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Magnetospheres are a ubiquitous feature of magnetized bodies embedded in a plasma flow. While large planetary magnetospheres have been studied for decades by spacecraft, ion-scale “mini” magnetospheres can provide a unique environment to study kinetic-scale, collisionless plasma physics in the laboratory to help validate models of larger systems. In this work, we present preliminary experiments of ion-scale magnetospheres performed on a unique high-repetition-rate platform developed for the Large Plasma Device at the University of California, Los Angeles. The experiments utilize a high-repetition-rate laser to drive a fast plasma flow into a pulsed dipole magnetic field embedded in a uniform magnetized background plasma. 2D maps of the magnetic field with high spatial and temporal resolution are measured with magnetic flux probes to examine the evolution of magnetosphere and current density structures for a range of dipole and upstream parameters. The results are further compared to 2D particle-in-cell simulations to identify key observational signatures of the kinetic-scale structures and dynamics of the laser-driven plasma. We find that distinct 2D kinetic-scale magnetopause and diamagnetic current structures are formed at higher dipole moments, and their locations are consistent with predictions based on pressure balances and energy conservation.

While oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g., ATM or p53 tumor suppressor mutations). Whether and how oncogenes can help "self-tolerize" by creating analogous functional defects in physiologic DDR networks is not known. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWSR1-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSBs), though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. We discover that the EWSR1-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native FET (EWSR1) protein function in activating the DNA damage sensor ATM. In multiple FET rearranged cancers, FET fusion oncoproteins induce functional ATM defects, rendering the compensatory ATR signaling axis as a collateral dependency and therapeutic target. More generally, we find that aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt physiologic DSB repair, revealing a mechanism for how growth-promoting oncogenes can also create functional defects within tumor suppressive DDR networks.

Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN's Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations., (© 2024. The Author(s).)

In this note, we combined pediatric sarcoma data from Columbia University with adult sarcoma data collected from TCGA, in order to see if one can automatically discern a unique pediatric cluster in the combined data set. Using a novel clustering pipeline based on optimal transport theory, this turned out to be the case. The overall methodology may find uses for the classification of data from other biological networking problems.

Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from "Carvedilol Effect on Chemotherapy-induced Cardiotoxicity" (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Endometrial mesenchymal stem/progenitor cells (eMSCs) are multipotent cells known to modulate the immune system and have clinical application for human and animal health. This makes these bovines cells attractive for dual use as cellular therapy and experimental model. The aim of this study was to isolate, evaluate the differentiation potential, immunophenotypic and immunocytochemistry characteristics, chromosomal stability, cloning efficiency, and cryopreservation response of bovine eMSCs collected in two phases of the estrous cycle. For this, cells were isolated and submitted to differentiation for adipogenic and osteogenic lineage. The cells were then characterized by flow cytometer (FC) (vimentin, CD29, CD44, MHC-II, CD34) and immunocytochemistry (vimentin, pan-cytokeratin, CD44) and submitted to cytogenetic and cloning efficiency assay. The cells were also cryopreserved using two different medium of cryopreservation and analyzed by FC for viability, necrosis, late-apoptosis + necrosis, and initial apoptosis rates before and after cryopreservation. We obtained homogeneous cell populations which have fibroblastic morphology and adherence to plastic. These cells expressed high levels of markers CD29, CD44, and vimentin, low expression levels for CD34 and no MHC-II. The cells were chromosomally stable (2n = 60) with high cloning efficiency and no difference (P > 0.05) between medium of cryopreservation or phase was observed after thawing. We showed the presence and differentiation potential of bovine eMSCs, with chromosomal stability and great response to cryopreservation with both medium, which has implications for build biobanks or development of new therapeutic approaches to combat uterine diseases or to study., (© 2016 International Federation for Cell Biology.)

