The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

Provenance of the Early Mesoproterozoic Radium Creek Group in the northern Mount Painter Inlier: Correlating isotopic signatures to inform tectonic reconstructions

New in situ zircon LA-ICPMS geochronologic and Hf-isotope data from the Radium Creek Group within the Mount Painter Inlier provide important temporal constraints on the Early Mesoproterozoic palaeogeography of eastern Proterozoic Australia. The entire Radium Creek Group was deposited in a single basin forming phase, and has a maximum depositional age of 1595. ±. 3.7. Ma. Detrital zircon from these metasedimentary rocks have U-Pb age populations at ca. 1595. Ma, 1660-1680. Ma, 1710-1780. Ma, ca. 1850. Ma and ca. 2500. Ma. These grains are characterised by isotopically diverse and evolved sources, and have crystallised within predominantly felsic igneous host-rocks. The relative age spectra and isotopic character has more similarity with the Gawler Craton than the Arunta Block, Curnamona Province or the Mount Isa Inlier. These observations suggest that the Mount Painter Province was adjacent to the Gawler Craton in the Early Mesoproterozoic. Our data supports a coherent South Australian Craton at ca. 1595. Ma and a contiguous continental mass that included the North and South Australian cratons. The Mount Painter Inlier occupied a complex plate tectonic setting in the overriding plate of two convergent margins. © 2014 Elsevier B.V

The influence of protein malnutrition on the production of GM-CSF and M-CSF by macrophages

ABSTRACT It is well established that protein malnutrition (PM) impairs immune defenses and increases susceptibility to infection. Macrophages are cells that play a central role in innate immunity, constituting one of the first barriers against infections. Macrophages produce several soluble factors, including cytokines and growth factors, important to the immune response. Among those growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). GM-CSF and M-CSF are important to monocyte and macrophage development and stimulation of the immune response process. Knowing the importance of GM-CSF and M-CSF, we sought to investigate the influence of PM on macrophage production of these growth factors. Two-month-old male BALB/c mice were subjected to PM with a low-protein diet (2%) and compared to a control diet (12%) mouse group. Nutritional status, hemogram and the number of peritoneal cells were evaluated. Additionally, peritoneal macrophages were cultured and the production of GM-CSF and M-CSF and mRNA expression were evaluated. To determine if PM altered macrophage production of GM-CSF and M-CSF, they were stimulated with TNF-α. The PM animals had anemia, leukopenia and a reduced number of peritoneal cells. The production of M-CSF was not different between groups; however, cells from PM animals, stimulated with or without TNF-α, presented reduced capability to produce GM-CSF. These data imply that PM interferes with the production of GM-CSF, and consequently would affect the production and maturation of hematopoietic cells and the immune response

Measurement of ϒ production in pp collisions at √s = 2.76 TeV

The production of ϒ(1S), ϒ(2S) and ϒ(3S) mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 pb−1 collected in proton–proton collisions at a centre-of-mass energy of √s = 2.76 TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the ϒ transverse momentum and rapidity, over the ranges pT < 15 GeV/c and 2.0 < y < 4.5. The total cross-sections in this kinematic region, assuming unpolarised production, are measured to be σ (pp → ϒ(1S)X) × B ϒ(1S)→μ+μ− = 1.111 ± 0.043 ± 0.044 nb, σ (pp → ϒ(2S)X) × B ϒ(2S)→μ+μ− = 0.264 ± 0.023 ± 0.011 nb, σ (pp → ϒ(3S)X) × B ϒ(3S)→μ+μ− = 0.159 ± 0.020 ± 0.007 nb, where the first uncertainty is statistical and the second systematic

Ethnic profiling in the Netherlands? A reflection on expanding preventive powers, ethnic profiling and a changing social and political context

Criminal Justice: Legitimacy, accountability, and effectivit

Measurement of the gamma ray background in the Davis Cavern at the Sanford Underground Research Facility

Deep underground environments are ideal for low background searches due to the attenuation of cosmic rays by passage through the earth. However, they are affected by backgrounds from γ-rays emitted by 40K and the 238U and 232Th decay chains in the surrounding rock. The LUX-ZEPLIN (LZ) experiment will search for dark matter particle interactions with a liquid xenon TPC located within the Davis campus at the Sanford Underground Research Facility, Lead, South Dakota, at the 4,850-foot level. In order to characterise the cavern background, in-situ γ-ray measurements were taken with a sodium iodide detector in various locations and with lead shielding. The integral count rates (0--3300~keV) varied from 596~Hz to 1355~Hz for unshielded measurements, corresponding to a total flux in the cavern of 1.9±0.4~γ cm−2s−1. The resulting activity in the walls of the cavern can be characterised as 220±60~Bq/kg of 40K, 29±15~Bq/kg of 238U, and 13±3~Bq/kg of 232Th

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy