No selection on immunological markers in response to a highly virulent pathogen in an Arctic breeding bird

In natural populations, epidemics provide opportunities to look for intense natural selection on genes coding for life history and immune or other physiological traits. If the populations being considered are of management or conservation concern, then identifying the traits under selection (or ‘markers’) might provide insights into possible intervention strategies during epidemics. We assessed potential for selection on multiple immune and life history traits of Arctic breeding common eiders (Somateria mollissima) during annual avian cholera outbreaks (summers of 2006, 2007 & 2008). We measured prelaying body condition, immune traits, and subsequent reproductive investment (i.e., clutch size) and survival of female common eiders and whether they were infected with Pasteurella multocida, the causative agent of avian cholera. We found no clear and consistent evidence of directional selection on immune traits; however, infected birds had higher levels of haptoglobin than uninfected birds. Also, females that laid larger clutches had slightly lower immune responses during the prelaying period reflecting possible downregulation of the immune system to support higher costs of reproduction. This supports a recent study indicating that birds investing in larger clutches were more likely to die from avian cholera and points to a possible management option to maximize female survival during outbreaks

Impact of Structured Insulin Order Sets on Inpatient Hypoglycemia and Glycemic Control

Objective: In hospitalized patients, glycemic excursions outside recommended glycemic targets have been associated with increased morbidity and mortality. Despite recommendations to avoid use of correctional insulin alone for managing hyperglycemia, this approach remains common. We performed a quality improvement project aimed at both reducing hypoglycemic events and promoting increased use of basal insulin by updating our insulin order sets to reflect clinical practice guideline recommendations. Methods: Brooke Army Medical Center correctional insulin order sets were modified to reflect higher treatment thresholds and targets, and a basal insulin order was added with a recommended weight-based starting dose. Pre- and postintervention analyses were performed. Patients were included if they were prescribed subcutaneous insulin during their hospital stay. The following outcomes were measured: (1) glucose levels, and (2) prescriptions for basal insulin. Results: A significant reduction in hypoglycemia events was noted following the intervention (glucose \u3c70 mg/dL: 9.2% pre-intervention vs. 8.8% postintervention; glucose \u3c55 mg/dL: 4.2% pre-intervention vs. 2.2% postintervention). When excluding patients that were ordered correctional insulin alone but did not receive a dose, an increase in basal insulin use was seen (50% pre-intervention vs. 61% postintervention). Rates and severity of hyperglycemia (glucose \u3e180 mg/dL) remained unchanged. Conclusion: The alteration in insulin order set parameters resulted in a significant reduction in hypoglycemia without significant increases in hyperglycemia. Although basal insulin use increased, optimal dosing recommendations were not often utilized. Further interventions are necessary to reduce hyperglycemia. Abbreviations: CPOE = computerized provider order entry; EMR = electronic medical record; HbA1c = hemoglobin A1c; LOS = length of stay; QI = quality improvement; SSI = sliding scale insulin

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Relative magnitudes of sources of uncertainty in assessing climate change impacts on water supply security for the southern Adelaide water supply system

The sources of uncertainty in projecting the impacts of climate change on runoff are increasingly well recognized; however, translating these uncertainties to urban water security has received less attention in the literature. Furthermore, runoff cannot be used as a surrogate for water supply security when studying the impacts of climate change due to the nonlinear transformations in modeling water supply and the effects of additional uncertainties, such as demand. Consequently, this study presents a scenario-based sensitivity analysis to qualitatively rank the relative contributions of major sources of uncertainty in projecting the impacts of climate change on water supply security through time. This can then be used by water authorities to guide water planning and management decisions. The southern system of Adelaide, South Australia, is used to illustrate the methodology for which water supply system reliability is examined across six greenhouse gas (GHG) emissions scenarios, seven general circulation models, six demand projections, and 1000 stochastic rainfall time series. Results indicate the order of the relative contributions of uncertainty changes through time; however, demand is always the greatest source of uncertainty and GHG emissions scenarios the least. In general, reliability decreases over the planning horizon, illustrating the need for additional water sources or demand mitigation, while increasing uncertainty with time suggests flexible management is required to ensure future supply security with minimum regret.F.L. Paton, H.R. Maier and G.C. Dand

Towards a Synthetic Chloroplast

The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner.We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages.Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices

No selection on immunological markers in response to a highly virulent pathogen in an Arctic breeding bird

In natural populations, epidemics provide opportunities to look for intense natural selection on genes coding for life history and immune or other physiological traits. If the populations being considered are of management or conservation concern, then identifying the traits under selection (or 'markers') might provide insights into possible intervention strategies during epidemics. We assessed potential for selection on multiple immune and life history traits of Arctic breeding common eiders (Somateria mollissima) during annual avian cholera outbreaks (summers of 2006, 2007 & 2008). We measured prelaying body condition, immune traits, and subsequent reproductive investment (i.e., clutch size) and survival of female common eiders and whether they were infected with Pasteurella multocida, the causative agent of avian cholera. We found no clear and consistent evidence of directional selection on immune traits; however, infected birds had higher levels of haptoglobin than uninfected birds. Also, females that laid larger clutches had slightly lower immune responses during the prelaying period reflecting possible downregulation of the immune system to support higher costs of reproduction. This supports a recent study indicating that birds investing in larger clutches were more likely to die from avian cholera and points to a possible management option to maximize female survival during outbreaks

STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non-Small Cell Lung Carcinoma

Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations

The 2.5 m Telescope of the Sloan Digital Sky Survey

We describe the design, construction, and performance of the Sloan Digital Sky Survey Telescope located at Apache Point Observatory. The telescope is a modified two-corrector Ritchey-Chretien design which has a 2.5-m, f/2.25 primary, a 1.08-m secondary, a Gascoigne astigmatism corrector, and one of a pair of interchangeable highly aspheric correctors near the focal focal plane, one for imaging and the other for spectroscopy. The final focal ratio is f/5. The telescope is instrumented by a wide-area, multiband CCD camera and a pair of fiber-fed double spectrographs. Novel features of the telescope include: (1) A 3 degree diameter (0.65 m) focal plane that has excellent image quality and small geometrical distortions over a wide wavelength range (3000 to 10,600 Angstroms) in the imaging mode, and good image quality combined with very small lateral and longitudinal color errors in the spectroscopic mode. The unusual requirement of very low distortion is set by the demands of time-delay-and-integrate (TDI) imaging; (2) Very high precision motion to support open loop TDI observations; and (3) A unique wind baffle/enclosure construction to maximize image quality and minimize construction costs. The telescope had first light in May 1998 and began regular survey operations in 2000.Comment: 87 pages, 27 figures. AJ (in press, April 2006