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Maxime Billot,1,2 Riccardo Calvani,3,4 Annele Urtamo,5 Juan Luis Sánchez-Sánchez,6 Cecilia Ciccolari-Micaldi,1 Milan Chang,7,8 Regina Roller-Wirnsberger,9 Gerhard Wirnsberger,10 Alan Sinclair,11 Nieves Vaquero-Pinto,12 Satu Jyväkorpi,5 Hanna Öhman,5 Timo Strandberg,13,14 Jos MGA Schols,15 Annemie MWJ Schols,16 Nick Smeets,17 Eva Topinkova,18 Helena Michalkova,19 Anna Rita Bonfigli,20 Fabrizia Lattanzio,20 Leocadio Rodríguez-Mañas,21 Hélio Coelho-Júnior,4 Marianna Broccatelli,4 Maria Elena D’Elia,4 Damiano Biscotti,4 Emanuele Marzetti,3,4 Ellen Freiberger22 1Clinical Gerontology, University Hospital of Limoges, Limoges, France; 2PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery), Poitiers University Hospital, Poitiers, France; 3Università Cattolica del Sacro Cuore, Rome, Italy; 4Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy; 5University of Helsinki, Department of General Practice and Primary Health Care, Helsinki University Central Hospital, Unit of Primary Health Care, Helsinki, Finland; 6Foundation for Biomedical Research Getafe University Hospital, Madrid, Spain; 7Faculty of Health Promotion, Sports and Leisure Studies, School of Education, University of Iceland, Reykjavik, Iceland; 8The Icelandic Gerontological Research Center, Landspitali University Hospital and University of Iceland, Reykjavik, Iceland; 9Medical University of Graz, Department of Internal Medicine, Graz, Austria; 10Medical University of Graz, Division of Nephrology, Department of Internal Medicine, Graz, Austria; 11Foundation for Diabetes Research in Older People, Diabetes Frail Ltd., Luton, UK; 12University Hospital of Ramon Cajal IRYCIS, Madrid, Spain; 13University of Helsinki, Clinicum, Helsinki, Finland; Helsinki University Hospital, Medicine and Rehabilitation, Helsinki, Finland; 14University of Oulu, Center for Life Course Health Research, Oulu, Finland; 15Department of Health Services Research, Maastricht University Medical Center, Maastricht, The Netherlands; 16Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, Maastricht, The Netherlands; 17Department of Health & Fitness, Maastricht University Medical Center, Maastricht, The Netherlands; 18 First Faculty of Medicine, Charles University, Prague, Czech Republic; 19Faculty of Social and Health Sciences, South Bohemian University, Ceske Budejovice, Czech Republic; 20Scientific Direction, IRCCS INRCA, Ancona, Italy; 21Geriatrics Service, University Hospital of Getafe, Madrid, Spain; 22Institute for Biomedicine of Aging, FAU Erlangen-Nürnberg, Nürnberg, GermanyCorrespondence: Maxime Billot CHU De Poitiers, PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery)Poitiers University Hospital, 2 Rue De La Miléterie, Poitiers 86021, FranceTel +33 549 443 224Email maxime.billot2@gmail.comAbstract: One of the most widely conserved hallmarks of aging is a decline in functional capabilities. Mobility loss is particularly burdensome due to its association with negative health outcomes, loss of independence and disability, and the heavy impact on quality of life. Recently, a new condition, physical frailty and sarcopenia, has been proposed to define a critical stage in the disabling cascade. Physical frailty and sarcopenia are characterized by weakness, slowness, and reduced muscle mass, yet with preserved ability to move independently. One of the strategies that have shown some benefits in combatting mobility loss and its consequences for older adults is physical activity. Here, we describe the opportunities and challenges for the development of physical activity interventions in people with physical frailty and sarcopenia. The aim of this article is to review age-related physio(patho)logical changes that impact mobility in old age and to provide recommendations and procedures in accordance with the available literature.Keywords: physical exercise, muscle mass, strength, walking, balance, better aging

The atrioventricular node (AVN) is a crucial component of the cardiac conduction system. Despite its pivotal role in regulating the transmission of electrical signals between atria and ventricles, a comprehensive understanding of the cellular electrophysiological mechanisms governing AVN function has remained elusive. This paper presents a detailed computational model of mouse AVN cell action potential (AP). Our model builds upon previous work and introduces several key refinements, including accurate representation of membrane currents and exchangers, calcium handling, cellular compartmentalization, dynamic update of intracellular ion concentrations, and calcium buffering. We recalibrated and validated the model against existing and unpublished experimental data. In control conditions, our model reproduces the AVN AP experimental features, (e.g. rate = 175 bpm, experimental range [121, 191] bpm). Notably, our study sheds light on the contribution of L-type calcium currents, through both Ca v 1.2 and Ca v 1.3 channels, in AVN cells. The model replicates several experimental observations, including the cessation of firing upon block of Ca v 1.3 or I Na,r current. I f block induces a reduction in beating rate of 11%. In summary, this work presents a comprehensive computational model of mouse AVN cell AP, offering a valuable tool for investigating pacemaking mechanisms and simulating the impact of ionic current blockades. By integrating calcium handling and refining formulation of ionic currents, our model advances understanding of this critical component of the cardiac conduction system, providing a platform for future developments in cardiac electrophysiology. KEY POINTS: This paper introduces a comprehensive computational model of mouse atrioventricular node (AVN) cell action potentials (APs). Our model is based on the electrophysiological data from isolated mouse AVN cells and exhibits an action potential and calcium transient that closely match the experimental records. By simulating the effects of blocking specific ionic currents, the model effectively predicts the roles of L-type Ca v 1.2 and Ca v 1.3 channels, T-type calcium channels, sodium currents (TTX-sensitive and TTX-resistant), and the funny current (I f ) in AVN pacemaking. The study also emphasizes the significance of other ionic currents, including I Kr , I to , I Kur , in regulating AP characteristics and cycle length in AVN cells. The model faithfully reproduces the rate dependence of action potentials under pacing, opening the possibility of use in impulse propagation models. The population-of-models approach showed the robustness of this new AP model in simulating a wide spectrum of cellular pacemaking in AVN., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

We present a mode-locked semiconductor laser oscillator that emits few picosecond pulses (5-8ps at a repetition rate of 379MHz and wavelength of 1064nm) with record peak power (112W) and pulse energy (0.5nJ) directly out of the oscillator (with no amplifier). To achieve this high power performance we employ a high-current broad-area, spatially multi-mode diode amplifier (0.3×5mm), placed in an external cavity that enforces oscillation in a single spatial mode. Consequently, the brightness of the beam is near-ideal (M 2  = 1.3). Mode locking is achieved by dividing the large diode chip (edge emitter) into two sections with independent electrical control: one large section for gain and another small section for a saturable absorber. Precise tuning of the reverse voltage on the absorber section allows to tune the saturation level and recovery time of the absorber, providing a convenient knob to optimize the mode-locking performance for various cavity conditions.

Background: Acute myocardial infarction (AMI) is the major cause of cardiovascular mortality worldwide. Most ischemic episodes are triggered by an increase in heart rate, which induces an imbalance between myocardial oxygen delivery and consumption. Developing drugs that selectively reduce heart rate by inhibiting ion channels involved in heart rate control could provide more clinical benefits. The Ca v 1.3-mediated L-type Ca 2+ current ( I Cav1.3 ) play important roles in the generation of heart rate. Therefore, they can constitute relevant targets for selective control of heart rate and cardioprotection during AMI., Objective: We aimed to investigate the relationship between heart rate and infarct size using mouse strains knockout for Ca v 1.3 ( Ca v 1.3 -/- ) L-type calcium channel and of the cardiac G protein gated potassium channel ( Girk4 -/- ) in association with the funny (f)-channel inhibitor ivabradine., Methods: Wild-type (WT), Ca v 1.3 +/- , Ca v 1.3 -/- and Girk4 -/- mice were used as models of respectively normal heart rate, moderate heart rate reduction, bradycardia, and mild tachycardia, respectively. Mice underwent a surgical protocol of myocardial IR (40 min ischemia and 60 min reperfusion). Heart rate was recorded by one-lead surface ECG recording, and infarct size measured by triphenyl tetrazolium chloride staining. In addition, Ca v 1.3 -/- and WT hearts perfused on a Langendorff system were subjected to the same ischemia-reperfusion protocol ex vivo , without or with atrial pacing, and the coronary flow was recorded., Results: Ca v 1.3 -/- mice presented reduced infarct size (-29%), while Girk4 -/- displayed increased infarct size (+30%) compared to WT mice. Consistently, heart rate reduction in Ca v 1.3 +/- or by the f-channel blocker ivabradine was associated with significant decrease in infarct size (-27% and -32%, respectively) in comparison to WT mice., Conclusion: Our results show that decreasing heart rate allows to protect the myocardium against IR injury in vivo and reveal a close relationship between basal heart rate and IR injury. In addition, this study suggests that targeting Ca v 1.3 channels could constitute a relevant target for reducing infarct size, since maximal heart rate dependent cardioprotective effect is already observed in Ca v 1.3 +/- mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Delgado-Betancourt, Chinda, Mesirca, Barrere, Covinhes, Gallot, Vincent, Bidaud, Kumphune, Nargeot, Piot, Wickman, Mangoni and Barrère-Lemaire.)

