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  • Article
    Kazim ARS, Jiang Y, Li S, He X.
    Microbiol Spectr. 2021 12 22;9(3):e0064421.
    α-Glucan is a major cell wall component and a virulence and adhesion factor for fungal cells. However, the biosynthetic pathway of α-glucan was still unclear. α-Glucan was shown to be composed mainly of 1,3-glycosidically linked glucose, with trace amounts of 1,4-glycosidically linked glucose. Besides the α-glucan synthetases, amylase-like proteins were also important for α-glucan synthesis. In our previous work, we showed that Aspergillus nidulans AmyG was an intracellular protein and was crucial for the proper formation of α-glucan. In the present study, we expressed and purified AmyG in an Escherichia coli system. Enzymatic characterization found that AmyG mainly functioned as an α-amylase that degraded starch into maltose. AmyG also showed weak glucanotransferase activity. Most intriguingly, supplementation with maltose in shaken liquid medium could restore the α-glucan content and the phenotypic defect of a ΔamyG strain. These data suggested that AmyG functions mainly as an intracellular α-amylase to provide maltose during α-glucan synthesis in A. nidulans. IMPORTANCE Short α-1,4-glucan was suggested as the primer structure for α-glucan synthesis. However, the exact structure and its source remain elusive. AmyG was essential to promote α-glucan synthesis and had a major impact on the structure of α-glucan in the cell wall. Data presented here revealed that AmyG belongs to the GH13_5 family and showed strong amylase function, digesting starch into maltose. Supplementation with maltose efficiently rescued the phenotypic defect and α-glucan deficiency in an ΔamyG strain but not in an ΔagsB strain. These results provide the first piece of evidence for the primer structure of α-glucan in fungal cells, although it might be specific to A. nidulans.
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  • Article
    Livingston JA, Hess KR, Naing A, Hong DS, Patel S, Benjamin RS, Ludwig JA, Conley A, Herzog CE, Anderson P, Meric-Bernstam F, Kurzrock R, Subbiah V.
    Oncotarget. 2016 Sep 27;7(39):64421-64430.
    BACKGROUND: We sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival.
    PATIENTS AND METHODS: We retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC's Phase I Clinical Trials Program.
    RESULTS: Ninety-two patients with Ewing sarcoma (N = 47), osteosarcoma (N = 22), chondrosarcoma (N = 16), and other tumors (N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials. The median overall survival (OS) was 8.8 months (95% confidence interval [CI] = 6.8-13.7 months). Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level <10.5 g/dL, platelet count >200 x103/L, creatinine level ≥1.3 mg/dL, and lactate dehydrogenase level >ULN. Patients with good RMH scores (0-1) had longer OS than patients with poor RMH scores (2-3) (HR = 5.8, 95% CI = 2.9-11.0; P < 0.0001), as did patients with low MDACC scores (0-1) as compared to patients with higher MDACC scores (2-4) (HR = 3.2, 95% CI = 1.9-5.6; P < 0.0001).
    CONCLUSION: The RMH prognostic score can be used to predict the OS of bone cancer patients referred for phase I trials. The MDACC score added no value to the RMH score and therefore does not have a role in assessment of patients with bone tumors. Patients with advanced bone sarcomas should be considered for phase I trials.
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  • Article
    Anderson VM, Wendt KL, Najar FZ, McCall LI, Cichewicz RH.
    mSystems. 2021 Oct 26;6(5):e0064421.
