitro with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g., Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In conclusion, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA.
TFOS DEWS II Management and Therapy Report
Jul 24, 2017   The Ocular Surface
Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R,   . . . . . .   , Tauber J, Wakamatsu TH, Xu J, Wolffsohn JS, Craig JP
TFOS DEWS II Management and Therapy Report
Jul 24, 2017
The Ocular Surface
The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype. Copyright © 2017 Elsevier Inc. All rights reserved.
Differential Connectivity of Gene Regulatory Networks Distinguishes Corticosteroid Response in Asthma
Jul 24, 2017   The Journal Of Allergy And Clinical Immunology
Qiu W, Guo F, Glass K, Guo Cheng Yuan , Quackenbush J, Zhou X, Tantisira KG
Differential Connectivity of Gene Regulatory Networks Distinguishes Corticosteroid Response in Asthma
Jul 24, 2017
The Journal Of Allergy And Clinical Immunology
Variations in drug response between individuals have prevented us from achieving high drug efficacy in treating many complex diseases, including asthma. Genetics plays an important role in accounting for such inter-individual variations in drug response. However, systematic approaches for addressing how genetic factors and their regulators determine variations in drug response in asthma treatment are lacking. We used PANDA (Passing Attributes between Networks for Data Assimilations) to construct the gene regulatory networks associated with good responders and poor responders to inhaled corticosteroids based on a subset of 145 Caucasian asthmatic children who participated in the Childhood Asthma Management Cohort (CAMP). PANDA utilizes gene expression profiles and published relationships among genes, transcription factors (TFs), and proteins to construct the directed networks of TFs and genes. We assessed the differential connectivity between the gene regulatory network of good responders vs. that of poor responders. When compared to poor responders, the network of good responders has differential connectivity and distinct ontologies (e.g., pro-apoptosis enriched in network of good responders and anti-apoptosis enriched in network of poor responders). Many of the key hubs identified in conjunction with clinical response are also cellular response hubs. Functional validation demonstrated abrogation of differences in corticosteroid treated cell viability following siRNA knockdown of two TFs and differential downstream expression between good-responders and poor-responders. We have identified and validated multiple transcription factors influencing asthma treatment response. Our results show that differential connectivity analysis can provide new insights into the heterogeneity of drug treatment effects. Copyright © 2017. Published by Elsevier Inc.
Genome-wide Single-Molecule Footprinting Reveals High RNA Polymerase II Turnover at Paused Promoters
Jul 24, 2017   Molecular Cell
Krebs AR, Imanci D, Hoerner L, Gaidatzis D, Burger L, Schübeler D
Genome-wide Single-Molecule Footprinting Reveals High RNA Polymerase II Turnover at Paused Promoters
Jul 24, 2017
Molecular Cell
Transcription initiation entails chromatin opening followed by pre-initiation complex formation and RNA polymerase II recruitment. Subsequent polymerase elongation requires additional signals, resulting in increased residence time downstream of the start site, a phenomenon referred to as pausing. Here, we harnessed single-molecule footprinting to quantify distinct steps of initiation in vivo throughout the Drosophila genome. This identifies the impact of promoter structure on initiation dynamics in relation to nucleosomal occupancy. Additionally, perturbation of transcriptional initiation reveals an unexpectedly high turnover of polymerases at paused promoters-an observation confirmed at the level of nascent RNAs. These observations argue that absence of elongation is largely caused by premature termination rather than by stable polymerase stalling. In support of this non-processive model, we observe that induction of the paused heat shock promoter depends on continuous initiation. Our study provides a framework to quantify protein binding at single-molecule resolution and refines concepts of transcriptional pausing. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Enhanced Energetic State and Protection from Oxidative Stress in Human Myoblasts Overexpressing BMI1
Jul 24, 2017   Stem Cell Reports
Dibenedetto S, Niklison-Chirou M, Cabrera CP, Ellis M, Robson LG, Knopp P, Tedesco FS, Ragazzi M, Di Foggia V, Barnes MR, Radunovic A, Marino S
Enhanced Energetic State and Protection from Oxidative Stress in Human Myoblasts Overexpressing BMI1
Jul 24, 2017
Stem Cell Reports
The Polycomb group gene BMI1 is essential for efficient muscle regeneration in a mouse model of Duchenne muscular dystrophy, and its enhanced expression in adult skeletal muscle satellite cells ameliorates the muscle strength in this model. Here, we show that the impact of mild BMI1 overexpression observed in mouse models is translatable to human cells. In human myoblasts, BMI1 overexpression increases mitochondrial activity, leading to an enhanced energetic state with increased ATP production and concomitant protection against DNA damage both in vitro and upon xenografting in a severe dystrophic mouse model. These preclinical data in mouse models and human cells provide a strong rationale for the development of pharmacological approaches to target BMI1-mediated mitochondrial regulation and protection from DNA damage to sustain the regenerative potential of the skeletal muscle in conditions of chronic muscle wasting. Copyright © 2017. Published by Elsevier Inc.
