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Abstract Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.

The presence in seawater of low-molecular-weight polyethylene (PE) and polydimethylsiloxane (PDMS), synthetic polymers with high chemical resistance, has been demonstrated in this study for the first time by developing a novel methodology for their recovery and quantification from surface seawater. These synthetic polymer debris (SPD) with very low molecular weights and sizes in the nano- and micro-metre range have escaped conventional analytical methods. SPD have been easily recovered from water samples (2 L) through filtration with a nitrocellulose membrane filter with a pore size of 0.45 μm. Dissolving the filter in acetone allowed the isolation of the particulates by centrifugation followed by drying. The isolated SPD were analysed by 1H nuclear magnetic resonance spectroscopy (1H NMR), identifying PE and PDMS. These polymers are thus persisting on seawater because of their low density and the ponderal concentrations were quantified in mg/m3. This method was used in an actual case study in which 120 surface seawater samples were collected during two sampling campaigns in the Mediterranean Sea (from the Gulf of Salerno to the Gulf of Policastro in South Italy). The developed analytical protocol allowed achieving unprecedented simplicity, rapidity and sensitivity. The 1H and 13C NMR structural analysis of the PE debris indicates the presence of oxidised polymer chains with very low molecular weights. Additionally, the origin of those low molecular weight polymers was investigated by analysing influents and effluents from a wastewater treatment plant (WWTP) in Salerno as a hot spot for the release of SPD: the analysis indicates the presence of low molecular weight polymers compatible with wax-PE, widely used for coating applications, food industry, cosmetics and detergents. Moreover, the origin of PDMS debris found in surface seawater can be ascribed to silicone-based antifoamers and emulsifiers.

Abstract The tumor microenvironment is a complex ecosystem that plays a critical role in cancer progression and treatment response. Recently, extracellular amyloid fibrils have emerged as novel components of the tumor microenvironment; however, their function remains elusive. In this study, we establish a direct connection between the presence of amyloid fibrils in the secretome and the activation of YAP, a transcriptional co-activator involved in cancer proliferation and drug resistance. Furthermore, we uncover a shared mechano-signaling mechanism triggered by amyloid fibrils in both melanoma and pancreatic ductal adenocarcinoma cells. Our findings highlight the crucial role of the glycocalyx protein Agrin which binds to extracellular amyloid fibrils and acts as a necessary factor in driving amyloid-dependent YAP activation. Additionally, we reveal the involvement of the HIPPO pathway core kinase LATS1 in this signaling cascade. Finally, we demonstrate that extracellular amyloid fibrils enhance cancer cell migration and invasion. In conclusion, our research expands our knowledge of the tumor microenvironment by uncovering the role of extracellular amyloid fibrils in driving mechano-signaling and YAP activation. This knowledge opens up new avenues for developing innovative strategies to modulate YAP activation and mitigate its detrimental effects during cancer progression.

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various cardiac and non-cardiac comorbidities. This is probably the reason why several HFpEF clinical trials in the past did not reach strong outcomes to recommend a single therapy for this syndrome; however, this paradigm has recently changed, and the unmet clinical need for HFpEF treatment found a proper response as a result of a new class of drug, the sodium–glucose cotransporter 2 inhibitors, which beneficially act through the whole spectrum of left ventricular ejection fraction. The aim of this review was to focus on the therapeutic target of HFpEF, the role of new drugs and the potential role of new devices to manage the syndrome.

Abstract Background Palpitations represent a common cause for consultation in the pediatric Emergency Department (ED). Unlike adults, palpitations in children are less frequently dependent from the heart, recognizing other causes. Case presentation A 11-year-old male came to our pediatric ED for epigastric pain, vomiting and palpitations. During the previous 6 month the patient was affected by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus). Electrocardiogram (ECG) revealed supraventricular tachycardia. Therefore, adenosine was administered unsuccessfully. The administration of adenosine, however, allowed us to make diagnosis of atypical atrial flutter. Multiple attempts at both electrical cardioversion, transesophageal atrial overdrive, and drug monotherapy were unsuccessful in our patient. Consequently, a triple therapy with amiodarone, flecainide, and beta-blocker was gradually designed to control the arrhythmic pattern with the restoration of a left upper atrial rhythm. There was not any evidence of sinus rhythm in the patient clinical history. Conclusions The present study underlines the rarity of this type of dysrhythmia in childhood and the difficulties in diagnosis and management, above all in a patient who has never showed sinus rhythm. Raising awareness of all available treatment options is essential for a better management of dysrhythmia in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