Background and Objectives: Mesenchymal stromal cells (MSCs) have great therapeutic potential, particularly in the process of tissue repair and immunomodulation through the secretion of biomolecules. Thus, the aim of this study was to evaluate the hypothesis that intramuscular transplantation of allogeneic MSCs obtained from equine umbilical cord (UC-MSCs) is safe, demonstrating that this is a suitable source of stem cells for therapeutic use., Methods and Results: For this, UC-MSCs were cultured, characterized and cryopreserved for future transplantation in six healthy mares. On day 0, transplantation of three million UC-MSCs diluted in Hank's Balanced Solution (HBSS) was performed on right and left sides of the rump muscle. As a control, HBSS injections were performed caudally in the same muscle. Muscle biopsies were obtained as a control 30 days before transplantation (D-30). The biopsies were collected again on day 2 (left side) and day 7 (right side) post transplantation and examined histologically. All procedures were preceded by ultrasound examination and blood sampling. Hematologic evaluation remained within normal limits and no differences were observed between time points (p>0.05). Ultrasound examination was suggestive of inflammation 48 hours after transplantation in both groups (control and treated). At histological evaluation it was found only discrete inflammation signals between D-30×D2 (p<0.05) in the treated group, without differences (p> 0.05) between the groups at different time points., Conclusions: Equine UC-MSCs under the experimental conditions did not promote severe inflammation that causes tissue damage or lead to its rejection by the host organism and therefore has a good potential for clinical use.

Objectives: The goal of this study was to test the effects of a respiratory filter intervention (filter) during controlled pollution exposure., Background: Air pollution is considered a risk factor for heart failure (HF) decompensation and mortality., Methods: This study was a double-blind, randomized to order, controlled, 3-way crossover, single-center clinical trial. It enrolled 26 patients with HF and 15 control volunteers. Participants were exposed in 3 separate sessions to clean air, unfiltered diesel exhaust exposure (DE), or filtered DE. Endpoints were endothelial function assessed by using the reactive hyperemia index (RHi), arterial stiffness, serum biomarkers, 6-min walking distance, and heart rate variability., Results: In patients with HF, DE was associated with a worsening in RHi from 2.17 (interquartile range [IQR]: 1.8 to 2.5) to 1.72 (IQR: 1.5 to 2.2; p = 0.002) and an increase in B-type natriuretic peptide (BNP) from 47.0 pg/ml (IQR: 17.3 to 118.0 pg/ml) to 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml; p = 0.004). Filtration reduced the particulate concentration (325 ± 31 μg/m(3) vs. 25 ± 6 μg/m(3); p < 0.001); in the group with HF, filter was associated with an improvement in RHi from 1.72 (IQR: 1.5 to 2.2) to 2.06 (IQR: 1.5 to 2.6; p = 0.019) and a decrease in BNP from 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml) to 44.0 pg/ml (IQR: 20.0 to 110.0 pg/ml; p = 0.015) compared with DE. In both groups, DE decreased the 6-min walking distance and arterial stiffness, although filter did not change these responses. DE had no effect on heart rate variability or exercise testing., Conclusions: To our knowledge, this trial is the first to show that a filter can reduce both endothelial dysfunction and BNP increases in patients with HF during DE. Given these potential benefits, the widespread use of filters in patients with HF exposed to traffic-derived air pollution may have beneficial public health effects and reduce the burden of HF. (Effects of Air Pollution Exposure Reduction by Filter Mask on Heart Failure; NCT01960920)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Knowledge of both the common and atypical presentations of human immunodeficiency virus (HIV)-associated dermatoses may be helpful in arousing suspicion of HIV, especially in patients with no reported risk factors. Herein, we report the case of an otherwise healthy, nonpromiscuous 29-year-old man who presented to our institution with an eight-week history of plaques with oyster shell-like scales on the trunk, extremities and genital area. The plaques were associated with fever, and intermittent knee pain and swelling. Initial diagnostic tests were suggestive of drug hypersensitivity syndrome, and the patient's condition improved with treatment using oral prednisone. However, the lesions recurred when the dose of prednisone was tapered, even after the culprit drug had long been discontinued. Repeat skin punch biopsy and arthrocentesis revealed a diagnosis of psoriasis vulgaris with psoriatic arthritis. Due to the atypical presentation of psoriasis, the patient was counselled to undergo HIV testing, which came back positive. Clinicians should be attuned to the skin signs heralding HIV/acquired immunodeficiency syndrome, in order to facilitate early diagnosis and treatment.

Background: Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure., Methods: In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin-NGAL and the urinary excretion of aquaporin 2 (AQP2), urea transporter (UT-A1), and sodium/hydrogen exchanger 3 (NHE3)., Results: Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09-0.98; P=0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P=0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP2, UT-A1 and NHE3 was significantly higher in HSS than in placebo., Conclusions: HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Pluripotent cells can be derived from various types of somatic cells by nuclear reprogramming using defined transcription factors. It is, however, unclear whether human cancer cells can be similarly reprogrammed and subsequently terminally differentiated with abrogation of tumorigenicity. Here, using sarcomas we show that human-derived complex karyotype solid tumors: (1) can be reprogrammed into a pluripotent-like state as defined by all in vitro criteria used to define pluripotent stem cells generated from somatic cells; (2) can be terminally differentiated into mature connective tissue and red blood cells; and (3) terminal differentiation is accompanied with loss of both proliferation and tumorigenicity. We go on to perform the first global DNA promoter methylation and gene expression analyses comparing human cancers to their reprogrammed counterparts and report that reprogramming/differentiation results in significant epigenetic remodeling of oncogenes and tumor suppressors, while not significantly altering the differentiation status of the reprogrammed cancer cells, in essence dedifferentiating them to a state slightly before the mesenchymal stem cell differentiation stage. Our data demonstrate that direct nuclear reprogramming can restore terminal differentiation potential to human-derived cancer cells, with simultaneous loss of tumorigenicity, without the need to revert to an embryonic state. We anticipate that our models would serve as a starting point to more fully assess how nuclear reprogramming overcomes the multitude of genetic and epigenetic aberrancies inherent in human cancers to restore normal terminal differentiation pathways. Finally, these findings suggest that nuclear reprogramming may be a broadly applicable therapeutic strategy for the treatment of cancer.

Background: Sudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy., Methods and Results: We examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all-cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54.1%) died. Death occurred in 56.4% Chagas patients and 53.7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2.76; CI 1.34-5.69; p = 0.006), LVEDD (left ventricular end diastolic diameter) (HR 1.07; CI 1.04-1.10; p<0.001), creatinine clearance (HR 0.98; CI 0.97-0.99; p = 0.006) and use of amiodarone (HR 3.05; CI 1.47-6.34; p = 0.003) were independently associated with heart failure mortality. LVEDD (HR 1.04; CI 1.01-1.07; p = 0.005) and use of beta-blocker (HR 0.52; CI 0.34-0.94; p = 0.014) were independently associated with sudden death mortality., Conclusions: In severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death., Trial Registration: ClinicalTrials.gov NCT00505050 (REMADHE).

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiationbased therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.

Aims: Trials of disease management programmes (DMP) in heart failure (HF) have shown controversial results regarding quality of life. We hypothesized that a DMP applied over the long-term could produce different effects on each of the quality-of-life components., Methods and Results: We extended the prospective, randomized REMADHE Trial, which studied a DMP in HF patients. We analysed changes in Minnesota Living with Heart Failure Questionnaire components in 412 patients, 60.5% male, age 50.2 +/- 11.4 years, left ventricular ejection fraction 34.7 +/- 10.5%. During a mean follow-up of 3.6 +/- 2.2 years, 6.3% of patients underwent heart transplantation and 31.8% died. Global quality-of-life scores improved in the DMP intervention group, compared with controls, respectively: 57.5 +/- 3.1 vs. 52.6 +/- 4.3 at baseline, 32.7 +/- 3.9 vs. 40.2 +/- 6.3 at 6 months, 31.9 +/- 4.3 vs. 41.5 +/- 7.4 at 12 months, 26.8 +/- 3.1 vs. 47.0 +/- 5.3 at the final assessment; P < 0.01. Similarly, the physical component (23.7 +/- 1.4 vs. 21.1 +/- 2.2 at baseline, 16.2 +/- 2.9 vs. 18.0 +/- 3.3 at 6 months, 17.3 +/- 2.9 vs. 23.1 +/- 5.7 at 12 months, 11.4 +/- 1.6 vs. 19.9 +/- 2.4 final; P < 0.01), the emotional component (13.2 +/- 1.0 vs. 12.1 +/- 1.4 at baseline, 11.7 +/- 2.7 vs. 12.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 16.8 +/- 5.9 at 12 months, 6.7 +/- 1.0 vs. 10.6 +/- 1.4 final; P < 0.01) and the additional questions (20.8 +/- 1.2 vs. 19.3 +/- 1.8 at baseline, 14.3 +/- 2.7 vs. 17.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 21.0 +/- 5.5 at 12 months, 6.7 +/- 1.4 vs. 17.3 +/- 2.2 final; P < 0.01) were better (lower) in the intervention group. The emotional component improved earlier than the others. Post-randomization quality of life was not associated with events., Conclusion: Components of the quality-of-life assessment responded differently to DMP. These results indicate the need for individualized DMP strategies in patients with HF. Trial registration information www.clincaltrials.gov NCT00505050-REMADHE.

