Age and Ovariectomy Abolish Beneficial Effects of Female Sex on Rat Ventricular Myocytes Exposed to Simulated Ischemia and Reperfusion

Sex differences in responses to myocardial ischemia have been described, but whether cardiomyocyte function is influenced by sex in the setting of ischemia and reperfusion has not been elucidated. This study compared contractions and intracellular Ca2+ in isolated ventricular myocytes exposed to ischemia and reperfusion. Cells were isolated from anesthetized 3-month-old male and female Fischer 344 rats, paced at 4 Hz (37°C), exposed to simulated ischemia (20 mins) and reperfused. Cell shortening (edge detector) and intracellular Ca2+ (fura-2) were measured simultaneously. Cell viability was assessed with Trypan blue. Ischemia reduced peak contractions and increased Ca2+ levels equally in myocytes from both sexes. However, contraction amplitudes were reduced in reperfusion in male myocytes, while contractions recovered to exceed control levels in females (62.6±5.1 vs. 140.1±15.8%; p<0.05). Only 60% of male myocytes excluded trypan blue dye after ischemia and reperfusion, while all female cardiomyocytes excluded the dye (p<0.05). Parallel experiments were conducted in myocytes from ∼24-month-old female rats or 5–6-month-old rats that had an ovariectomy at 3–4 weeks of age. Beneficial effects of female sex on myocyte viability and contractile dysfunction in reperfusion were abolished in cells from 24-month-old females. Aged female myocytes also exhibited elevated intracellular Ca2+ and alternans in ischemia. Cells from ovariectomized rats displayed increased Ca2+ transients and spontaneous activity in ischemia compared to sham-operated controls. None of the myocytes from ovariectomized rats were viable after 15 minutes of ischemia, while 75% of sham cells remained viable at end of reperfusion (p<0.05). These findings demonstrate that cardiomyocytes from young adult females are more resistant to ischemia and reperfusion injury than cells from males. Age and OVX abolish these beneficial effects and induce Ca2+ dysregulation at the level of the cardiomyocyte. Thus, beneficial effects of estrogen in ischemia and reperfusion are mediated, in part, by effects on cardiomyocytes

Earliest Cretaceous cocoons or plant seed structures from the Wealden Group, Hastings, UK

We thank Jason Hilton (University of Birmingham) and Alan Spencer (Imperial College) for discussion. RG is a member of the Interdisciplinary Centre for Ancient Life (UMRI). We are grateful for the reviews of both Jorge Genise, and Duncan McIlroy whose comments and guidance greatly improved the manuscript.Postprin

Using legume-based mixtures to enhance the nitrogen use efficiency and economic viability of cropping systems - Final report (LK09106/HGCA3447)

As costs for mineral fertilisers rise, legume-based leys are recognised as a potential alternative nitrogen source for crops. Here we demonstrate that including species-rich legume-based leys in rotations helps to maximise synergies between agricultural productivity and other ecosystem services. By using functionally diverse plant species mixtures, these services can be optimised and fine-tuned to regional and farm-specific needs. Replicated field experiments were conducted over three years at multiple locations, testing the performance of 12 legume species and 4 grass species sown in monocultures, as well as in a mixture of 10 of the legumes and all 4 grasses (called the All Species Mix, ASM). In addition, we compared this complex mixture to farmer-chosen ley mixtures on 34 sites across the UK. The trials showed that there is a large degree of functional complementarity among the legume species. No single species scored high on all evaluation criteria. In particular, the currently most frequently used species, white clover, is outscored by other legume species on a number of parameters such as early development and resistance to decomposition. Further complementarity emerged from the different responses of legume species to environmental variables, with soil pH and grazing or cutting regime being among the more important factors. For example, while large birdsfoot trefoil showed better performance on more acidic soils, the opposite was true for sainfoin, lucerne and black medic. In comparison with the monocultures, the ASM showed increased ground cover, increased above-ground biomass and reduced weed biomass. Benefits of mixing species with regard to productivity increased over time. In addition, the stability of biomass production across sites was greater in the ASM than in the legume monocultures. Within the on-farm trials, we further found that on soils low in organic matter the biomass advantage of the ASM over the Control ley was more marked than on the soils with higher organic matter content. Ecological modelling revealed that the three best multifunctional mixtures all contained black medic, lucerne and red clover. Within the long term New Farming Systems (NFS) rotational study, the use of a clover bi-crop showed improvement to soil characteristics compared to current practice (e.g. bulk density and water infiltration rate). Improvements in wheat yield were also noted with respect to the inclusion of a clover bi-crop in 2010, but there was evidence of a decline in response as the N dose was increased. Cumulatively, over both the wheat crop and the spring oilseed rape crop, the clover bi-crop improved margin over N. The highest average yield response (~9%) was associated with the ASM legume species mix cover cropping approach

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice

Female mice lacking ATRX in the pancreas have increased sensitivity to pancreatic cancer, whereas male mice without ATRX are protected. This study identifies such susceptibility in pancreatic cancer and highlights the need for sex-specific approaches in cancer treatment. BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for \u3e30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler.-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS\u27s ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic METHODS: Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRASG12D). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion. RESULTS: Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients. CONCLUSIONS: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS\u27s ability to promote pancreatic intraepithelial lesion formation

The design, construction and performance of the MICE target

The pion-production target that serves the MICE Muon Beam consists of a titanium cylinder that is dipped into the halo of the ISIS proton beam. The design and construction of the MICE target system are described along with the quality-assurance procedures, electromagnetic drive and control systems, the readout electronics, and the data-acquisition system. The performance of the target is presented together with the particle rates delivered to the MICE Muon Beam. Finally, the beam loss in ISIS generated by the operation of the target is evaluated as a function of the particle rate, and the operating parameters of the target are derived

Home administration of lanreotide Autogel® by patients with acromegaly, or their partners, is safe and effective

Summary. Objective The introduction of ready-to-use lanreotide Autogel® has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety. Design Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel® at their established dose. Effects were monitored for up to 40 weeks. Patients Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel® (60, 90 or 120 mg) for ≥ 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study. Results All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%–99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study. Conclusions Patients with acromegaly or their partners were able to administer lanreotide Autogel® injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients