Self-amplifying RNA (saRNA) enables sustained protein expression from a single administration. In this study, we developed an intramuscular saRNA-lipid nanoparticle (saNppa-LNP) therapy encoding natriuretic peptide type A (Nppa) for cardioprotection. A single injection induced sustained pro-atrial natriuretic peptide (pro-ANP) secretion for 4 weeks; pro-ANP was subsequently cleaved by the cardiac protease corin into active ANP, producing robust cardioprotection in mouse and swine myocardial infarction models. At equivalent doses, saNppa achieved greater efficacy than conventional mRNA. Single-nucleus transcriptomics identified natriuretic peptide receptor 1-positive (Npr1+) endothelial and epicardial cells as primary effectors, with saNppa-LNPs reshaping their paracrine profile to promote cardiomyocyte regeneration and suppress fibrosis. Longitudinal biosafety assessments revealed no systemic toxicity. Together, these results demonstrate that one-shot saNppa-LNP therapy offers durable cardioprotection, supporting the broader potential of saRNA-LNP-based approaches for cardiac therapy.

BACKGROUND:Ex vivo oxygenated perfusion systems are a promising approach to extend cardiac allograft preservation beyond the typical 4 to 6 hours limit allowed by static cold storage (SCS). Hypothermic oxygenated perfusion (HOPE) has been proven to safely preserve donor hearts, yet its underlying molecular mechanisms have not been extensively evaluated. The aim of the study is to characterize cardiomyocyte viability, transcriptomic and metabolomic responses, and functional recovery of porcine hearts preserved with HOPE for up to 48 hours, including evaluating their ability to regain sinus rhythm following bench-top normothermic reperfusion. METHODS:Seventeen Yorkshire pigs underwent donor cardiectomy. In the first arm, 10 hearts were preserved for up to 48 hours using either SCS (n=5) or HOPE (n=5). Endomyocardial biopsies were collected at 0, 12, 24, and 48 hours for histology, RNA sequencing, flow cytometry, and metabolomics. In the second arm, 6 HOPE-preserved hearts (3, 24, 48 hours) and 2 SCS-preserved heart (3 and 24 hours) underwent 2 hours of normothermic reperfusion to simulate transplantation and assess reanimation. RESULTS:HOPE preserved cardiomyocyte viability and structural integrity for 48 hours, in contrast to SCS in both arms of the study. RNA sequencing and untargeted metabolomics revealed conserved energy-substrate profiles in HOPE and progressive ischemic metabolite accumulation in SCS. All HOPE hearts regained stable sinus rhythm. CONCLUSIONS:HOPE enables 48 hours ex vivo heart preservation while maintaining cardiomyocyte integrity, normal gross and microscopic architecture, and rapid functional recovery on bench-top reperfusion in a preclinical model. These findings establish a foundation for redefining clinical preservation times and widening geographic donor access.

Position calibration in the deep sea is typically done by means of acoustic multilateration using three or more acoustic emitters installed at known positions. Rather than using hydrophones as receivers that are exposed to the ambient pressure, the sound signals can be coupled to piezo ceramics glued to the inside of existing containers for electronics or measuring instruments of a deep sea infrastructure. The ANTARES neutrino telescope operated from 2006 until 2022 in the Mediterranean Sea at a depth exceeding 2000 m. It comprised nearly 900 glass spheres with 432 mm diameter and 15 mm thickness, equipped with photomultiplier tubes to detect Cherenkov light from tracks of charged elementary particles. In an experimental setup within ANTARES, piezo sensors have been glued to the inside of such – otherwise empty – glass spheres. These sensors recorded signals from acoustic emitters with frequencies from 46545 to 60235 Hz. Two waves propagating through the glass sphere are found as a result of the excitation by the waves in the water. These can be qualitatively associated with symmetric and asymmetric Lamb-like waves of zeroth order: a fast (early) one with v_e ≈ 5 mm/μs and a slow (late) one with v_ℓ≈ 2 mm/μs . Taking these findings into account improves the accuracy of the position calibration. The results can be transferred to the KM3NeT neutrino telescope, currently under construction at multiple sites in the Mediterranean Sea, for which the concept of piezo sensors glued to the inside of glass spheres has been adapted for monitoring the positions of the photomultiplier tubes.

