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Objective: Left anterior descending Myocardial Bridge (LADMB) is considered a benign condition and actually becomes a forgotten cause of serious cardiac events. This study was conducted to estimate the prevalence of LADMB and its association to atherosclerosis. Methods: An observational retrospective study was conducted on patients referred for coronary angiography between June 2012 and June 2020. Coronary angiography database was revisedand studied population was divided into 2 groups: LADMB group versus Non-LADMB group. Results: LADMB was detected in 510 patients out of 35813 included in the study resulting in a prevalence at 1.42%. The mean age was 66.5 years. Male gender was more common than female (70vs30%). The prevalence of significant atherosclerotic LAD disease was more than two times higher in the non-LADMB group compared to the LADMB group. Statistical analysis revealed a significant negative association between LADMB and atherosclerosis (p

Abstract While existing remedies failed to fully address the consequences of heart failure, stem cell therapy has been introduced as a promising approach. The present review is a comprehensive appraisal of the impacts of using mesenchymal stem cells (MSCs) in clinical trials mainly conducted on ischemic cardiomyopathy. The benefits of MSC therapy for dysfunctional myocardium are likely attributed to numerous secreted paracrine factors and immunomodulatory effects. The positive outcomes associated with MSC therapy are scar size reduction, reverse remodeling, and angiogenesis. Also, a decreasing in the level of chronic inflammatory markers of heart failure progression like TNF-α is observed. The intense inflammatory reaction in the injured myocardial micro-environment predicts a poor response of scar tissue to MSC therapy. Subsequently, the interval delay between myocardial injury and MSC therapy is not yet determined. The optimal requested dose of cells ranges between 100 to 150 million cells. Allogenic MSCs have different advantages compared to autogenic cells and intra-myocardial injection is the preferred delivery route. The safety and efficacy of MSCs-based therapy have been confirmed in numerous studies, however several undefined parameters like route of administration, optimal timing, source of stem cells, and necessary dose are limiting the routine use of MSCs therapeutic approach in clinical practice. Lastly, pre-conditioning of MSCs and using of exosomes mediated MSCs or genetically modified MSCs may improve the overall therapeutic effect. Future prospective studies establishing a constant procedure for MSCs transplantation are required in order to apply MSC therapy in our daily clinical practice and subsequently improving the overall prognosis of ischemic heart failure patients.

Experience replay is widely used in AI to bootstrap reinforcement learning (RL) by enabling an agent to remember and reuse past experiences. Classical techniques include shuffled-, reversed-ordered- and prioritized-memory buffers, which have different properties and advantages depending on the nature of the data and problem. Interestingly, recent computational neuroscience work has shown that these techniques are relevant to model hippocampal reactivations recorded during rodent navigation. Nevertheless, the brain mechanisms for orchestrating hippocampal replay are still unclear. In this paper, we present recent neurorobotics research aiming to endow a navigating robot with a neuro-inspired RL architecture (including different learning strategies, such as model-based (MB) and model-free (MF), and different replay techniques). We illustrate through a series of numerical simulations how the specificities of robotic experimentation (e.g., autonomous state decomposition by the robot, noisy perception, state transition uncertainty, non-stationarity) can shed new lights on which replay techniques turn out to be more efficient in different situations. Finally, we close the loop by raising new hypotheses for neuroscience from such robotic models of hippocampal replay.

Introduction. The prevalence of coronary artery disease (CAD) detected in preoperative work-up for transcatheter aortic valve implantation (TAVI) is high. Instead, the management of a concomitant CAD remains unclear. We evaluate the impact of CAD and percutaneous coronary intervention (PCI) on TAVI procedures. Materials and Methods. A retrospective study was conducted on 1336 consecutive patients who underwent TAVI in Toulouse University Hospital, Rangueil, France. The studied population was divided into 2 groups: CAD-TAVI group and No CAD-TAVI group. Then, the CAD-TAVI group was segregated into 2 subgroups: PCI-TAVI group and No PCI-TAVI group. In-hospital adverse clinical outcomes were assessed in each group. Results. Pre-TAVI work-up revealed significant CAD in 36% of 1030 patients eligible for inclusion in the study. The overall prevalence of in-hospital death, stroke, major or life-threatening bleeding, minor bleeding, major vascular complications, minor vascular complications, pacemaker implantation, and acute kidney injury was 2.7%, 2.4%, 2.8%, 3.6%, 3.9%, 7.5%, 12.5%, and 2.7%, respectively. Among the studied population, 55% were admitted to the cardiac care unit. No significant statistical difference was observed between groups. Discussion. CAD-TAVI population was not more likely to develop in-hospital adverse clinical outcomes post-TAVI procedure compared to others. Also, no significant difference regarding in-hospital death was observed. In parallel, performing PCI prior to TAVI did not increase the risk of in-hospital death and complications. The difference in terms of the distribution of antithrombotic regimen may explain the higher prevalence of bleeding events in the PCI-TAVI group. Conclusion. This study provides direct clinical relevance useful in daily practice. No negative impact has been attributed to the presence of a concomitant CAD and/or preoperative PCI on the TAVI hospitalization period.

Background. Vascular complications (VCs) are commonly observed after transfemoral transcatheter aortic valve implantation (TAVI) procedures. Closure devices for the access site were developed to reduce their incidence. We aim to evaluate the prevalence, predictors, and outcomes of the occurrence of post-TAVI VCs. Materials and Methods. A retrospective study was conducted on 1336 consecutive patients who underwent TAVI at the University Hospital of Toulouse, France, between January 2016 and March 2020. All included procedures were performed through the common femoral artery, and ProGlide® was the used closure device. The studied population was divided into two groups depending on the occurrence of VCs defined according to Valve Academic Research Consortium-2 criteria. Results. The mean age of the studied population was 84.4 ± 6.9, and 48% were male. 90% of TAVI interventions were performed through the right femoral artery. The prevalence of VCs was 18.8%, and 3.7% were major. Prolonged procedure duration was an independent predictor of VCs. Using the right access site and smaller introducer size (14 Fr) were preventive factors. No significant difference in mortality rate was detected between the two groups. Conclusion. This study showed a low prevalence for post-TAVI VCs, especially for the major type. An increase in bleeding events and prolonged cardiac care unit stay were the common adverse outcomes.

Ribosomal DNA (rDNA) is the most transcribed genomic region and contains hundreds of tandem repeats. Maintaining these rDNA repeats as well as the level of rDNA transcription is essential for cellular homeostasis. DNA damages generated in rDNA need to be efficiently and accurately repaired and rDNA repeats instability has been reported in cancer, aging and neurological diseases. Here, we describe that the histone demethylase JMJD6 is rapidly recruited to nucleolar DNA damage and is crucial for the relocalisation of rDNA in nucleolar caps. Yet, JMJD6 is dispensable for rDNA transcription inhibition. Mass spectrometry analysis revealed that JMJD6 interacts with the nucleolar protein Treacle and modulates its interaction with NBS1. Moreover, cells deficient for JMJD6 show increased sensitivity to nucleolar DNA damage as well as loss and rearrangements of rDNA repeats upon irradiation. Altogether our data reveal that rDNA transcription inhibition is uncoupled from rDNA relocalisation into nucleolar caps and that JMJD6 is required for rDNA stability through its role in nucleolar caps formation.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [123I]IMT, [18F]FET, [18F]FDOPA, [123I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [123I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [123I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [125I]5-iodo-L-TIC(OH), [125I]6-iodo-L-TIC(OH) and [125I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [18F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [18F]F− with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%).

Recent studies suggest key roles of RNA in DNA double-strand breaks repair. Here the authors identify the helicase senataxin to be involved in DNA repair and resolve RNA:DNA hybrids forming at DNA double-strand breaks.

Repair of double strand break by homologous recombination was examined using U2OS cells or RG37 cells harbouring specific substrate developed by Puget et al. (2005) and Dumay et al. (2006), respectively, to measure the repair of DNA double strand breaks by homologous recombination. The substrate is composed of two inactive copies of the GFP gene. The upstream copy is inactive due to the absence of promoter, the downstream copy present a promoter but is inactivated by the insertion of the sequence coding for the recognition site of the I-SceI enzyme. The substrate is stably expressed in cells after its insertion in the genome and present as a unique copy. The unique DNA double strand break is then induced by the expression of the I-SceI enzyme after cell transfection with a plasmid coding for the I-SceI enzyme.