Dissipative solitons are fundamental wave-pulses that preserve their form in the presence of periodic loss and gain. The canonical realization of dissipative solitons is Kerr-lens mode locking in lasers, which delicately balance nonlinear and linear propagation in both time and space to generate ultrashort optical pulses. This linear-nonlinear balance dictates a unique pulse energy, which cannot be increased (say by elevated pumping), indicating that excess energy is expected to be radiated in the form of dispersive or diffractive waves. Here we show that Kerr-lens mode-locked lasers can overcome this expectation. Specifically, by breaking the spatial symmetry between the forward and backward halves of the round-trip in a linear cavity, the laser can modify the soliton in space to incorporate the excess energy. Increasing the pump power leads therefore to a different soliton solution, rather than to dispersive/diffractive loss. We predict this symmetry breaking by a complete numerical simulation of the spatio-temporal dynamics in the cavity, and confirm it experimentally in a Kerr-lens mode-locked Ti:Sapphire laser with quantitative agreement to the simulation. The simulation opens a window to directly observe the nonlinear space-time dynamics that molds the soliton pulse, and possibly to optimize it., (© 2022. The Author(s).)

Background: Survival rates among non-small cell lung cancer (NSCLC) stage IIIA (N2) patients are generally low and depend on the treatment., Patients and Methods: We aimed to identify predictive markers for long term survival in responders and non-responders to chemotherapy, analyzing tumour and non-tumour samples by microarray (n=35) and whole exome sequencing (WES, n=25)., Results: WES data showed correlation of overall survival of all patients with rs9905892 in the SLFN12L gene. High frequency of mutations (4/6, 66.7%) was identified in members of SWI/SNF complex in responder patients and in patients that were alive after seven years. Microarray data for immune components showed that VISTA (VSIR) was down-regulated in tumoral tissue., Conclusion: Our research suggests that mutations in SWI/SNF complex associate with long term survival after multimodal treatment, while down-regulation of VISTA might indicate its immunomodulatory role in NSCLC stage III (N2) patients., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Passive mode-locking relies critically on a saturable loss mechanism to form ultrashort pulses. However, in Kerr-lens mode-locking (KLM), no actual absorption takes place, but rather losses appear due to diffraction, and actual light must escape the cavity. The Kerr-lens effect works to generate through diffraction an effective instantaneous saturable absorber that depends delicately on the interplay between the spatial and temporal profiles of the pulse. Despite the importance of KLM as a technique for generating ultrafast pulses and the fundamental role of diffraction losses in its operation, these losses have never been observed directly. Here, we measure the light that leaks out due to diffraction losses in a hard-aperture Kerr-lens mode-locked Ti:sapphire laser, and compare the measured results with a numerical theory that explicitly calculates the spatiotemporal behavior of the pulse.

The effects of flow on the acoustic behavior of metamaterials can be very significant and possibly destructive. To avoid these detrimental effects, it would be a good idea to have a "magic layer" that allows acoustics to pass through while suppressing the sound-flow interactions. A possible realization of this layer based on Kevlar fabric is tested in this paper. It is shown that, in the presence of Kevlar, flow-sound interactions that can lead to acoustic amplification and whistling phenomena are avoided. Thus, Kevlar will permit liner designs including large slits. However, it adds large acoustic losses, which limits interesting resonance effects in applications.