KM3NeT/ORCA is an underwater neutrino telescope under construction in the Mediterranean Sea. Its primary scientific goal is to measure the atmospheric neutrino oscillation parameters and to determine the neutrino mass ordering. ORCA can constrain the oscillation parameters $\Delta m^{2}_{31}$ and $\theta_{23}$ by reconstructing the arrival direction and energy of multi-GeV neutrinos crossing the Earth. Searches for deviations from the Standard Model of particle physics in the forward scattering of neutrinos inside Earth matter, produced by Non-Standard Interactions, can be conducted by investigating distortions of the standard oscillation pattern of neutrinos of all flavours. This work reports on the results of the search for non-standard neutrino interactions using the first six detection units of ORCA and 433 kton-years of exposure. No significant deviation from standard interactions was found in a sample of 5828 events reconstructed in the 1 GeV$-$1 TeV energy range. The flavour structure of the non-standard coupling was constrained at 90\% confidence level to be $|\varepsilon_{\mu\tau} | \leq 5.4 \times 10^{-3}$, $|\varepsilon_{e\tau} | \leq 7.4 \times 10^{-2}$, $|\varepsilon_{e\mu} | \leq 5.6 \times 10^{-2}$ and $-0.015 \leq \varepsilon_{\tau\tau} - \varepsilon_{\mu\mu} \leq 0.017$. The results are comparable to the current most stringent limits placed on the parameters by other experiments.

In the era of precision measurements of neutrino oscillation parameters, it is necessary for experiments to disentangle discrepancies that may indicate physics beyond the Standard Model in the neutrino sector. KM3NeT/ORCA is a water Cherenkov neutrino detector under construction and anchored at the bottom of the Mediterranean Sea. The detector is designed to study the oscillations of atmospheric neutrinos and determine the neutrino mass ordering. This paper focuses on the initial configuration of ORCA, referred to as ORCA6, which comprises six out of the foreseen 115 detection units of photosensors. A high-purity neutrino sample was extracted during 2020 and 2021, corresponding to an exposure of 433 kton-years. This sample is analysed following a binned log-likelihood approach to search for invisible neutrino decay, in a three-flavour neutrino oscillation scenario, where the third neutrino mass state ν3 decays into an invisible state, e.g. a sterile neutrino. The resulting best fit of the invisible neutrino decay parameter is α_3=0.92_-0.57^+1.08×10^-4 eV2, corresponding to a scenario with θ23 in the second octant and normal neutrino mass ordering. The results are consistent with the Standard Model, within a 2.1 σ interval.

Patient-specific factors critically influence the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) for cardiac regeneration. In this work, we identify lymphocyte count as a key clinical predictor of BM-MSC proliferative capacity, with coronary artery disease significantly delaying expansion in patients undergoing cardiac surgery. Thus, we established cell selection criteria for patient-derived MSCs for further differentiation into cardiomyocytes. To overcome the limitations of MSCs in cardiac differentiation, we developed a novel protocol using conditioned medium mimicking patient-specific in vivo conditions from iPSC-derived cardiomyocytes (iPSC-CM). This approach successfully generated functional cardiomyocytes from patient-specific BM-MSCs, as evidenced by spontaneous calcium transitions, structural maturation, and electrophysiological activity. Our results provide a unique protocol for inducing MSC differentiation for cell therapy from patient selection to patient-specific personalized preparation as a differentiation strategy.

Neutrinos described as an open quantum system may interact with the environment which introduces stochastic perturbations to their quantum phase. This mechanism leads to a loss of coherence along the propagation of the neutrino - a phenomenon commonly referred to as decoherence - and ultimately, to a modification of the oscillation probabilities. Fluctuations in space-time, as envisaged by various theories of quantum gravity, are a potential candidate for a decoherence-inducing environment. Consequently, the search for decoherence provides a rare opportunity to investigate quantum gravitational effects which are usually beyond the reach of current experiments. In this work, quantum decoherence effects are searched for in neutrino data collected by the KM3NeT/ORCA detector from January 2020 to November 2021. The analysis focuses on atmospheric neutrinos within the energy range of a few GeV to 100 GeV. Adopting the open quantum system framework, decoherence is described in a phenomenological manner with the strength of the effect given by the parameters Γ_21 and Γ_31. Following previous studies, a dependence of the type Γ_ij∝ (E/E_0)^n on the neutrino energy is assumed and the cases n = -2,-1 are explored. No significant deviation with respect to the standard oscillation hypothesis is observed. Therefore, 90 % CL upper limits are estimated as Γ_21 < 4.6· 10^-21GeV and Γ_31 < 8.4· 10^-21GeV for n = -2, and Γ_21 < 1.9· 10^-22GeV and Γ_31 < 2.7· 10^-22GeV for n = -1, respectively.

BACKGROUND:The relationship between myocardial injury after cardiac surgery (MICS), ischemia on electrocardiogram (ECG), and mortality is uncertain. In this study we aimed to determine whether potential ischemic ECG changes after cardiac surgery are associated with 30-day mortality. METHODS:In a cohort of adults who underwent cardiac surgery, experts interpreted ECGs preoperatively; on postoperative days 0, 1, 2, and 3; and on the last day before discharge (59,539 total ECGs reviewed) for new potential ischemic ECG changes. RESULTS:Among 12,594 patients, 9097 (72.2%) had potential ischemic ECG changes; 259 (2.1%) died within 30 days after surgery. Among patients with troponin elevation meeting MICS criteria, in models adjusting for EuroSCORE II, the hazard ratio (HR) for 30-day mortality was 0.57 (95% confidence interval [CI] 0.35-0.94, P = 0.03) for new Q waves, 2.17 (95% CI 1.14-4.13, P = 0.02) for ST depression ≥ 2 mm, and 0.58 (95% CI 0.39-0.87, P = 0.007) for T-wave inversion 1-1.9 mm. ST elevation was not significantly associated with 30-day mortality. The only ECG change for which coronary artery bypass grafting (CABG) was an effect modifier was new left bundle branch block (LBBB), with an HR of 2.78 (95% CI 1.69-4.60, P = 0.0001) with CABG and an HR of 1.10 (95% CI 0.54-2.21, P = 0.27) without CABG (P value for interaction = 0.03). CONCLUSIONS:After cardiac surgery, potential ischemic ECG changes are common and have divergent associations with mortality. ST depression was associated with a higher risk of death, whereas new Q waves and T-wave inversions were associated with a lower risk of death. A new LBBB was associated with a higher risk of death only among patients who underwent CABG. Potential ischemic ECG changes are common after cardiac surgery and lack specificity for the diagnosis of myocardial infarction.

A critical obstacle in cardiac cell therapy is the unpredictable and poorly understood initial electrophysiological integration of grafted cardiomyocytes into the host tissue, a process that dictates therapeutic success and arrhythmic risk. Current models fail to capture the earliest stages of functional coupling formation. Here, we employed a tailored bioengineering platform, where single cardiomyocytes were stabilized on minimalist electrospun polycaprolactone (PCL) nanofibers, to model the "graft-host" interface and study the dynamics of excitation wave transmission in real-time. Using high-speed optical mapping enhanced by a custom SUPPORT neural network, we achieved the first quantitative insights into the efficiency of nascent intercellular contacts. We determined that within the first 3 h, these initial connections are 39-44 times less effective at conducting excitation than mature contacts within the native monolayer, explaining the observed partial (46%) synchronization of grafted cells. This work provides the first direct measurement of the functional deficit during the initial minutes and hours of graft integration. It establishes that simple, inert polymer fibers can act as a catalytic scaffold to enable this fundamental biological process, offering a powerful strategy to deconstruct and ultimately control the integration of engineered tissues (or cells) for safer cell therapies.

Ionization profile monitors (IPMs) are widely used in accelerators for non-destructive and fast diagnostics of high energy particle beams. Two such monitors - one vertical and one horizontal - are being developed for installation in the IOTA storage ring at Fermilab. They will be used for turn-by-turn (microseconds scale) measurements of the 70 MeV/c IOTA proton beam sizes. In this paper we present the IPMs design (largely following the FNAL Booster IPMs which employ no external guiding magnetic fields), their mechanical, vacuum, and electric subsystems and DAQ, and discuss anticipated effects on the beams circulating in IOTA.

High-significance evidences of the existence of a high-energy diffuse flux of cosmic neutrinos have emerged in the last decade from several observations by the IceCube Collaboration. The ANTARES neutrino telescope took data for 15 years in the Mediterranean Sea, from 2007 to 2022, and collected a high-purity all-flavour neutrino sample. The search for a diffuse cosmic neutrino signal using this dataset is presented in this article. This final analysis did not provide a statistically significant observation of the cosmic diffuse flux: this is converted into limits on the properties of the cosmic neutrino spectrum. In particular, given the sensitivity of the ANTARES neutrino telescope between 1 and 50 TeV, constraints on single-power-law hypotheses are derived for the cosmic diffuse flux below 20 TeV.

Cooling of beams circulating in storage rings is critical for many applications including particle colliders and synchrotron light sources. A method enabling unprecedented beam -cooling rates, optical stochastic cooling (OSC), was recently demonstrated in the Integrable Optics Test Accelerator (IOTA) electron storage ring at Fermilab [J. Jarvis et al., Nature (London) 608, 287 (2022)]. This paper describes the numerical implementation of the OSC process in the particle -tracking program ELEGANT and discusses the validation of the developed model with available experimental data. The model is also employed to highlight some features associated with different modes of operation of OSC. The developed simulation tool should be valuable in guiding future configurations of optical stochastic cooling and, more broadly, modeling self -field -based beam manipulations.

The IOTA Proton Injector (IPI), currently under installation at the Fermilab Accelerator Science and Technology facility (FAST), is a machine capable of delivering 20 mA pulses of protons at 2.5 MeV to the Integrable Optics Test Accelerator (IOTA) ring. First beam in the IPI beamline is anticipated in the first half of 2024, when it will operate alongside the existing electron injector beamline to facilitate further beam physics research and continued development of novel accelerator technologies at the IOTA ring. This report details the expected operational profile, known challenges, and the current state of installation.

Актуальность. Катетерная изоляция устьев легочных вен — основной метод интервенционного лечения пациентов с фибрилляцией предсердий, рефрактерных к антиаритмической терапии. Существуют ограниченные данные о сравнении роботизированной магнитной навигации и мануальной радиочастотной аблации у пациентов с фибрилляцией предсердий и увеличенным левым предсердием. Цель. Сравнить безопасность и отдаленную эффективность радиочастотной катетерной аблации с применением роботизированной магнитной навигации и мануального подхода у пациентов с фибрилляцией предсердий и увеличенным левым предсердием. Методы. В ретроспективное исследование включили 534 пациента (средний возраст 59,2 ± 8,7 года, 41,6 % женщины) с различными формами фибрилляции предсердий и увеличенным левым предсердием (> 4,5 см), которым выполнили радиочастотную изоляцию устьев легочных вен в период с 2016 по 2019 г. Пациентов разделили на две группы в зависимости от метода катетерной аблации: роботизированная магнитная навигация (n = 267) и мануальная радиочастотная аблация (n = 267). Первичная конечная точка по безопасности включала периоперационные осложнения, по эффективности — отсутствие пароксизмов фибрилляции предсердий / трепетания предсердий / предсердной тахикардии > 30 с через 3 мес. после первичной процедуры аблации без приема антиаритмической терапии. Для сравнения результатов лечения в обеих группах применяли псевдорандомизацию 1:1 (англ. propensity score matching, PSM) на основе 11 ковариат. После PSM-анализа в каждой группе отобрали по 235 пациентов. Для дополнительной оценки эффективности исходную когорту разделили на две группы в зависимости от формы фибрилляции предсердий: пароксизмальная (n = 355) и непароксизмальная (n = 179). После PSM-анализа количество больных в группах составило 310 и 136 для пароксизмальной и непароксизмальной форм соответственно. Результаты. В общей когорте после PSM (n = 470) пациенты были полностью сбалансированы по формам фибрилляции предсердий. Средний размер левого предсердия составил 4,98 ± 0,61 и 4,94 ± 0,58 см в группах роботизированной магнитной навигации и мануальной радиочастотной аблации соответственно. С 22 (4,7 %) пациентами из обеих групп не удалось связаться для оценки отдаленной эффективности лечения; ее оценивали по данным 448 больных в обеих группах. Медиана периода наблюдения составила 24 мес. (минимум 3, максимум 72 мес.). В сопоставленной когорте в группе мануальной радиочастотной аблации у 11 (4,7 %) пациентов развились периоперационные осложнения по сравнению с 2 (0,9 %) пациентами в группе роботизированной магнитной навигации (р = 0,021, отношение шансов 5,7 [95% доверительный интервал: 1,22, 53,5]). В общей когорте отсутствие фибрилляции предсердий / трепетания предсердий / предсердной тахикардии через 36 мес. составило 62,6 и 47,9 % в группах роботизированной магнитной навигации и мануальной радиочастотной аблации соответственно (р = 0,005 для всего периода наблюдения; отношение рисков 1,54 [95% доверительный интервал: 1,14, 2,08]). При пароксизмальной фибрилляции предсердий (n = 310) отсутствие фибрилляции предсердий / трепетания предсердий / предсердной тахикардии через 36 мес. в группах роботизированной магнитной навигации и мануальной радиочастотной аблации составило 67,1 и 60,6 % соответственно (p = 0,15 для всего периода наблюдения; отношение рисков 1,34 [95% доверительный интервал: 0,90, 1,98]). При непароксизмальной фибрилляции предсердий (n = 136) сохранение синусового ритма было статистически значимо выше в группе роботизированной магнитной навигации по сравнению с группой мануальной радиочастотной аблации (59,6 и 30,4 % через 36 мес. соответственно, p = 0,005 для всего периода наблюдения; отношение рисков 2,01 [95% доверительный интервал: 1,23, 3,29]) за счет персистирующей фибрилляции предсердий. Заключение. По данным ретроспективного исследования с помощью PSM-анализа, применение роботизированной магнитной навигации для интервенционного лечения пациентов с фибрилляцией предсердий и увеличенным левым предсердием связано с меньшим количеством периоперационных осложнений и большей вероятностью сохранения синусового ритма по сравнению с мануальной радиочастотной аблацией за счет непароксизмальных форм фибрилляции предсердий. Необходимо проведение проспективных рандомизированных исследований для сравнения этих подходов к аблации у пациентов с фибрилляцией предсердий и увеличенным левым предсердием. Поступила в редакцию 24 апреля 2024 г. Принята к печати 8 мая 2024 г. Финансирование Работа П.С. Рузанкина и С.Е. Хрущева выполнялась в рамках государственного задания ИМ СО РАН, проект FWNF-2024-0001. Конфликт интересов Авторы заявляют об отсутствии конфликта интересов. Вклад авторов Концепция и дизайн работы: А.Б. Романов, В.В. Белобородов, В.В. Шабанов, А.Г. Филиппенко Сбор и анализ данных: В.В. Белобородов, А.Б. Романов, Д.А. Елесин, В.А. Бобошко, В.В. Шабанов, А.Г. Филиппенко Статистическая обработка данных: П.С. Рузанкин, С.Е. Хрущев, А.Б. Романов Написание статьи: А.Б. Романов, В.В. Белобородов, П.С. Рузанкин, С.Е. Хрущев Исправление статьи: А.Б. Романов, В.В. Белобородов, П.С. Рузанкин, С.Е. Хрущев Утверждение окончательного варианта статьи: все авторы

The KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories.

Objective: Lung transplantation remains limited by the shortage of healthy organs. Cross-circulation with a healthy swine recipient provides a durable physiologic environment to recover injured donor lungs. In a clinical application, a recipient awaiting lung transplantation could be placed on cross-circulation to recover damaged donor lungs, enabling eventual transplantation. Our objective was to assess the ability of recipient swine with respiratory compromise to tolerate cross-circulation and support recovery of donor lungs subjected to extended cold ischemia. Methods: Swine donor lungs (n = 6) were stored at 4 degrees C for 24 hours while recipient swine (n = 6) underwent gastric aspiration injury before cross-circulation. Longitudinal multiscale analyses (blood gas, bronchoscopy, radiography, histopathology, cytokine quantification) fi cation) were performed to evaluate recipient swine and extracorporeal lungs on cross-circulation. Results: Recipient swine lung injury resulted in sustained, impaired oxygenation (arterial oxygen tension/inspired oxygen fraction ratio 205 +/- 39 mm Hg vs 454 +/- 111 mm Hg at baseline). Radiographic, bronchoscopic, and histologic assessments demonstrated bilateral infiltrates, fi ltrates, airway cytokine elevation, and significantly fi cantly worsened lung injury scores. Recipient swine provided sufficient fi cient metabolic support for extracorporeal lungs to demonstrate robust functional improvement (0 hours, arterial oxygen tension/inspired oxygen fraction ratio 138 +/- 28.2 mm Hg; 24 hours, 539 +/- 156 mm Hg). Multiscale analyses demonstrated improved gross appearance, aeration, and cellular regeneration in extracorporeal lungs by 24 hours. Conclusions: We demonstrate that acutely injured recipient swine tolerate cross- circulation and enable recovery of donor lungs subjected to extended cold storage. This proof-of-concept study supports feasibility of cross-circulation for recipients with isolated lung disease who are candidates for this clinical application. (J Thorac Cardiovasc Surg 2024;167:e106-30)

The measurement of the flux of muons produced in cosmic ray air showers is essential for the study of primary cosmic rays. Such measurements are important in extensive air shower detectors to assess the energy spectrum and the chemical composition of the cosmic ray flux, complementary to the information provided by fluorescence detectors. Detailed simulations of the cosmic ray air showers are carried out, using codes such as CORSIKA, to estimate the muon flux at sea level. These simulations are based on the choice of hadronic interaction models, for which improvements have been implemented in the post-LHC era. In this work, a deficit in simulations that use state-of-the-art QCD models with respect to the measurement deep underwater with the KM3NeT neutrino detectors is reported. The KM3NeT/ARCA and KM3NeT/ORCA neutrino telescopes are sensitive to TeV muons originating mostly from primary cosmic rays with energies around 10 TeV. The predictions of state-of-the-art QCD models show that the deficit with respect to the data is constant in zenith angle; no dependency on the water overburden is observed. The observed deficit at a depth of several kilometres is compatible with the deficit seen in the comparison of the simulations and measurements at sea level.