Between 1995 and 1996, the Annette and Irwin Eskind Biomedical Library (EBL) at Vanderbilt University Medical Center (VUMC) radically revised the model of service it provides to the VUMC community. ...An in-depth training program was developed for librarians, who began to migrate to clinical settings and establish clinical librarianship and information brokerage services beyond the library's walls. To ensure that excellent service would continue within the library, EBL's training program was adapted for library assistants, providing them with access to information about a wide variety of work roles and processes over a four to eight-month training period. Concurrently, customer service areas were reorganized so that any question--whether reference or circulation--could be answered at any of four service points, eliminating the practice of passing customers from person to person between the reference and circulation desks. To provide an incentive for highly trained library assistants to remain at EBL, management and library assistants worked together to redesign the career pathway based on defined stages of achievement, self-directed participation in library-wide projects, and demonstrated commitment to lifelong learning. Education and training were the fundamental principles at the center of all this activity.
We present time-of-arrival (TOA) measurements and timing models of 47 millisecond pulsars observed from 2004 to 2017 at the Arecibo Observatory and the Green Bank Telescope by the North American ...Nanohertz Observatory for Gravitational Waves (NANOGrav). The observing cadence was three to four weeks for most pulsars over most of this time span, with weekly observations of six sources. These data were collected for use in low-frequency gravitational wave searches and for other astrophysical purposes. We detail our observational methods and present a set of TOA measurements, based on "narrowband" analysis, in which many TOAs are calculated within narrow radio-frequency bands for data collected simultaneously across a wide bandwidth. A separate set of "wideband" TOAs will be presented in a companion paper. We detail a number of methodological changes, compared to our previous work, which yield a cleaner and more uniformly processed data set. Our timing models include several new astrometric and binary pulsar measurements, including previously unpublished values for the parallaxes of PSRs J1832−0836 and J2322+2057, the secular derivatives of the projected semimajor orbital axes of PSRs J0613−0200 and J2229+2643, and the first detection of the Shapiro delay in PSR J2145−0750. We report detectable levels of red noise in the time series for 14 pulsars. As a check on timing model reliability, we investigate the stability of astrometric parameters across data sets of different lengths. We also report flux density measurements for all pulsars observed. Searches for stochastic and continuous gravitational waves using these data will be subjects of forthcoming publications.
We present a new analysis of the profile data from the 47 millisecond pulsars comprising the 12.5 yr data set of the North American Nanohertz Observatory for Gravitational Waves, which is presented ...in a parallel paper (Alam et al., hereafter NG12.5). Our reprocessing is performed using "wideband" timing methods, which use frequency-dependent template profiles, simultaneous time-of-arrival (TOA) and dispersion measure (DM) measurements from broadband observations, and novel analysis techniques. In particular, the wideband DM measurements are used to constrain the DM portion of the timing model. We compare the ensemble timing results to those in NG12.5 by examining the timing residuals, timing models, and noise-model components. There is a remarkable level of agreement across all metrics considered. Our best-timed pulsars produce encouragingly similar results to those from NG12.5. In certain cases, such as high-DM pulsars with profile broadening or sources that are weak and scintillating, wideband timing techniques prove to be beneficial, leading to more precise timing model parameters by 10%-15%. The high-precision, multiband measurements of several pulsars indicate frequency-dependent DMs. Compared to the narrowband analysis in NG12.5, the TOA volume is reduced by a factor of 33, which may ultimately facilitate computational speed-ups for complex pulsar timing array analyses. This first wideband pulsar timing data set is a stepping stone, and its consistent results with NG12.5 assure us that such data sets are appropriate for gravitational wave analyses.
Thrombospondin (Thbs) proteins are induced in sites of tissue damage or active remodeling. The endoplasmic reticulum (ER) stress response is also prominently induced with disease where it regulates ...protein production and resolution of misfolded proteins. Here we describe a function for Thbs as ER-resident effectors of an adaptive ER stress response. Thbs4 cardiac-specific transgenic mice were protected from myocardial injury, whereas Thbs4−/− mice were sensitized to cardiac maladaptation. Thbs induction produced a unique profile of adaptive ER stress response factors and expansion of the ER and downstream vesicles. Thbs bind the ER lumenal domain of activating transcription factor 6α (Atf6α) to promote its nuclear shuttling. Thbs4−/− mice showed blunted activation of Atf6α and other ER stress-response factors with injury, and Thbs4-mediated protection was lost upon Atf6α deletion. Hence, Thbs can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Atf6α.
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► Thrombospondin proteins reside in the ER to regulate an adaptive ER stress response ► Thbs4 protects the heart from disease after MI injury or protein misfolding ► Thbs4 functions by inducing Atf6α shuttling and nuclear accumulation ► Thrombospondin proteins integrate ER function with ECM protein remodeling in disease
Although typically considered to function as secreted proteins, thrombospondin proteins also reside in the ER where they can directly regulate an adaptive ER stress response and protect the heart from myocardial infarction injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We describe a rapid target enrichment method for next-generation sequencing, termed anchored multiplex PCR (AMP), that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded ...(FFPE) specimens. AMP is effective in detecting gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions and copy number changes. Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity (95% confidence limit: 96.5-100%) and 100% specificity (95% confidence limit: 99.3-100%) compared with reference assays. On the basis of our experience with performing AMP on 986 clinical FFPE samples, we show its potential as both a robust clinical assay and a powerful discovery tool, which we used to identify new therapeutically important gene fusions: ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma, MSN-ROS1, TRIM4-BRAF, VAMP2-NRG1, TPM3-NTRK1 and RUFY2-RET in lung cancer, FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma. AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Despite their limited spatial extent, freshwater ecosystems host remarkable biodiversity, including one-third of all vertebrate species. This biodiversity is declining dramatically: Globally, ...wetlands are vanishing three times faster than forests, and freshwater vertebrate populations have fallen more than twice as steeply as terrestrial or marine populations. Threats to freshwater biodiversity are well documented but coordinated action to reverse the decline is lacking. We present an Emergency Recovery Plan to bend the curve of freshwater biodiversity loss. Priority actions include accelerating implementation of environmental flows; improving water quality; protecting and restoring critical habitats; managing the exploitation of freshwater ecosystem resources, especially species and riverine aggregates; preventing and controlling nonnative species invasions; and safeguarding and restoring river connectivity. We recommend adjustments to targets and indicators for the Convention on Biological Diversity and the Sustainable Development Goals and roles for national and international state and nonstate actors.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological ...features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe ...asthma is unknown. Objective We sought to evaluate relationships between the bronchial microbiome and features of severe asthma. Methods Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA–based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41). Results In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index ( P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores ( P < .01), sputum total leukocyte values ( P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5) , an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH 2-related epithelial gene expression signature, but expression of TH 17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001). Conclusions Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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