Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

Biological predictors of suicidality in schizophrenia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65166/1/j.1600-0447.1996.tb09883.x.pd

Characterization of bone repair in rat femur after treatment with calcium phosphate cement and autogenous bone graft

<p>Abstract</p> <p>Background</p> <p>In this study, the biocompatibility, stability and osteotransductivity of a new cement based on alpha-tricalcium phosphate (alpha-TCP) were investigated in a bone repair model using a rat model.</p> <p>Methods</p> <p>The potential of alpha-TCP on bone repair was compared to autogenous bone grafting, and unfilled cavities were used as negative control. Surgical cavities were prepared and designated as test (T), implanted with alpha-TCP blocks; negative control (C - ), unfilled; and positive control (C + ), implanted with autogenous bone graft. Results were analyzed on postoperative days three, seven, 14, 21 and 60.</p> <p>Results</p> <p>The histological analyses showed the following results. Postoperative day three: presence of inflammatory infiltrate, erythrocytes and proliferating fibroblasts in T, C - and C + samples. Day seven: extensive bone neoformation in groups T and C + , and beginning of alpha-TCP resorption by phagocytic cells. Days 14 and 21: osteoblastic activity in the three types of cavities. Day 60: In all samples, neoformed bone similar to surrounding bone. Moderate interruption on the ostectomized cortical bone.</p> <p>Conclusions</p> <p>Bone neoformation is seen seven days after implantation of alpha-TCP and autogenous bone. Comparison of C - with T and C + samples showed that repair is faster in implanted cavities; on day 60, control groups presented almost complete bone repair. Alpha-TCP cement presents biocompatibility and osteotransductivity, besides stability, but 60 days after surgery the cavities were not closed.</p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Person-centred care in interventions to limit weight gain in pregnant women with obesity - a systematic review

Background Person-centred care, asserting that individuals are partners in their care, has been associated with care satisfaction but the value of using it to support women with obesity during pregnancy is unknown. Excessive gestational weight gain is associated with increased risks for both mother and baby and weight gain therefore is an important intervention target. The aims of this review was to 1) explore to what extent and in what manner interventions assessing weight in pregnant women with obesity use person-centred care and 2) assess if interventions including aspects of person-centred care are more effective at limiting weight gain than interventions not employing person-centred care. Methods Ten databases were systematically searched in January 2014. Studies had to report an intervention offered to pregnant women with obesity and measure gestational weight gain to be included. All included studies were independently double coded to identify to what extent they included three defined aspects of person-centred care: 1) “initiate a partnership” including identifying the person’s circumstances and motivation; 2) “working the partnership” through sharing the decision-making regarding the planned action and 3) “safeguarding the partnership through documentation” of care preferences. Information on gestational weight gain, study quality and characteristics were also extracted. Results Ten studies were included in the review, of which five were randomised controlled trials (RCT), and the remaining observational studies. Four interventions included aspects of person-centred care; two observational studies included both “initiating the partnership”, and “working the partnership”. One observational study included “initiating the partnership” and one RCT included “working the partnership”. No interventions included “safeguarding the partnership through documentation”. Whilst all studies with person-centred care aspects showed promising findings regarding limiting gestational weight gain, so did the interventions not including person-centred care aspects. Conclusions The use of an identified person-centred care approach is presently limited in interventions targeting gestational weight gain in pregnant women with obesity. Hence to what extent person-centred care may improve health outcomes and care satisfaction in this population is currently unknown and more research is needed. That said, our findings suggest that use of routines incorporating person-centredness are feasible to include within these interventions

High-Pitch, Low-Voltage and Low-Iodine-Concentration CT Angiography of Aorta: Assessment of Image Quality and Radiation Dose with Iterative Reconstruction

Objective: To assess the image quality of aorta obtained by dual-source computed tomography angiography (DSCTA), performed with high pitch, low tube voltage, and low iodine concentration contrast medium (CM) with images reconstructed using iterative reconstruction (IR). Methods: One hundred patients randomly allocated to receive one of two types of CM underwent DSCTA with the electrocardiogram-triggered Flash protocol. In the low-iodine group, 50 patients received CM containing 270 mg I/mL and were scanned at low tube voltage (100 kVp). In the high-iodine CM group, 50 patients received CM containing 370 mg I/mL and were scanned at the tube voltage (120 kVp). The filtered back projection (FBP) algorithm was used for reconstruction in both groups. In addition, the IR algorithm was used in the low-iodine group. Image quality of the aorta was analyzed subjectively by a 3-point grading scale and objectively by measuring the CT attenuation in terms of the signal- and contrast-to-noise ratios (SNR and CNR, respectively). Radiation and CM doses were compared.Results: The CT attenuation, subjective image quality assessment, SNR, and CNR of various aortic regions of interest did not differ significantly between two groups. In the low-iodine group, images reconstructed by FBP and IR demonstrated significant differences in image noise, SNR, and CNR (p<0.05). The low-iodine group resulted in 34.3% less radiation (4.4 ± 0.5 mSv) than the high-iodine group (6.7 ± 0.6 mSv), and 27.3% less iodine weight (20.36 ± 2.65 g) than the high-iodine group (28 ± 1.98 g). Observers exhibited excellent agreement on the aortic image quality scores (κ = 0.904). Conclusions: CT images of aorta could be obtained within 2 s by using a DSCT Flash protocol with low tube voltage, IR, and low-iodine-concentration CM. Appropriate contrast enhancement was achieved while maintaining good image quality and decreasing the radiation and iodine doses

Skin Electroporation: Effects on Transgene Expression, DNA Persistence and Local Tissue Environment

BACKGROUND: Electrical pulses have been used to enhance uptake of molecules into living cells for decades. This technique, often referred to as electroporation, has become an increasingly popular method to enhance in vivo DNA delivery for both gene therapy applications as well as for delivery of vaccines against both infectious diseases and cancer. In vivo electrovaccination (gene delivery followed by electroporation) is currently being investigated in several clinical trials, including DNA delivery to healthy volunteers. However, the mode of action at molecular level is not yet fully understood. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates intradermal DNA electrovaccination in detail and describes the effects on expression of the vaccine antigen, plasmid persistence and the local tissue environment. Gene profiling of the vaccination site showed that the combination of DNA and electroporation induced a significant up-regulation of pro-inflammatory genes. In vivo imaging of luciferase activity after electrovaccination demonstrated a rapid onset (minutes) and a long duration (months) of transgene expression. However, when the more immunogenic prostate specific antigen (PSA) was co-administered, PSA-specific T cells were induced and concurrently the luciferase expression became undetectable. Electroporation did not affect the long-term persistence of the PSA-expressing plasmid. CONCLUSIONS/SIGNIFICANCE: This study provides important insights to how DNA delivery by intradermal electrovaccination affects the local immunological responses of the skin, transgene expression and clearance of the plasmid. As the described vaccination approach is currently being evaluated in clinical trials, the data provided will be of high significance

Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone

Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors