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Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1-/D mice). Ckmm-Cre+/- ;Ercc1-/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/- ;Ercc1-/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/- ;Ercc1-/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/- ;Ercc1-/fl and Ercc1-/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.

Background and objectivesBRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Distribution of social aid on target is important to help the welfare of people in need. In Bugel Subdistrict, Salatiga, this distribution has several problems, namely, data discrepancies, the application process is not transparent, and there is no distribution monitoring, resulting in social assistance recipients not being on target and affecting decisions on providing assistance for the next period. Therefore, a social assistance distribution information system is needed to assist in managing integrated data collection and monitoring distribution and application status. The information system requirements engineering method uses the system engineering life cycle method developed by Alexander Kossiakoff with a focus on the concept development stage. This research aims to identify the initial needs for a data management information system for social assistance recipients by producing a distribution of coordinate points as well as new distribution and submission monitoring features using a microservices architecture approach and visualizing with a design display using mobile first design technology referring to a responsive mobile display, containing detailed information, images , location routes to improve the performance of social assistance administrators with real-time data access

Abstract Is Stochastic Gradient Descent (SGD) substantially different from Metropolis Monte Carlo dynamics? This is a fundamental question at the time of understanding the most used training algorithm in the field of Machine Learning, but it received no answer until now. Here we show that in discrete optimization and inference problems, the dynamics of an SGD-like algorithm resemble very closely that of Metropolis Monte Carlo with a properly chosen temperature, which depends on the mini-batch size. This quantitative matching holds both at equilibrium and in the out-of-equilibrium regime, despite the two algorithms having fundamental differences (e.g. SGD does not satisfy detailed balance). Such equivalence allows us to use results about performances and limits of Monte Carlo algorithms to optimize the mini-batch size in the SGD-like algorithm and make it efficient at recovering the signal in hard inference problems.

The best treatment of unicameral bone cyst and aneurismatic bone cyst (ABC) is debated in the literature. For simple bone cysts, multiple treatments were proposed from observation only to open curettage. The historical treatment with intraosseous injection of methylprednisolone acetate into the bone cysts nowadays is reduced due to the morbidity of multiple injections and the risk of multiple pathologic fractures until the healing. Different types of treatments for ABC are reported, including surgery, percutaneous treatments, and medical treatments; however, there is currently no consensus on the best approach. The association of curettage, bone graft, and elastic stable intramedullary nail (ESIN) had a success rate of over 85%. Decompressing the cyst wall is more critical for increasing the healing rate than the type of graft used to fill the cavity. In ABC, sclerotherapy offers the advantages of lower invasiveness and morbidity, associated with better functional scores and faster return to full weight-bearing. Moreover, they can be used in challenging locations. Selective arterial embolization is a complex procedure and often requires association with other treatments. Further studies are needed to confirm the effectiveness of denosumab and its side effects on skeletally immature patients. Curettage with adjuvants and autogenous bone grafting still shows promising results and can be used in larger, aggressive defects or superficial lesions. For simple bone cysts, the combination of curettage, bone graft, and ESIN showed the best results. Sclerotherapy for ABC also shows promising results.

This work aims to compare and assess the performance of certain methodologies for shoreline mapping based on the use of medium (10 m) and high resolution (3 m) multi-spectral imagery, provided by Sentinel-2 (S2) and PlanetScope (PS), respectively. Being Sentinel-2 part of the Copernicus missions, its data are freely available. PS imagery are also freely available for scientific research, upon approval by the European Space Agency of a related project proposal. Several spectral indices, including Normalized Difference Water Index (NDWI), Modified Normalized Difference Water Index (MNDWI), Automated Water Extraction Index (AWEI), and Water Index (WI), were used for shoreline detection. In particular, two unsupervised classification techniques, the Gaussian Mixture Model (GMM) and K-means clustering were deployed as shoreline extraction methods. The outcomes of such approaches were validated using reference shorelines derived from aerial orthomosaics, generated from images acquired as close as possible to the satellite imagery dates, and the ”baseline and transect” approach for accuracy verification. Three tide-less Mediterranean beaches were used as study cases for comparison: the beach between Castelldefels and Gava in Spain, Feniglia and Marina di Grosseto in Italy. The results demonstrated sub-pixel accuracy in shoreline extraction, with Mean Absolute Distances ranging from 2 m to 5 m for S2 data and 1.5 m to 2 m for PS data. These findings highlight the potential of freely available satellite data for semi-automatic shoreline detection. Results obtained by using the combination of different indices and methodologies show that the best option may change depending on the considered context, hence future investigations should be dedicated to the development of a procedure for automatically determining the context-based (close to) optimal index-classifier combination.

Abstract The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

Neuromuscular diseases (NMD) cover a broad spectrum of different rare diagnoses in which the primary lesion is in the peripheral nervous system. The impairment caused by an NMD does not only interfere with physical status but also has a clear impact on health-related quality of life (HRQoL). It is therefore essential to know the coping style used by these patients. This study aims to analyze the coping strategies in a sample of people with NMD and how their coping style affects their HRQoL. This cross-sectional study included 61 adult patients diagnosed with a rare NMD. WHO-DAS II, SIP, SF-36, and COPE-60 instruments were administered. The results showed that people affected by NMDs tend to use more frequent coping strategies such as active planning, personal growth, and acceptance. In contrast, the least-used strategies were restraint, mental disengagement, venting, humor, and religion, which affected HRQoL negatively. Moreover, the degree of disability was a relevant variable, with an impact on HRQoL. Social support can be considered the main coping strategy that leads to an improvement in the psychosocial HRQoL (β = 503, p < 0.001). These findings are relevant to clinical practice, given the need to understand the coping variable to improve HRQoL.

We present an optical metasurface with symmetrical individual elements sustaining Fano resonances with high Q-factors. This study combines plane-wave illumination and modal analysis to investigate the resonant behavior that results in a suppression of the forward scattering, and we investigate the role of the lattice constant on the excited multipoles and on the spectral position and Q-factor of the Fano resonances, revealing the nonlocal nature of the resonances. The results show that the intrinsic losses play a crucial role in modulating the resonance amplitude in specific conditions and that the optical behavior of the device is extremely sensitive to the pitch of the metasurface. The findings highlight the importance of near-neighbor interactions to achieve high Q resonances and offer an important tool for the design of spectrally tunable metasurfaces using simple geometries.

Giant cell tumor of bone (GCTB) is characterized by uncertain biological behavior due to its local aggressiveness and metastasizing potential. In this study, we conducted a meta-analysis of the contemporary literature to evaluate all management strategies for GCTB metastases. A combination of the terms “lung metastases”, “giant cell tumor”, “bone”, “treatment”, and “oncologic outcomes” returned 133 patients meeting our inclusion criteria: 64 males and 69 females, with a median age of 28 years (7–63), at the onset of primary GCTB. Lung metastases typically occur at a mean interval of 26 months (range: 0–143 months) after treatment of the primary site, commonly presenting as multiple and bilateral lesions. Various treatment approaches, including surgery, chemotherapy, radiotherapy, and drug administration, were employed, while 35 patients underwent routine monitoring only. Upon a mean follow-up of about 7 years (range: 1–32 years), 90% of patients were found to be alive, while 10% had died. Death occurred in 25% of patients who had chemotherapy, whereas 96% of those not treated or treated with Denosumab alone were alive at a mean follow-up of 6 years (range: 1–19 years). Given the typically favorable prognosis of lung metastases in patients with GCTB, additional interventions beyond a histological diagnosis confirmation may not be needed. Denosumab, by reducing the progression of the disease, can play a pivotal role in averting or delaying lung failure.

Abstract Background Global climate change is recognized as a major and irreversible challenge for humanity, requiring people’s responsible and sustainable behaviors toward the environment. So far, the literature has widely investigated the role of cognitive determinants of ecological outcomes (e.g., pro-environmental behaviors and climate change perception), while less attention has been devoted to emotional processes, such as trait emotional intelligence (TEI). The current double study investigates whether TEI is directly and indirectly associated with climate change perception (CCP, Study 1) and pro-environmental behaviors (PEBs, Study 2) among young adults. Furthermore, the mediating role of connectedness to nature (CN), both as cognitive and emotional factors, was also analyzed. We hypothesized that CN (i.e., cognitive mediator) would positively mediate the relationship between TEI and CCP (H1), and Love and Care for Nature (LCN, i.e., emotional mediator) would positively mediate the relationship between TEI and PEBs (H2). Methods The study involved 342 young adults (F = 60.7%; age 19–40; Mage=22.99; SD = 2.66) in Study 1 and 365 young adults (F = 71.2%; age 17–35; Mage=22.2; SD = 3.98) in Study 2. Data were collected through an online tool shared by the snowball method. We administered the following self-reports: Trait Emotional Intelligence Questionnaire- Short Form (TEIQue- SF), Global Climate Change (GCC), and Connectedness to Nature Scale (CNS) (Study 1); Trait Emotional Intelligence Questionnaire- Short Form (TEIQue-SF), General Environmental Behaviors Scale (GEB), and Love and Care for Nature (LCN) (Study 2). Results Findings from Study 1 showed that higher TEI levels enhance CN (i.e., cognitive mediator), positively influencing CCP (estimate = 0.14; 95% CI = 0.07 to 0.23). Findings from Study 2 showed that higher TEI levels are associated with higher LCN levels (i.e., emotional mediator), influencing people’s engagement in PEBs (estimate = 0.7; 95% CI = 0.03 to 0.11). Conclusion It is crucial to design environmental education programs that promote greater emotional intelligence ability and encourage individuals’ involvement in ecological outcomes.

The selection of an affordable method to fabricate plasmonic metasurfaces needs to guarantee complex control over both tunability and reproducibility of their spectral and morphological properties, making plasmonic metasurfaces suitable for integration into different sensing devices. Displacement Talbot lithography could be a valid solution thanks to the limited fabrication steps required, also providing the highly desired industrial scalability. Fabricated plasmonic metasurfaces are represented by a gold nanohole array on a glass substrate based on a triangular pattern. Scanning electron microscopy measurements have been recorded, showing the consistency of the surface features with the optimized design parameters. Reflectance and transmittance measurements have also been carried out to test the reliability and standardization of the metasurface’s optical response. Furthermore, these plasmonic metasurfaces have also been successfully tested for probing refractive index variations in a microfluidic system, paving the way for their use in sensitive, real-time, label-free, and multiplexing detection of bio-molecular events.

Plasmonic arrays are grating-like structures able to couple an incoming electromagnetic field into either localized or propagating surface plasmonic modes. A triangular array of elliptical holes in a gold layer were realized resorting to displacement Talbot lithography. Scanning electron microscopy was used to evaluate the geometrical features and finite time domain simulations were performed to verify the consistency of the design. The optical response was characterized by angle-resolved reflectance and transmittance measurements. The results demonstrate the good quality and uniformity of the array. Furthermore, the study on the dependence of the optical response on both the hexagonal lattice and the elliptical hole-defined symmetry properties was conducted allowing the distinction of their effects on both the localized and propagating plasmonic modes. The results indicate that the localized component of the plasmonic modes is mainly affected by the elliptical shape, while the propagating part is influenced by the hexagonal lattice symmetry.

Abstract The utilization of kidneys from donors with acute kidney injury (AKI) is often limited by unpredictable post-transplantation outcomes. The aim of our study was to identify protein mediators implicated in either recovery or failure of these organs. Forty kidney biopsies from donors with (20) and without AKI (20) were selected and then subdivided according to the post-transplant outcome defined as a threshold of 45 ml/min for the eGFR at 1 year from transplantation. Tissue homogenates were analysed by western blot to assess how the levels of 17 pre-selected proteins varied across the four groups. Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg and twofold reduction of STAT1 compared to the other groups (p

Abstract Endothelial cells (EC) differentiate from multiple sources, including the cardiopharyngeal mesoderm, which gives rise also to cardiac and branchiomeric muscles. The enhancers activated during endothelial differentiation within the cardiopharyngeal mesoderm are not completely known. Here, we use a cardiogenic mesoderm differentiation model that activates an endothelial transcription program to identify endothelial regulatory elements activated in early cardiogenic mesoderm. Integrating chromatin remodeling and gene expression data with available single-cell RNA-seq data from mouse embryos, we identify 101 putative regulatory elements of EC genes. We then apply a machine-learning strategy, trained on validated enhancers, to predict enhancers. Using this computational assay, we determine that 50% of these sequences are likely enhancers, some of which are already reported. We also identify a smaller set of regulatory elements of well-known EC genes and validate them using genetic and epigenetic perturbation. Finally, we integrate multiple data sources and computational tools to search for transcriptional factor binding motifs. In conclusion, we show EC regulatory sequences with a high likelihood to be enhancers, and we validate a subset of them using computational and cell culture models. Motif analyses show that the core EC transcription factors GATA/ETS/FOS is a likely driver of EC regulation in cardiopharyngeal mesoderm.

Abstract Background Osteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is due to a combination of factors, although the pivotal mechanisms underlying the disease are still obscure. Moreover, current treatments are still poorly effective, and patients experience a painful and degenerative disease course. Methods We used an integrative approach that led us to extract a consensus signature from a meta-analysis of three different OA cohorts. We performed a network-based drug prioritization to detect the most relevant drugs targeting these genes and validated in vitro the most promising candidates. We also proposed a risk score based on a minimal set of genes to predict the OA clinical stage from RNA-Seq data. Results We derived a consensus signature of 44 genes that we validated on an independent dataset. Using network analysis, we identified Resveratrol, Tenoxicam, Benzbromarone, Pirinixic Acid, and Mesalazine as putative drugs of interest for therapeutics in OA for anti-inflammatory properties. We also derived a list of seven gene-targets validated with functional RT-qPCR assays, confirming the in silico predictions. Finally, we identified a predictive subset of genes composed of DNER, TNFSF11, THBS3, LOXL3, TSPAN2, DYSF, ASPN and HTRA1 to compute the patient’s risk score. We validated this risk score on an independent dataset with a high AUC (0.875) and compared it with the same approach computed using the entire consensus signature (AUC 0.922). Conclusions The consensus signature highlights crucial mechanisms for disease progression. Moreover, these genes were associated with several candidate drugs that could represent potential innovative therapeutics. Furthermore, the patient’s risk scores can be used in clinical settings.

Spatial soil databases can help model complex phenomena in which soils are a decisive factor – for example, evaluating agricultural potential or estimating carbon storage capacity. The Latin America and Caribbean Soil Information System, SISLAC, is a regional initiative promoted by the Food and Agriculture Organization's (FAO) Latin America and the Caribbean Soil Partnership to contribute to sustainable management of soil. SISLAC includes data from 49 084 soil profiles distributed unevenly across the continent, making it the region's largest soil database. In addition, there are other soil databases in the region with about 40 000 soil profiles that can be integrated into SISLAC and improve it. However, some problems hinder its usages, such as the quality of the data and their high dimensionality. The objective of this research is evaluate the quality of the SISLAC data and the other available soil databases to generate a new improved version that meets the minimum quality requirements to be used for different purposes or practical applications. The results show that 15 % of the existing soil profiles had an inaccurate description of the diagnostic horizons and 17 % of the additional profiles already existed in SISLAC; therefore, a total of 32 % of profiles were excluded for these two reasons. Further correction of an additional 4.5 % of existing inconsistencies improved overall data quality. The improved database consists of 66 746 profiles and is available for public use at https://doi.org/10.5281/zenodo.7876731 (Díaz-Guadarrama and Guevara, 2023). This revised version of SISLAC data offers the opportunity to generate information that helps decision-making on issues in which soils are a decisive factor. It can also be used to plan future soil surveys in areas with low density or where updated information is required.

Abstract Background Postoperative pain management in lumbar spine surgery care remains a challenge. The aim of this study was to evaluate the impact of a person-centred postoperative pain management intervention programme on lumbar spine surgery patients on postoperative pain, shared decision-making, and satisfaction with postoperative pain management. Methods The study was performed with a controlled before-and-after interventional design in an orthopaedic unit at a university hospital. Person-centred pain management for patients undergoing spine surgery was developed in co-creation by a multi-professional team and implemented throughout the care pathway. The usual care group (pre-intervention) served as a comparison to the intervention group. Pain intensity, shared decision-making in pain management, and patient satisfaction with results of pain management, served as patient-reported measures, collected using the International Pain Outcomes questionnaire and analysed using descriptive statistics. Results The intervention showed no benefit for patients’ pain and satisfaction, while shared decision-making in pain management was significant lower in the intervention group than in the conventional group. The per-protocol analysis showed no significant differences between groups. Conclusion The initial assumption of the study, that the implementation of a co-created structured person-centred care pathway would improve patient-reported outcomes, was not confirmed. The periodically low fidelity to the intervention due to organizational constraints (due to sub-optimal organizational conditions and managerial support) may have affected the results.