Calcium/Calmodulin Dependent Protein Kinase Type-II Associates with Flightless-I to Influence its Nuclear Localization

Ca2+/calmodulin-dependent protein kinase type-II (CaMK-II) is a Ser/Thr protein kinase regulated by Ca2+ and Calmodulin. It is a highly conserved and broadly expressed enzyme and has a unique structure and dynamic regulation. It has the ability to remain active in the absence of Ca 2+ as a result of Ca2+ dependent autophosphorylation. CaMK-II phospliorylates proteins involved in neurotransmitter secretion, long term potentiation, cytoskeletal dynamics, gene transcription, and cell motility. To support existing and identify new intracellular roles of CaMK-II, potential binding partners were identified. This was accomplished by transfecting and purifying FLAG-tagged CaMK-II\u27s (α, βE, δC, and δE). CaMK-II associated proteins were then identified using tandem mass spectrometry. Known binding partners were identified using this approach, including CaMK-II and calmodulin, verifying the approach\u27s validity. Additionally several unexpected but interesting proteins were identified, including the gelsolin related actin binding protein, Flightless-I. Fli-I is an actin binding and capping protein that also functions as a transcriptional coactivator. The CaMK-II-Fli-I interaction was confirmed with endogenous (un-tagged) proteins. The association and localization of Fli-I are dependent on CaMK-II\u27s activity state, although Fli-I is not a substrate of CaMK-II. When CaMK-II is inhibited, Fli-I translocates to the nucleus. Conversely when CaMK-II is artificially activated using a Ca2+ ionophore, Fli-I returns to the cytosol. The discovery of this reversible interaction epresents a potentially new CaMK-II regulated pathway and likely serves as a link between Ca2+ based signal transduction pathways and regulation of the actin component of the cytoskeleton and transcription

Maternal infection and risk of intrapartum death: a population based observational study in South Asia.

BACKGROUND: Approximately 1.2 million stillbirths occur in the intrapartum period, and a further 717,000 annual neonatal deaths are caused by intrapartum events, most of which occur in resource poor settings. We aim to test the 'double-hit' hypothesis that maternal infection in the perinatal period predisposes to neurodevelopmental sequelae from an intrapartum asphyxia insult, increasing the likelihood of an early neonatal death compared with asphyxia alone. This is an observational study of singleton newborn infants with signs of intrapartum asphyxia that uses data from three previously conducted cluster randomized controlled trials taking place in rural Bangladesh and India. METHODS: From a population of 81,778 births in 54 community clusters in rural Bangladesh and India, we applied mixed effects logistic regression to data on 3890 singleton infants who had signs of intrapartum asphyxia, of whom 769 (20%) died in the early neonatal period. Poor infant condition at five minutes post-delivery was our proxy measure of intrapartum asphyxia. We had data for two markers of maternal infection: fever up to three days prior to labour, and prolonged rupture of membranes (PROM). Cause-specific verbal autopsy data were used to validate our findings using previously mentioned mixed effect logistic regression methods and the outcome of a neonatal death due to intrapartum asphyxia. RESULTS: Signs of maternal infection as indicated by PROM, combined with intrapartum asphyxia, increased the risk of an early neonatal death relative to intrapartum asphyxia alone (adjusted odds ratio (AOR) 1.28, 95% CI 1.03 - 1.59). Results from cause-specific verbal autopsy data verified our findings where there was a significantly increased odds of a early neonatal death due to intrapartum asphyxia in newborns exposed to both PROM and intrapartum asphyxia (AOR: 1.52, 95% CI 1.15 - 2.02). CONCLUSIONS: Our data support the double-hit hypothesis for signs of maternal infection as indicated by PROM. Interventions for pregnant women with signs of infection, to prevent early neonatal deaths and disability due to asphyxia, should be investigated further in resource-poor populations where the chances of maternal infection are high

Rapid Microwave Preparation of Thermoelectric TiNiSn and TiCoSb Half-Heusler Compounds