    The success of natural product-based drug discovery is predicated on having chemical collections that offer broad coverage of metabolite diversity. We propose a simple set of tools combining genetic barcoding and metabolomics to help investigators build natural product libraries aimed at achieving predetermined levels of chemical coverage. It was found that such tools aided in identifying overlooked pockets of chemical diversity within taxa, which could be useful for refocusing collection strategies. We have used fungal isolates identified as Alternaria from a citizen-science-based soil collection to demonstrate the application of these tools for assessing and carrying out predictive measurements of chemical diversity in a natural product collection. Within Alternaria, different subclades were found to contain nonequivalent levels of chemical diversity. It was also determined that a surprisingly modest number of isolates (195 isolates) was sufficient to afford nearly 99% of Alternaria chemical features in the data set. However, this result must be considered in the context that 17.9% of chemical features appeared in single isolates, suggesting that fungi like Alternaria might be engaged in an ongoing process of actively exploring nature's metabolic landscape. Our results demonstrate that combining modest investments in securing internal transcribed spacer (ITS)-based sequence information (i.e., establishing gene-based clades) with data from liquid chromatography-mass spectrometry (i.e., generating feature accumulation curves) offers a useful route to obtaining actionable insights into chemical diversity coverage trends in a natural product library. It is anticipated that these outcomes could be used to improve opportunities for accessing bioactive molecules that serve as the cornerstone of natural product-based drug discovery. IMPORTANCE Natural product drug discovery efforts rely on libraries of organisms to provide access to diverse pools of compounds. Actionable strategies to rationally maximize chemical diversity, rather than relying on serendipity, can add value to such efforts. Readily implementable biological (i.e., ITS sequence analysis) and chemical (i.e., mass spectrometry-based feature and scaffold measurements) diversity assessment tools can be employed to monitor and adjust library development tactics in real time. In summary, metabolomics-driven technologies and simple gene-based specimen barcoding approaches have broad applicability to building chemically diverse natural product libraries.
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  • Article
    Boothe DL, Cohen AH, Troyer TW.
    PLoS One. 2013;8(5):e64421.
    The motor output for walking is produced by a network of neurons termed the spinal central pattern generator (CPG) for locomotion. The basic building block of this CPG is a half-center oscillator composed of two mutually inhibitory sets of interneurons, each controlling one of the two dominant phases of locomotion: flexion and extension. To investigate symmetry between the two components of this oscillator, we analyzed the statistics of natural variation in timing during fictive locomotion induced by stimulation of the midbrain locomotor region in the cat. As a complement to previously published analysis of these data focused on burst and cycle durations, we present a new analysis examining the strength of phase locking at the transitions between flexion and extension. Across our sample of nerve pairs, phase locking at the transition from extension to flexion (E to F) is stronger than at the transition from flexion to extension (F to E). This pattern did not reverse when considering bouts of fictive locomotion that were flexor vs. extensor dominated, demonstrating that asymmetric locking at the transitions between phases is dissociable from which phase dominates cycle duration. We also find that the strength of phase locking is correlated with the mean latency between burst offset and burst onset. These results are interpreted in the context of a hypothesis where network inhibition and intrinsic oscillatory mechanisms make distinct contributions to flexor-extensor alternation in half-center networks.
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  • Book
    Gregory S. Ogrinc MD, MS, Linda A. Headrick, MD, MS, Amy J. Barton, PhD, RN, FAAN, ANEF, ... Show More Mary A. Dolansky, PhD, RN, FAAN, Wendy S. Madigosky, MD, MSPH, FAAFP, Rebecca S. (Suzie) Miltner, PhD, RN, FAAN, Allyson G. Hall, PhD, MBA/MHS ; foreword by Kedar Mate, MD.
    Summary: Fundamentals of Health Care Improvement: A Guide to Improving Your Patient's Care, 4th edition, is intended to help health professional learners diagnose, measure, analyze, change, and lead improvements in health care, with the aim to shape reliable, high-quality systems of care in partnership with patients. Co-published by Joint Commission Resources and the Institute of Healthcare Improvement, this fourth edition includes updated resources, including examples, figures, tables, and tools. New to this edition is a focus on health equity and disparities of care brought to light by the COVID-19 pandemic. This focus explores the relationship between social determinants of health and how improvement methods and skills can help identify and close disparity gaps in systems of care. Also new to this edition is an expanded discussion of effective teamwork and the importance of creating multidisciplinary health care teams that partner with patients and families. -- Provided by publisher.

    Contents:
    Identifying gaps in quality and working in teams to close those gaps
    Finding scientific evidence for clinical improvement
    Identifying a focus for improvement
    Process literacy, culture, context, and systems in health care
    Measurement part 1: data analysis for decision making in health care
    Measurement part 2: using run charts and statistical process control charts to gain insight into systems
    Understanding and making changes in a system
    Spreading improvements
    Publishing and presenting quality improvement
    Appendix: Tools to help your improvement work.
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