Modeling RNA Secondary Structure with Sequence Comparison and Experimental Mapping Data
Jul 24, 2017   Biophysical Journal
Tan Z, Sharma G, Mathews DH
Modeling RNA Secondary Structure with Sequence Comparison and Experimental Mapping Data
Jul 24, 2017
Biophysical Journal
Secondary structure prediction is an important problem in RNA bioinformatics because knowledge of structure is critical to understanding the functions of RNA sequences. Significant improvements in prediction accuracy have recently been demonstrated though the incorporation of experimentally obtained structural information, for instance using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) mapping. However, such mapping data is currently available only for a limited number of RNA sequences. In this article, we present a method for extending the benefit of experimental mapping data in secondary structure prediction to homologous sequences. Specifically, we propose a method for integrating experimental mapping data into a comparative sequence analysis algorithm for secondary structure prediction of multiple homologs, whereby the mapping data benefits not only the prediction for the specific sequence that was mapped but also other homologs. The proposed method is realized by modifying the TurboFold II algorithm for prediction of RNA secondary structures to utilize basepairing probabilities guided by SHAPE experimental data when such data are available. The SHAPE-mapping-guided basepairing probabilities are obtained using the RSample method. Results demonstrate that the SHAPE mapping data for a sequence improves structure prediction accuracy of other homologous sequences beyond the accuracy obtained by sequence comparison alone (TurboFold II). The updated version of TurboFold II is freely available as part of the RNAstructure software package. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.
The n→π* Interaction
Jul 24, 2017   Accounts Of Chemical Research
Newberry RW, Raines RT
The n→π* Interaction
Jul 24, 2017
Accounts Of Chemical Research
The carbonyl group holds a prominent position in chemistry and biology not only because it allows diverse transformations but also because it supports key intermolecular interactions, including hydrogen bonding. More recently, carbonyl groups have been found to interact with a variety of nucleophiles, including other carbonyl groups, in what we have termed an n→π* interaction. In an n→π* interaction, a nucleophile donates lone-pair (n) electron density into the empty π* orbital of a nearby carbonyl group. Mixing of these orbitals releases energy, resulting in an attractive interaction. Hints of such interactions were evident in small-molecule crystal structures as early as the 1970s, but not until 2001 was the role of such interactions articulated clearly. These non-covalent interactions were first discovered during investigations into the thermostability of the proline-rich protein collagen, which achieves a robust structure despite a relatively low potential for hydrogen bonding. It was found that by modulating the distance between two carbonyl groups in the peptide backbone, one could alter the conformational preferences of a peptide bond to proline. Specifically, only the trans conformation of a peptide bond to proline allows for an attractive interaction with an adjacent carbonyl group, so when one increases the proximity of the two carbonyl groups, one enhances their interaction and promotes the trans conformation of the peptide bond, which increases the thermostability of collagen. More recently, attention has been paid to the nature of these interactions. Some have argued that rather than resulting from electron donation, carbonyl interactions are a particular example of dipolar interactions that are well-approximated by classical mechanics. However, experimental evidence has demonstrated otherwise. Numerous examples now exist where an increase in the dipole moment of a carbonyl group decreases the strength of its interactions with other carbonyl groups, demonstrating unequivocally that a dipolar mechanism is insufficient to describe these interactions. Rather, these interactions have important quantum-mechanical character that can be evaluated through careful experimental analysis and judicious use of computation. Although individual n→π* interactions are relatively weak (∼0.3-0.7 kcal/mol), the ubiquity of carbonyl groups across chemistry and biology gives the n→π* interaction broad impact. In particular, the n→π* interaction is likely to play an important role in dictating protein structure. Indeed, bioinformatics analysis suggests that approximately one-third of residues in folded proteins satisfy the geometric requirements to engage in an n→π* interaction, which is likely to be of particular importance for the α-helix. Other carbonyl-dense polymeric materials like polyesters and peptoids are also influenced by n→π* interactions, as are a variety of small molecules, some with particular medicinal importance. Research will continue to identify molecules whose conformation and activity are affected by the n→π* interaction and will clarify their specific contributions to the structures of biomacromolecules.
Bioinformatics Data Analysis of Next-Generation Sequencing Data from Heterogeneous Tumor Samples
Jul 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Landman SR, Hwang TH
Bioinformatics Data Analysis of Next-Generation Sequencing Data from Heterogeneous Tumor Samples
Jul 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Tumor heterogeneity is a major challenge when it comes to treating cancer and also complicates research aimed at determining genetic sources for tumorigenesis. Leveraging high-throughput sequencing technology has been an effective approach for advancing our understanding of genetic diseases, and this type of data can also be used to better understand and make inferences about tumor heterogeneity. Here we describe the basics of genomics data analysis, as well as analysis pipelines for investigating tumor heterogeneity with next-generation sequencing data.
Increased Neonatal Respiratory Morbidity Associated with Gestational and Pregestational Diabetes: A Retrospective Study
Jul 24, 2017   American Journal Of Perinatology
Kawakita T, Bowers K, Hazrati S, Zhang C, Grewal J, Chen Z, Sun L, Grantz KL

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