I Kr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go -Related Gene (hERG, K v 11.1) potassium channels. The blockage of these channels by pharmacological compounds is associated to drug-induced long QT syndrome (LQTS), which is a life-threatening disorder characterized by ventricular arrhythmias and defects in cardiac repolarization that can be illustrated using cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs). This study was meant to assess the modification in hiPS-CMs excitability and contractile properties by BeKm-1, a natural scorpion venom peptide that selectively interacts with the extracellular face of hERG, by opposition to reference compounds that act onto the intracellular face. Using an automated patch-clamp system, we compared the affinity of BeKm-1 for hERG channels with some reference compounds. We fully assessed its effects on the electrophysiological, calcium handling, and beating properties of hiPS-CMs. By delaying cardiomyocyte repolarization, the peptide induces early afterdepolarizations and reduces spontaneous action potentials, calcium transients, and contraction frequencies, therefore recapitulating several of the critical phenotype features associated with arrhythmic risk in drug-induced LQTS. BeKm-1 exemplifies an interesting reference compound in the integrated hiPS-CMs cell model for all drugs that may block the hERG channel from the outer face. Being a peptide that is easily modifiable, it will serve as an ideal molecular platform for the design of new hERG modulators displaying additional functionalities.

The purpose of the present study was to analyze the incidence, presentation, and treatment of mesh erosion into the esophagus or stomach after mesh hiatoplasty for primary or recurrent hiatal hernia. The study is a single-institution, retrospective cohort study. From November 2005 to December 2016, 122 patients consecutively underwent mesh hiatoplasty in our department, 91 during a primary surgery and 31 for a surgical revision. Follow-up was complete for 74%. Six patients of this series were evaluated for mesh erosion. In all cases, the mesh employed was a dual-type circular one. The mean time from surgery to erosion diagnosis was 42 months (median time 46 months, interquartile range 64 months). Three patients were asymptomatic, 1 had dysphagia, 1 had reflux recurrence, and 1 presented with mediastinal perforation. The absolute erosion rate was 4.9%. For patients under surveillance, the erosion rate was 6.6%, or 1 case every 48 patient-years of follow-up. The erosion rate after primary surgery was 3% or 1/86 patient-years of follow-up, and after surgery for recurrent hernia recurrence was 16% or 1/29 patient-years of follow-up. The mesh was left in place in 2 asymptomatic cases and endoscopically removed in 2 cases. Two patients submitted to surgical removal of the mesh, and only one needed a limited gastroesophageal junction resection for a conversion to a Roux-en-Y gastric bypass. The patient with esophageal perforation submitted to mesh removal, drainage, and an anterior partial fundoplication. There was no mortality. Mesh erosion after hiatoplasty presents with a high rate, especially when hiatoplasty is performed during revisional antireflux surgery. Most patients can be managed conservatively, and endoscopic removal should be considered a first-line therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Aims: Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca(2+) ([Ca(2+)]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca(2+) channels in controlling SAN [Ca(2+)]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca(2+) channel isoform in SAN cells, we studied [Ca(2+)]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1.3 knockout (KO) mice (Cav1.3(-/-))., Methods and Results: We found that Cav1.3 deficiency strongly impaired [Ca(2+)]i dynamics, reducing the frequency of local [Ca(2+)]i release events and preventing their synchronization. This impairment inhibited the generation of Ca(2+) transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Cav1.3(-/-) cells. Although these experiments showed abolished Ca(2+) entry through L-type Ca(2+) channels in the diastolic depolarization range of KO SAN cells, their sarcoplasmic reticulum Ca(2+) load remained normal. β-Adrenergic stimulation enhanced pacemaking of both genotypes, though, Cav1.3(-/-) SAN cells remained slower than WT. Conversely, we rescued pacemaker activity in Cav1.3(-/-) SAN cells and intact tissues through caffeine-mediated stimulation of Ca(2+)-induced Ca(2+) release., Conclusions: Cav1.3 channels play a critical role in the regulation of [Ca(2+)]i dynamics, providing an unanticipated mechanism for triggering local [Ca(2+)]i releases and thereby controlling pacemaker activity. Our study also provides an additional pathophysiological mechanism for congenital SAN dysfunction and heart block linked to Cav1.3 loss of function in humans., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

A 75 year old male patient was monitored for 3 years by Doppler Ultrasonography (US) for an abdominal aorta aneurysm (AAA). Because the aneurysm increased significantly, an aortic prosthesis was installed via an endovascular procedure. After one month of post-surgery monitoring, both Doppler US exam and contrast enhancement US (CEUS) suspected the presence of a leak at the level of the prosthesis. A new surgical procedure was scheduled and intraoperative arteriography confirmed an endoleak type II. Although not always able to specify the correct type of linkage, CEUS remains a reliable method for investigating the postoperative complications of AAA.