The Comet assay (or Single Cell Gel Electrophoresis assay) is a sensitive technique to detect DNA damage at the level of an individual cell. This technique is based on micro-electrophoresis of cells DNA content. Briefly, cells are embedded in agarose, lysed and submitted to an electric field, before the staining step with a fluorescent DNA binding dye. Damaged DNA (charged DNA) migrates in this field, forming the tail of a “comet”, while undamaged DNA remained in the head of the “comet”. The following document describes the protocol to realize a neutral comet assay. This assay can be applied to different cell types and has been useful for numerous applications in fields of toxicology or DNA damage and repair.

hMSL2 (male-specific lethal 2, human) is a RING finger protein with ubiquitin ligase activity. Although it has been shown to target histone H2B at lysine 34 and p53 at lysine 351, suggesting roles in transcription regulation and apoptosis, its function in these and other processes remains poorly defined. To further characterize this protein, we have disrupted the Msl2 gene in chicken DT40 cells. Msl2(-/-) cells are viable, with minor growth defects. Biochemical analysis of the chromatin in these cells revealed aberrations in the levels of several histone modifications involved in DNA damage response pathways. DNA repair assays show that both Msl2(-/-) chicken cells and hMSL2-depleted human cells have defects in non-homologous end joining (NHEJ) repair. DNA damage assays also demonstrate that both Msl2 and hMSL2 proteins are modified and stabilized shortly after induction of DNA damage. Moreover, hMSL2 mediates modification, presumably ubiquitylation, of a key DNA repair mediator 53BP1 at lysine 1690. Similarly, hMSL1 and hMOF (males absent on the first) are modified in the presence of hMSL2 shortly after DNA damage. These data identify a novel role for Msl2/hMSL2 in the cellular response to DNA damage. The kinetics of its stabilization suggests a function early in the NHEJ repair pathway. Moreover, Msl2 plays a role in maintaining normal histone modification profiles, which may also contribute to the DNA damage response.

Chromatin undergoes major remodeling around DNA double-strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high-resolution map of γH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the chromatin landscape induced around DSBs, we now report the profile of SMC3, a subunit of the cohesin complex, previously characterized as required for repair by homologous recombination. We found that recruitment of cohesin is moderate and restricted to the immediate vicinity of DSBs in human cells. In addition, we show that cohesin controls γH2AX distribution within domains. Indeed, as we reported previously for transcription, cohesin binding antagonizes γH2AX spreading. Remarkably, depletion of cohesin leads to an increase of γH2AX at cohesin-bound genes, associated with a decrease in their expression level after DSB induction. We propose that, in agreement with their function in chromosome architecture, cohesin could also help to isolate active genes from some chromatin remodelling and modifications such as the ones that occur when a DSB is detected on the genome.

The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM-dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400.

BACKGROUND:DNA polymerase lambda (Pollambda) is a DNA repair polymerase, which likely plays a role in base excision repair (BER) and in non-homologous end joining (NHEJ) of DNA double-strand breaks (DSB). PRINCIPAL FINDINGS:Here, we described a novel natural allelic variant of human Pollambda (hPollambda) characterized by a single nucleotide polymorphism (SNP), C/T variation in the first base of codon 438, resulting in the amino acid change Arg to Trp. In vitro enzyme activity assays of the purified W438 Pollambda variant revealed that it retained both DNA polymerization and deoxyribose phosphate (dRP) lyase activities, but had reduced base substitution fidelity. Ectopic expression of the W438 hPollambda variant in mammalian cells increases mutation frequency, affects the DSB repair NHEJ pathway, and generates chromosome aberrations. All these phenotypes are dependent upon the catalytic activity of the W438 hPollambda. CONCLUSIONS:The expression of a cancer-related natural variant of one specialized DNA polymerase can be associated to generic instability at the cromosomal level, probably due a defective NHEJ. These results establish that chromosomal aberrations can result from mutations in specialized DNA repair polymerases.

La ocupación en la producción de azúcar en Tucumán ha decaído considerablemente en la última década. Como la producción de azúcar es la actividad más importante en la región se ha producido una alta tasa de desempleo y una emigración de trabajadores. Este proceso no ha sido continuo, sino sujeto a fluctuaciones debido a la inestabilidad del precio y oferta del producto. Este trabajo analiza las tendencias del mercado y la producción y concluye que la caída del empleo es una consecuencia del estancamiento de la demanda combinado con un rápido aumento del rendimiento de la caña de azúcar. La inestabilidad es por otra parte la consecuencia de los altos costos, la gran proporción de pequeños productores y la existencia de ajustes de tipo telaraña. El artículo finaliza con la proyección de posibles niveles de empleo en los próximos cinco años, de acuerdo a diferentes hipótesis alternativas.

Measurement of cardiac troponin (cTn) levels in blood is standard for diagnosis and risk stratification in cardiac emergencies. To investigate the causes, link to underlying coronary artery disease and prognostic value of cTn release in infective endocarditis (IE). Eighty-six consecutive patients hospitalized for acute IE, with at least one cTn drawn and a coronary angiogram performed, were reviewed retrospectively. Factors related to the increase of cTn above the 99th percentile or above 10 times normal (> 10N), as well as their prognostic impact, were assessed. The mean patient age was 63 + 14 years, the majority were men (n = 68, 79%) with staphylococcus IE (n = 34, 40%). Cardiac troponins were elevated above the 99th percentile for 74 (86%) patients and > 10N for 25 (29%) patients. There was no statistically significant correlation between elevated cTn and the presence of an underlying coronary artery disease (Table 1). Cardiac troponin elevation above the 99th percentile was significantly associated with impaired renal function (P = 0.04) and staphylococcus infection (P = 0.02). A rise of cTn > 10N was significantly associated with acute pulmonary edema (P = 0.001), myocardial abscess (P = 0.01), staphylococcus (P = 0.0004), streptococcus (P = 0.008), and renal function (p = 0.0001). The average follow-up period was 919±816 days, and an elevation of cTn > 10 N had a clear prognostic impact (HR 2.38, 95%CI: 1.18–4.84, P = 0.01) (Fig. 1). Troponin elevation in IE is frequent and appears to be related to direct and indirect myocardial injury. It is associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

Myocardial infarction with non obstructive coronary arteries (MINOCA) is a complex working diagnosis including coronary and non-coronary causes, like spontaneous coronary dissection, coronary thrombosis or embolism, myocarditis and cardiomyopathy. The prevalence of MINOCA is increasing, but the underlying etiology remains undetermined in more than 10% of cases. Hypotheses on the potential contributing role of myocardial bridge (MB) in takotsubo cardiomyopathy and coronary artery spasm (CAS) have been raised. We aim to investigate the relationship between MB and MINOCA. An observational retrospective study was conducted on 15,036 patients who had been referred for coronary angiography and who fulfilled the Definition of Myocardial Infarction. The study population was divided into STEMI and Non-STEMI patients, from which we defined two main groups: the MINOCA group and the coronary artery disease (CAD) group. The prevalence of MB was calculated in each group (Fig. 1). The distribution of angiographic MB among the groups was significantly greater in the MINOCA group (2.9% vs. 0.8%, P < 0.001). MINOCA accounted for 14.5% of spontaneous myocardial infarctions, and the clinical presentation was frequently NSTEMI rather than STEMI (84.3% vs. 15.7%, P < 0.001). Adjusted multivariate analyses showed a positive association between MB and MINOCA [OR = 3.28, 95% CI (2.34; 4.61) P < 0.001]. Cardiovascular risk factors were less common in the MINOCA population, which was younger and more often female. The main finding of the present study was that MB is an independent predictor for MINOCA, increasing the corresponding risk by threefold. Because MB prevalence differed significantly between the controls (CAD group) and in the MINOCA group, which was positively correlated to MB, it seems likely that MB would be a potential cause of MINOCA. Future prospective studies are necessary to highlight the physiologic significance of MB in some MINOCA patients. [ABSTRACT FROM AUTHOR]

Summary: We present a case of empyema caused by overinfection of pleural fluid secondary to pulmonary thromboembolism, with negative progress, and the symptoms still persisting after optimum anticoagulant treatment. Given the patient′s negative progress, the possibility of an onset of rheumatoid arthritis (RA) is considered. The diagnosis of onset RA should be considered for unexplained pleural effusion, even though negative rheumatoid factor. [Copyright &y& Elsevier]