Background: Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation., Methods: The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up., Conclusion: The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of beta-blockers in patients with Chagas cardiomyopathy., Methods and Results: We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and beta-blocker therapy. Primary end point was all-cause mortality or heart transplantation. Altogether 456 patients were studied; 27 (5.9%) were submitted to heart transplantation and 202 (44.3%) died. Chagas etiology was present in 68 (14.9%) patients; they had lower body mass index (24.1+/-4.1 versus 26.3+/-5.1, P=0.001), smaller end-diastolic left ventricle diameter (6.7+/-1.0 mm versus 7.0+/-0.9 mm, P=0.001), smaller proportion of beta-blocker therapy (35.8% versus 68%, P<0.001), and higher proportion of spironolactone therapy (74.6% versus 57.8%, P=0.003). Twenty-four (35.8%) patients with Chagas disease were under beta-blocker therapy and had lower serum sodium (136.6+/-3.1 versus 138.4+/-3.1 mEqs, P=0.05) and lower body mass index (22.5+/-3.3 versus 24.9+/-4.3, P=0.03) compared with those who received beta-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under beta-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with beta-blockers was higher than that of patients without beta-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P=0.009) and beta-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P=0.044) were associated with better survival., Conclusions: Our study suggests that beta-blockers may have beneficial effects on survival of patients with heart failure and Chagas heart disease and warrants further investigation in a prospective, randomized trial. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00505050.

Objective: To assess the effects of bisoprolol on exercise capacity and ventricular function in patients with heart failure., Methods: Clinical and hemodynamic variables, ventricular function and remodeling, and ergospirometry of patients with heart failure of different etiologies were evaluated before and after the administration of bisoprolol., Results: Twenty-two patients were analyzed; one patient did not tolerate medication and 14 patients reached the study goal. The group consisted of 9 men and 5 women, the mean age was 52 (36-64) years, and patients were followed during 551 days (238-1109). We observed an improvement in NYHA functional class, reduction in resting heart rate (78.8+/-8.7 vs 63+/-6.4 bpm, p <0.001), increase in left ventricular ejection fraction (31.3+/-8.5% vs 39+/-14.7%. p=0.043), and a tendency towards improved quality of life scores (31+/-20.6 vs 17.8+/-14.8. p=0.058). The maximum heart rate dropped during exercise (138.1+/-20.2 vs 116.7+/-27.1. p=0.01), as did peak oxygen consumption (20.9+/-6.8 vs 15.1+/-3.5. p<0.001); no change was observed on the EV/VCO2 slope. The effects were observed for all etiologies, including Chagas disease., Conclusion: Bisoprolol was safe and well tolerated in patients with heart failure. Bisoprolol therapy improved the symptoms, hemodynamic variables, as well as the cardiac function for all etiologies; however, it did not result in improved exercise capacity.

Background: Right ventricular (RV) dysfunction remains one of the most prominent complications during the period immediately after heart transplantation (HT); however, late adaptation of the RV has not been well described. The aim of our study was to evaluate RV function and remodeling using magnetic resonance imaging (MRI) and to correlate it with exercise capacity and also with hemodynamic data obtained before HT., Methods: We prospectively evaluated RV function of 25 heart-transplanted patients, without cardiac allograft vasculopathy, who were documented by negative dobutamine stress echocardiography during late follow-up (Group 1, 6 +/- 4.3 years) using MRI. We then compared Group 1 with a control group consisting of 10 patients, who were < or =1 year post-HT (Group 2), hemodynamically stable, and with the same pre-operative hemodynamic features as Group 1. Their pulmonary arterial systolic blood pressure (PSBP) varied from 17 to 67 mm Hg (43.2 +/- 15.3) and pulmonary vascular resistance (PVR) from 1.0 to 5.4 Wood units (2.5 +/- 1.12). The following parameters were studied: RV end-diastolic volume (EDV) and systolic volume (ESV); stroke volume (SV); ejection fraction (EF); and mass (M). We also evaluated the VO2 peak and slope VE/VCO2 values during a treadmill test. Data were analyzed and correlated with the hemodynamic values of PVR and PSBP obtained pre-HT., Results: In Group 1, treadmill evaluation data showed exercise VO2 peak (19.9 +/- 3.19 ml/kg/min) and slope VE/VCO2 (36.9 +/- 4.5) values comparable to those of sedentary individuals; RV variables according to MRI were within normal ranges, with the following mean values for Groups 1 and 2, respectively: RVEDV, 99.6 +/- 4.0 ml vs 127 +/- 16 ml (p = 0.03); RVESV, 42 +/- 2 ml vs 58.5 +/- 9 ml (p = 0.01); RVSV, 57 +/- 3 ml vs 71 +/- 10 ml (p = 0.1); RVEF, 58 +/- 1.4% vs 54 +/- 3.8% (p = 0.29); and RVM, 43.4 +/- 1.9 g vs 74 +/- 8.8 g (p = 0.001). There was no correlation between hemodynamic pulmonary values before HT or any other index of late RV performance, including RV remodeling and hypertrophy, in our study population (p = not significant)., Conclusions: In contrast to what we would expect for heart transplant patients at late follow-up, the RV may adapt to pulmonary pressure and resistance, with reverse remodeling characterized by volume and mass reduction, leading to normalization of RV function despite abnormal hemodynamic pulmonary values being measured before HT. There was no influence on the low exercise capacity observed in these patients, in the absence of cardiac allograft vasculopathy.

Bacterial conjugation is a promiscuous DNA transport mechanism. Conjugative plasmids transfer themselves between most bacteria, thus being one of the main causal agents of the spread of antibiotic resistance among pathogenic bacteria. Moreover, DNA can be transferred conjugatively into eukaryotic host cells. In this review, we aim to address several basic questions regarding the DNA transfer mechanism. Conjugation can be visualized as a DNA rolling-circle replication (RCR) system linked to a type IV secretion system (T4SS), the latter being macromolecular transporters widely involved in pathogenic mechanisms. The scheme 'replication + secretion' suggests how the mechanism would work on the DNA substrate and at the bacterial membrane. But, how do these two parts come into contact? Furthermore, how is the DNA transported? T4SS are known to be involved in protein secretion in different organisms, but DNA is a very different macromolecule. The so-called coupling proteins could be the answer to both questions by performing a dual role in conjugation: coupling the two main components of the machinery (RCR and T4SS) and actively mediating DNA transport. We postulate that the T4SS is responsible for transport of the pilot protein (the relaxase) to the recipient. The DNA that is covalently linked to it is initially transported in a passive manner, trailing on the relaxase. We speculate that the pilus appendage could work as a needle, thrusting the substrate proteins to cross one or several membrane barriers into the recipient cytoplasm. This is the first step in conjugation. The second step is the active pumping of the DNA to the recipient, using the already available T4SS transport conduit. It is proposed that this second step is catalysed by the coupling proteins. Our 'shoot and pump' model solves the protein-DNA transport paradox of T4SS.

Endocrine disruptors are hormone mimics that modify hormonal action in humans and animals. It is thought that some endocrine disruptors modify estrogen and androgen action in humans and animals by suppressing aromatase activity. Aromatase cytochrome P450 is the key enzyme that converts C19 androgens to aromatic C18 estrogenic steroids. We have developed a novel aromatase inhibitor screening method that allows us to identify antiaromatase activity of various environmental chemicals. The screen was developed by coexpressing the human aromatase and the mouse androgen receptor in yeast cells, which carry the androgen-responsive ss-galactosidase reporter plasmid. Functional expression of aromatase in yeast has been demonstrated using the [3H]-water release assay with intact cells as well as with yeast microsomes. The aromatase activity could be blocked by known aromatase inhibitors such as aminoglutethimide (AG). Yeast-produced androgen receptors were able to transactivate a yeast basal promoter linked to an androgen-responsive element in response to androgens. The resultant triple yeast transformant responded to the treatment of testosterone, androstenedione, or 5 alpha-dihydrotestosterone (5 alpha-DHT). In the absence of the aromatase inhibitor AG, transcriptional activation was observed only for the nonaromatizable androgen 5 alpha-DHT. However, the two aromatizable androgens (testosterone and androstenedione) induced the reporter activity in the presence of AG. Using this yeast-based assay, we confirmed that two flavones, chrysin and alpha-naphtholflavone, are inhibitors of aromatase. Thus, this yeast system allows us to develop a high-throughput screening method, without using radioactive substrate, to identify aromatase inhibitors as well as new ligands (nonaromatizable androgen mimics) for the androgen receptors. In addition, this screening method also allows us to distinguish nonandrogenic aromatase inhibitors from inhibitors with androgenic activity. This yeast screening method will be useful to screen environmental chemicals for their antiaromatase activity and for their interaction with androgen receptor.