Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding : systematic review and meta-analysis of data from individual patients

Peer reviewedPublisher PD

Effects of residual N management on economics of wheat and canola

Non-Peer Reviewe

On the Apparent Orbital Inclination Change of the Extrasolar Transiting Planet TrES-2b

On June 15, 2009 UT the transit of TrES-2b was detected using the University of Arizona's 1.55 meter Kuiper Telescope with 2.0-2.5 millimag RMS accuracy in the I-band. We find a central transit time of $T_c = 2454997.76286 \pm0.00035$ HJD, an orbital period of $P = 2.4706127 \pm 0.0000009$ days, and an inclination angle of $i = 83^{\circ}.92 \pm 0.05$, which is consistent with our re-fit of the original I-band light curve of O'Donovan et al. (2006) where we find $i = 83^{\circ}.84 \pm0.05$. We calculate an insignificant inclination change of $\Delta i = -0^{\circ}.08 \pm 0.07$ over the last 3 years, and as such, our observations rule out, at the $\sim 11 \sigma$ level, the apparent change of orbital inclination to $i_{predicted} = 83^{\circ}.35 \pm0.1$ as predicted by Mislis and Schmitt (2009) and Mislis et al. (2010) for our epoch. Moreover, our analysis of a recently published Kepler Space Telescope light curve (Gilliland et al. 2010) for TrES-2b finds an inclination of $i = 83^{\circ}.91 \pm0.03$ for a similar epoch. These Kepler results definitively rule out change in $i$ as a function of time. Indeed, we detect no significant changes in any of the orbital parameters of TrES-2b.Comment: 19 pages, 1 table, 7 figures. Re-submitted to ApJ, January 14, 201

Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin protein, leading to progressive muscle weakness and premature death due to respiratory and/or cardiac complications. Cardiac involvement is characterized by progressive dilated cardiomyopathy, decreased fractional shortening and metabolic dysfunction involving reduced metabolism of fatty acids—the major cardiac metabolic substrate. Several mouse models have been developed to study molecular and pathological consequences of dystrophin deficiency, but do not recapitulate all aspects of human disease pathology and exhibit a mild cardiac phenotype. Here we demonstrate that Cmah (cytidine monophosphate-sialic acid hydroxylase)-deficient mdx mice (Cmah−/−;mdx) have an accelerated cardiac phenotype compared to the established mdx model. Cmah−/−;mdx mice display earlier functional deterioration, specifically a reduction in right ventricle (RV) ejection fraction and stroke volume (SV) at 12 weeks of age and decreased left ventricle diastolic volume with subsequent reduced SV compared to mdx mice by 24 weeks. They further show earlier elevation of cardiac damage markers for fibrosis (Ctgf), oxidative damage (Nox4) and haemodynamic load (Nppa). Cardiac metabolic substrate requirement was assessed using hyperpolarized magnetic resonance spectroscopy indicating increased in vivo glycolytic flux in Cmah−/−;mdx mice. Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic genes (Pdk1, Pdk4, Ppara), also denote disturbed cardiac metabolism and shift towards glucose utilization in Cmah−/−;mdx mice. Moreover, we show long-term treatment with peptide-conjugated exon skipping antisense oligonucleotides (20-week regimen), resulted in 20% cardiac dystrophin protein restoration and significantly improved RV cardiac function. Therefore, Cmah−/−;mdx mice represent an appropriate model for evaluating cardiac benefit of novel DMD therapeutics

c-axis Josephson Tunnelling in Twinned and Untwinned YBCO-Pb Junctions

Within a microscopic two band model of planes and chains with a pairing potential in the planes and off diagonal pairing between planes and chains we find that the chains make the largest contribution to the Josephson tunnelling current and that through them the d-wave part of the gap contributes to the current. This is contrary to the usual assumption that for a d-wave tetragonal superconductor the c-axis Josephson current for incoherent tunnelling into an s-wave superconductor is zero while that of a d-wave orthorhombic superconductor with a small s-wave component to its gap it is small but non-zero. Nevertheless it has been argued that the effect of twins in YBCO would lead to cancellation between pairs of twins and so the observation of a current in c-axis YBCO-Pb experiments is evidence against a d-wave type order parameter. We argue that both theory and experiment give evidence that the two twin orientations are not necessarily equally abundant and that the ratio of tunnelling currents in twinned and untwinned materials should be related to the relative abundance of the two twin orientations.Comment: 6 pages, RevTeX 3.0, 15 PostScript figur

UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells

Esophageal cancer remains a poor prognosis cancer due to advanced stage of presentation and drug resistant disease. To understand the molecular mechanisms influencing response to chemotherapy, we examined genes that are differentially expressed between drug sensitive, apoptosis competent esophageal cancer cells (OE21, OE33, FLO-1) and those which are more resistant and do not exhibit apoptosis (KYSE450 and OE19). Members of the ISG15 (ubiquitin-like) protein modification pathway, including UBE2L6 and ISG15, were found to be more highly expressed in the drug sensitive cell lines. In this study, we evaluated the contribution of these proteins to the response of drug sensitive cells. Depletion of UBE2L6 or ISG15 with siRNA did not influence caspase-3 activation or nuclear fragmentation following treatment with 5-fluorouracil (5-FU). We assessed autophagy by analysis of LC3II expression and Cyto-ID staining. Depletion of either ISG15 or UBE2L6 resulted in enhanced endogenous autophagic flux. An increase in autophagic flux was also observed following treatment with cytotoxic drugs (5-FU, rapamycin). In ISG15 depleted cells, this increase in autophagy was associated with improved recovery of drug treated cells. In contrast, UBE2L6 depleted cells, did not show enhanced recovery. UBE2L6 may therefore influence additional targets that limit the pro-survival effect of ISG15 depletion. These data identify UBE2L6 and ISG15 as novel inhibitors of autophagy, with the potential to influence chemosensitivity in esophageal cancer cells

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model

MiR-193b promotes autophagy and non-apoptotic cell death in oesophageal cancer cells

Background: Successful treatment of oesophageal cancer is hampered by recurrent drug resistant disease. We have previously demonstrated the importance of apoptosis and autophagy for the recovery of oesophageal cancer cells following drug treatment. When apoptosis (with autophagy) is induced, these cells are chemosensitive and will not recover following chemotherapy treatment. In contrast, when cancer cells exhibit only autophagy and limited Type II cell death, they are chemoresistant and recover following drug withdrawal. Methods: MicroRNA (miRNA) expression profiling of an oesophageal cancer cell line panel was used to identify miRNAs that were important in the regulation of apoptosis and autophagy. The effects of miRNA overexpression on cell death mechanisms and recovery were assessed in the chemoresistant (autophagy inducing) KYSE450 oesophageal cancer cells. Results: MiR-193b was the most differentially expressed miRNA between the chemosensitive and chemoresistant cell lines with higher expression in chemosensitive apoptosis inducing cell lines. Colony formation assays showed that overexpression of miR-193b significantly impedes the ability of KYSE450 cells to recover following 5-fluorouracil (5-FU) treatment. The critical mRNA targets of miR-193b are unknown but target prediction and siRNA data analysis suggest that it may mediate some of its effects through stathmin 1 regulation. Apoptosis was not involved in the enhanced cytotoxicity. Overexpression of miR-193b in these cells induced autophagic flux and non-apoptotic cell death. Conclusion: These results highlight the importance of miR-193b in determining oesophageal cancer cell viability and demonstrate an enhancement of chemotoxicity that is independent of apoptosis induction

Management and Tillage Infl uence Barley Forage Productivity and Water Use in Dryland Cropping Systems

Annual cereal forages are resilient in water use (WU), water use efficiency (WUE), and weed control compared with grain crops in dryland systems. The combined influence of tillage and management systems on annual cereal forage productivity and WU is not well documented. We conducted a field study for the effects of tillage (no-till and tilled) and management (ecological and conventional) systems on WU and performance of forage barley (Hordeum vulgare L.) and weed biomass in two crop rotations (wheat [Triticum aestivum L.]–forage barley–pea [Pisum sativum L.] and wheat–forage barley–corn [Zea mays L.] –pea) from 2004 to 2010 in eastern Montana. Conventional management included recommended seeding rates, broadcast N fertilization, and short stubble height of wheat. Ecological management included 33% greater seeding rates, banded N fertilization at planting, and taller wheat stubble. Forage barley in ecological management had 28 more plants m–2, 2 cm greater height, 65 more tillers m–2, 606 kg ha–1 greater crop biomass, 3.5 kg ha–1 mm–1greater WUE, and 47% reduction in weed biomass at harvest than in conventional management. Pre-plant and post-harvest soil water contents were similar among tillage and management systems, but barley WU was 13 mm greater in 4-yr than 3-yr rotation. Tillage had little effect on barley performance and WU. Dryland forage barley with higher seeding rate and banded N fertilization in more diversified rotation produced more yield and used water more efficiently than that with conventional seeding rate, broadcast N fertilization, and less diversified rotation in the semiarid northern Great Plains