Structure of Frequency-Interacting RNA Helicase from \u3ci\u3eNeurospora crassa\u3c/i\u3e Reveals High Flexibility in a Domain Critical for Circadian Rhythm and RNA Surveillance

The FRH (frequency-interacting RNA helicase) protein is the Neurospora crassa homolog of yeast Mtr4, an essential RNA helicase that plays a central role in RNA metabolism as an activator of the nuclear RNA exosome. FRH is also a required component of the circadian clock, mediating protein interactions that result in the rhythmic repression of gene expression. Here we show that FRH unwinds RNA substrates in vitro with a kinetic profile similar to Mtr4, indicating that while FRH has acquired additional functionality, its core helicase function remains intact. In contrast with the earlier FRH structures, a new crystal form of FRH results in an ATP binding site that is undisturbed by crystal contacts and adopts a conformation consistent with nucleotide binding and hydrolysis. Strikingly, this new FRH structure adopts an arch domain conformation that is dramatically altered from previous structures. Comparison of the existing FRH structures reveals conserved hinge points that appear to facilitate arch motion. Regions in the arch have been previously shown to mediate a variety of protein-protein interactions critical for RNA surveillance and circadian clock functions. The conformational changes highlighted in the FRH structures provide a platform for investigating the relationship between arch dynamics and Mtr4/FRH function

Attributable costs of enterococcal bloodstream infections in a nonsurgical hospital cohort

BACKGROUND: Vancomycin-resistant enterococcal (VRE) bloodstream infections (BSI) are associated with increased morbidity and mortality. OBJECTIVE: To determine the attributable costs of vancomycin-sensitive (VSE) and VRE BSI and the independent impact of vancomycin-resistance on hospital costs. METHODS: A retrospective cohort study was conducted of 21,154 non-surgical patients admitted to an academic medical center between 2002 and 2003. Using administrative data, attributable hospital costs (inflation adjusted to $2007) and length of stay were estimated with multivariate generalized least squares (GLS) models and propensity score matched-pairs. RESULTS: The cohort included 182 VSE and 94 VRE BSI cases. After adjustment for demographics, comorbidities, procedures, non-enterococcal BSI, and early mortality, the attributable costs of VSE BSI were$2,250 (95% confidence interval [CI], $1,758–$2,880) in the standard GLS model and $2,023 (95$1,588–$2,575) in the propensity-score weighted GLS model and the attributable costs of VRE BSI were$4,479 (95% CI, $3,500–$5,732) in the standard GLS model and $4,036 (95$3,170–$5,140) in the propensity-score weighted GLS model. The median of the difference in costs between matched-pairs was$5,282 ($2,042–$8,043) for VSE BSI and $9,949 (95$1,579–$24,693) for VRE BSI. The attributable costs of vancomycin-resistance were$1,713 (95% CI, $1,338–$2,192) in the standard GLS model and $1,546 (95$1,214–$1,968) in the propensity-score weighted GLS model. Attributable length of stay ranged from 1.1–2.2 days for VSE BSI and 2.2–3.5 days for VRE BSI cases. CONCLUSIONS: VSE and VRE BSI were independently associated with hospital costs and length of stay. Vancomycin-resistance was associated with increased costs

An ATP-binding cassette-type cysteine transporter in Campylobacter jejuni inferred from the structure of an extracytoplasmic solute receptor protein

Campylobacter jejuni is a Gram-negative food-borne pathogen associated with gastroenteritis in humans as well as cases of the autoimmune disease Guillain Barre syndrome. C. jejuni is asaccharolytic because it lacks an active glycolytic pathway for the use of sugars as a carbon source. This suggests an increased reliance on amino acids as nutrients and indeed the genome sequence of this organism indicates the presence of a number of amino acid uptake systems. Cj0982, also known as CjaA, is a putative extracytoplasmic solute receptor for one such uptake system as well as a major surface antigen and vaccine candidate. The crystal structure of Cj0982 reveals a two-domain protein with density in the enclosed cavity between the domains that clearly defines the presence of a bound cysteine ligand. Fluorescence titration experiments were used to demonstrate that Cj0982 binds cysteine tightly and specifically with a K-d of similar to 10(-7) M consistent with a role as a receptor for a high- affinity transporter. These data imply that Cj0982 is the binding protein component of an ABC-type cysteine transporter system and that cysteine uptake is important in the physiology of C. jejuni

Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140217/1/sur.2013.9999.pd

The ACS Nearby Galaxy Survey Treasury

The ACS Nearby Galaxy Survey Treasury (ANGST) is a systematic survey to establish a legacy of uniform multi-color photometry of resolved stars for a volume-limited sample of nearby galaxies (D<4 Mpc). The survey volume encompasses 69 galaxies in diverse environments, including close pairs, small & large groups, filaments, and truly isolated regions. The galaxies include a nearly complete range of morphological types spanning a factor of ~10^4 in luminosity and star formation rate. The survey data consists of images taken with ACS on HST, supplemented with archival data and new WFPC2 imaging taken after the failure of ACS. Survey images include wide field tilings covering the full radial extent of each galaxy, and single deep pointings in uncrowded regions of the most massive galaxies in the volume. The new wide field imaging in ANGST reaches median 50% completenesses of m_F475W=28.0 mag, m_F606W=27.3 mag, and m_F814W=27.3 mag, several magnitudes below the tip of the red giant branch (TRGB). The deep fields reach magnitudes sufficient to fully resolve the structure in the red clump. The resulting photometric catalogs are publicly accessible and contain over 34 million photometric measurements of >14 million stars. In this paper we present the details of the sample selection, imaging, data reduction, and the resulting photometric catalogs, along with an analysis of the photometric uncertainties (systematic and random), for both the ACS and WFPC2 imaging. We also present uniformly derived relative distances measured from the apparent magnitude of the TRGB.Comment: 54 pages, including 24 pages of figures and 16 pages of tables. Project website and data available at http://www.nearbygalaxies.org/ . Data is also available through MAST. Scheduled to appear in the Astrophysical Journal Supplements. (Replaced to fix several figures that were damaged during compression

Bichromatic beam splitter for three-level atoms

We investigate schemes for the clean splitting of beams of three-level atoms using two standing-wave laser fields within an optical cavity. The proposed beam splitter is shown to work for atoms in the Λ ladder, and ssV configurations. For appropriate values of Rabi frequencies and detunings, we obtain a triangular type of potential for the atomic states of interest. As well as modeling the coherent evolution of the systems, we have used quantum Monte Carlo wave-function methods to model the effects of spontaneous emission on the resulting diffraction pattern, finding significant differences between the three configurations. We also investigate the limits of the Raman-Nath approximation for our systems, using the symmetric split-operator technique to include the effects of the kinetic term in the Hamiltonian. We also present the results of calculations in which the split output beams are recombined, demonstrating the expected interference for differently prepared input beams. In comparison with two-level beam splitters using a single standing wave, we obtain a superior splitting, while, in comparison with magneto-optical beam splitters, our system possesses the worthwhile practical advantages of experimental simplicity

Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

Objective: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. Participants: A multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. Design/Methods: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. Results: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60min of < 9 g/dL) after cosyntropin (250 g) administration and a random plasma cortisol of < 10 g/dL may be used by clinicians. We suggest against using plasma-free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using IV hydrocortisone < 400mg/day for 3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO(2) < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). Conclusions: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force

Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI

Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy beta and nuclear recoils in liquid argon with DEAP-1

The DEAP-1 low-background liquid argon detector was used to measure scintillation pulse shapes of electron and nuclear recoil events and to demonstrate the feasibility of pulse-shape discrimination (PSD) down to an electron-equivalent energy of 20 keV. In the surface dataset using a triple-coincidence tag we found the fraction of beta events that are misidentified as nuclear recoils to be $<1.4\times 10^{-7}$ (90% C.L.) for energies between 43-86 keVee and for a nuclear recoil acceptance of at least 90%, with 4% systematic uncertainty on the absolute energy scale. The discrimination measurement on surface was limited by nuclear recoils induced by cosmic-ray generated neutrons. This was improved by moving the detector to the SNOLAB underground laboratory, where the reduced background rate allowed the same measurement with only a double-coincidence tag. The combined data set contains $1.23\times10^8$ events. One of those, in the underground data set, is in the nuclear-recoil region of interest. Taking into account the expected background of 0.48 events coming from random pileup, the resulting upper limit on the electronic recoil contamination is $<2.7\times10^{-8}$ (90% C.L.) between 44-89 keVee and for a nuclear recoil acceptance of at least 90%, with 6% systematic uncertainty on the absolute energy scale. We developed a general mathematical framework to describe PSD parameter distributions and used it to build an analytical model of the distributions observed in DEAP-1. Using this model, we project a misidentification fraction of approx. $10^{-10}$ for an electron-equivalent energy threshold of 15 keV for a detector with 8 PE/keVee light yield. This reduction enables a search for spin-independent scattering of WIMPs from 1000 kg of liquid argon with a WIMP-nucleon cross-section sensitivity of $10^{-46}$ cm$^2$, assuming negligible contribution from nuclear recoil backgrounds.Comment: Accepted for publication in Astroparticle Physic

Nonlinear modeling of venous leg ulcer healing rates

<p>Abstract</p> <p>Background</p> <p>The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics.</p> <p>Methods</p> <p>We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments.</p> <p>Results</p> <p>A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model.</p> <p>Conclusion</p> <p>We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.</p