The study of the physical properties of the topside ionosphere is fundamental to investigating the energy balance of the ionosphere and developing accurate models to predict relevant phenomena, which are often at the root of Space Weather effects in the near-Earth environment. One of the most important physical parameters characterising the ionospheric medium is electrical conductivity, which is crucial for the onset and amplification of ionospheric currents and for calculating the power density dissipated by such currents. We characterise, for the first time, electrical conductivity in the direction perpendicular to the geomagnetic field, namely Pedersen and Hall conductivities, in the topside ionosphere at an altitude of about 450 km. For this purpose, we use eight years of in situ simultaneous measurements of electron density, electron temperature and geomagnetic field strength acquired by the Swarm A satellite. We present global statistical maps of perpendicular electrical conductivity and study their variations depending on magnetic latitude and local time, seasons, and solar activity. Our findings indicate that the most prominent features of perpendicular electrical conductivity are located at low latitudes and are probably driven by the complex dynamics of the Equatorial Ionisation Anomaly. At higher latitudes, perpendicular conductivity is a few orders of magnitude lower than that at low latitudes. Nevertheless, conductivity features are modulated by solar activity and seasonal variations at all latitudes.

Unveiling the physical properties of the Earth’s ionosphere is crucial for the comprehension of the dynamic processes that occur within it across various spatial and temporal scales [...]

Ionospheric plasma density irregularities, which are one of the primary sources of disturbance for the Global Navigation Satellite System, significantly impact the propagation of electromagnetic signals, leading to signal degradation and potential interruptions. In the equatorial ionospheric F region after sunset, certain plasma density irregularities, identified as equatorial plasma bubbles, encounter optimal conditions for their formation and development. The energy spectra of electron density fluctuations associated with these irregularities exhibit a power-law scaling behavior qualitatively similar to the Kolmogorov power law observed in fluid turbulence theory. This intriguing similarity raises the possibility that these plasma density irregularities may possess turbulent characteristics. In this study, we analyzed electron density, temperature, and pressure data obtained from the China Seismo-Electromagnetic Satellite (CSES-01) to delve into the spectral properties of equatorial plasma depletions in the ionospheric F region at an altitude of about 500 km. This research marks the first exploration of these properties utilizing CSES-01 data and focuses on 14 semi-orbits that crossed the equator after midnight (01:00–03:00 LT), characterized by a geomagnetic quiet condition (Kp < 1). The analysis of electron temperature, density and pressure within equatorial plasma depletions revealed power-law scaling behavior for all the selected parameters. Notably, the spectral index values of these parameters are different from each other. The significance of these findings in terms of investigating plasma depletions via magnetic field signatures, as well as their relationship to the occurrence of Rayleigh–Taylor convective turbulence, is examined and discussed.

Cardiac amyloidosis is the most frequent infiltrative disease caused by the deposition of misfolded proteins in the cardiac tissue, leading to heart failure, brady- and tachyarrhythmia and death. Conduction disorders, atrial fibrillation (AF) and ventricular arrhythmia (VA) significantly impact patient outcomes and demand recognition. However, several issues remain unresolved regarding early diagnosis and optimal management. Extreme bradycardia is the most common cause of arrhythmic death, while fast and sustained VAs can be found even in the early phases of the disease. Risk stratification and the prevention of sudden cardiac death are therefore to be considered in these patients, although the time for defibrillator implantation is still a subject of debate. Moreover, atrial impairment due to amyloid fibrils is associated with an increased risk of AF resistant to antiarrhythmic therapy, as well as recurrent thromboembolic events despite adequate anticoagulation. In the last few years, the aging of the population and progressive improvements in imaging methods have led to increases in the diagnosis of cardiac amyloidosis. Novel therapies have been developed to improve patients’ functional status, quality of life and mortality, without data regarding their effect on arrhythmia prevention. In this review, we consider the latest evidence regarding the arrhythmic risk stratification of cardiac amyloidosis, as well as the available therapeutic strategies.