The 18-electron ternary intermetallic systems TiNiSn and TiCoSb are promising for applications as high-temperature thermoelectrics and comprise earth-abundant, and relatively nontoxic elements. Heusler and half-Heusler compounds are usually prepared by conventional solid state methods involving arc-melting and annealing at high temperatures for an extended period of time. Here, we report an energy-saving preparation route using a domestic microwave oven, reducing the reaction time significantly from more than a week to one minute. A microwave susceptor material rapidly heats the elemental starting materials inside an evacuated quartz tube resulting in near single phase compounds. The initial preparation is followed by a densification step involving hot-pressing, which reduces the amount of secondary phases, as verified by synchrotron X-ray diffraction, leading to the desired half-Heusler compounds, demonstrating that hot-pressing should be treated as part of the preparative process. For TiNiSn, high thermoelectric power factors of 2 mW/mK^2 at temperatures in the 700 to 800 K range, and zT values of around 0.4 are found, with the microwave-prepared sample displaying somewhat superior properties to conventionally prepared half-Heuslers due to lower thermal conductivity. The TiCoSb sample shows a lower thermoelectric figure of merit when prepared using microwave methods because of a metallic second phase

Dissecting the Cygnus Region with TeV Gamma Rays and Neutrinos

Recent Milagro observations of the Cygnus region have revealed both diffuse TeV gamma-ray emission and a bright and extended TeV source, MGRO J2019+37, which seems to lack an obvious counterpart at other wavelengths. Additional study of this curious object also promises to provide important clues concerning one of the Milky Way's most active environments. We point out some of the principal facts involved by following three modes of attack. First, to gain insight into this mysterious source, we consider its relation to known objects in both the Cygnus region and the rest of the Galaxy. Second, we find that a simple hadronic model can easily accommodate Milagro's flux measurement (which is at a single energy), as well as other existing observations spanning nearly seven orders of magnitude in gamma-ray energy. Third, since a hadronic gamma-ray spectrum necessitates an accompanying TeV neutrino flux, we show that IceCube observations may provide the first direct evidence of a Galactic cosmic-ray accelerator.Comment: 6 pages, 4 figures, references updated to match published versio

An Introduction to the Chandra Carina Complex Project

The Great Nebula in Carina provides an exceptional view into the violent massive star formation and feedback that typifies giant HII regions and starburst galaxies. We have mapped the Carina star-forming complex in X-rays, using archival Chandra data and a mosaic of 20 new 60ks pointings using the Chandra X-ray Observatory's Advanced CCD Imaging Spectrometer, as a testbed for understanding recent and ongoing star formation and to probe Carina's regions of bright diffuse X-ray emission. This study has yielded a catalog of properties of >14,000 X-ray point sources; >9800 of them have multiwavelength counterparts. Using Chandra's unsurpassed X-ray spatial resolution, we have separated these point sources from the extensive, spatially-complex diffuse emission that pervades the region; X-ray properties of this diffuse emission suggest that it traces feedback from Carina's massive stars. In this introductory paper, we motivate the survey design, describe the Chandra observations, and present some simple results, providing a foundation for the 15 papers that follow in this Special Issue and that present detailed catalogs, methods, and science results.Comment: Accepted for the ApJS Special Issue on the Chandra Carina Complex Project (CCCP), scheduled for publication in May 2011. All 16 CCCP Special Issue papers are available at http://cochise.astro.psu.edu/Carina_public/special_issue.html through 2011 at least. 43 pages; 18 figure

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE):a multicentre, open-label randomised controlled trial

Background: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. Methods: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP &gt;upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse—ie, quiescent symptoms (HBI &lt;5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin &lt;200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). Findings: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0–191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker–treatment interaction effect (absolute difference 1 percentage points, 95% CI –15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p&lt;0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). Interpretation: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. Funding: Wellcome and PredictImmune Ltd.</p

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients