Meiosis progression and donor age affect expression profile of DNA repair genes in bovine oocytes

Several genetic and physiological factors increase the risk of DNA damage in mammalian oocytes. Two critical events are meiosis progression, from maturation to fertilization, due to the extensive chromatin remodelling during genome decondensation and aging which is associated to a progressive oxidative stress. In this work, we studied the transcriptional patterns of three genes, RAD51, APEX-1 and MLH1, involved in DNA repair mechanisms. The analyses were performed by Real-Time quantitative PCR (RT-qPCR) in immature and in vitro matured oocytes collected from 17 ± 3 mo old heifers and 94 ± 20 mo old cows. Batches of 30-50 oocytes for each group (three replicates) were collected from ovarian follicles of slaughtered animals. The oocytes were freed from cumulus cells at the time of follicle removal, or after IVM carried out in M199 supplemented with 10% foetal calf serum, 10 IU LH /ml, 0.1 IU FSH /ml and 1 µg 17β-oestradiol/ml. Total RNA was extracted by Trizol method. The expression of bovine GAPDH gene was used as internal standard, while primers for bovine RAD51, APEX-1 and MLH1 genes were designed from DNA sequences retrieved from GeneBank. Results obtained indicate a clear up-regulation of RAD51, APEX-1 and MLH1 genes after IVM ranging between 2- and 4-fold compared to GV oocytes. However, only RAD51 showed a significant transcript increase between the immature oocytes collected from young and old individuals. This finding candidates RAD51 as gene marker for discriminating bovine immature oocytes in relation to the donor age

Dynamical response of the Galileo Galilei on the ground rotor to test the equivalence principle: Theory, simulation, and experiment. II. The rejection of common mode forces

"Galileo Galilei on the ground" (GGG) is a fast rotating differential accelerometer designed to test the equivalence principle (EP). Its sensitivity to differential effects, such as the effect of an EP violation, depends crucially on the capability of the accelerometer to reject all effects acting in common mode. By applying the theoretical and simulation methods reported in Part I of this work, and tested therein against experimental data, we predict the occurrence of an enhanced common mode rejection of the GGG accelerometer. We demonstrate that the best rejection of common mode disturbances can be tuned in a controlled way by varying the spin frequency of the GGG rotor. (c) 2006 American Institute of Physics

Bone marrow mesenchymal stem cells increase motility of prostate cancer cells via production of stromal cell-derived factor-1α

Prostate cancer frequently metastasizes to the bone, and the interaction between cancer cells and bone microenvironment has proven to be crucial in the establishment of new metastases. Bone marrow mesenchymal stem cells (BM-MSCs) secrete various cytokines that can regulate the behaviour of neighbouring cell. However, little is known about the role of BM-MSCs in influencing the migration and the invasion of prostate cancer cells. We hypothesize that the stromal cell-derived factor-1α released by BM-MSCs may play a pivotal role in these processes. To study the interaction between factors secreted by BM-MSCs and prostate cancer cells we established an in vitro model of transwell co-culture of BM-MSCs and prostate cancer cells DU145. Using this model, we have shown that BM-MSCs produce soluble factors which increase the motility of prostate cancer cells DU145. Neutralization of stromal cell-derived factor-1α (SDF1α) via a blocking antibody significantly limits the chemoattractive effect of bone marrow MSCs. Moreover, soluble factors produced by BM-MSCs greatly activate prosurvival kinases, namely AKT and ERK 1/2. We provide further evidence that SDF1α is involved in the interaction between prostate cancer cells and BM-MSCs. Such interaction may play an important role in the migration and the invasion of prostate cancer cells within bone

Why, When and How Should Clinicians Use Physiology in Patients with Acute Coronary Syndromes?

Current data support the use of coronary physiology in patients with acute coronary syndrome (ACS). In patients with ST-elevation MI, the extent of myocardial damage and microvascular dysfunction create a complex conundrum to assimilate when considering clinical management and risk stratification. In this setting, the index of microcirculatory resistance emerged as an accurate tool to identify patients at risk of suboptimal myocardial reperfusion after primary percutaneous coronary intervention who may benefit from novel adjunctive therapies. In the context of non-ST-elevation ACS, coronary physiology should be carefully interpreted and often integrated with intracoronary imaging, especially in cases of ambiguous culprit lesion. Conversely, the functional assessment of bystander coronary disease is favoured by the available evidence, aiming to achieve complete revascularisation. Based on everyday clinical scenarios, the authors illustrate the available evidence and provide recommendations for the functional assessment of infarct-related artery and non-culprit lesions in patients with ACS

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

Maverick dark matter at colliders

Assuming that dark matter is a weakly interacting massive particle (WIMP) species X produced in the early Universe as a cold thermal relic, we study the collider signal of pp or ppbar -> XXbar + jets and its distinguishability from standard-model background processes associated with jets and missing energy. We assume that the WIMP is the sole particle related to dark matter within reach of the LHC--a "maverick" particle--and that it couples to quarks through a higher dimensional contact interaction. We simulate the WIMP final-state signal XXbar + jet and dominant standard-model (SM) background processes and find that the dark-matter production process results in higher energies for the colored final state partons than do the standard-model background processes, resulting in more QCD radiation and a higher jet multiplicity. As a consequence, the detectable signature of maverick dark matter is an excess over standard-model expectations of events consisting of large missing transverse energy, together with large leading jet transverse momentum and scalar sum of the transverse momenta of the jets. Existing Tevatron data and forthcoming LHC data can constrain (or discover!) maverick dark matter.Comment: 11 pages, 7 figure