1,450 research outputs found

    Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models

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    Summary: Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson’s, Huntington’s, Alzheimer’s, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention

    First Evidence of Microplastics in Human Urine, a Preliminary Study of Intake in the Human Body

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    The ubiquitous presence of microplastics (MPs) and their health effects is a recent scientific topic. However, the investigation of MPs in human/biological matrices has several limitations due to analytical methods and sample treatment protocols. In this study, the presence of MPs in the urine samples of six volunteers from different cities in the south of Italy (three men and three women) was investigated by Raman microspectroscopy. The analysis pinpointed four pigmented microplastic fragments (4–15 μm size), with irregular shapes, which were characterized in terms of morphology and chemical composition. Polyethylene vinyl acetate (PVA), polyvinyl chloride (PVC), polypropylene (PP), and polyethylene (PE) MPs were found in four samples (PVA and PVC in one female sample and PP and PE in three male samples). This preliminary study suggests that MPs could pass through the gastrointestinal tract and are eliminated through biological processes

    Normal and abnormal appearance of fetal ganglionic eminence at second-trimester three-dimensional ultrasound

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    Objectives: To describe the appearance and size of the ganglionic eminence (GE) in normal fetuses at mid trimester three-dimensional (3D) neurosonography and to report the association between GE alterations (cavitation or enlargement) and malformations of cortical development (MCD). Methods: This was a prospective multicenter cohort study, with retrospective analysis of pathological cases. From January to June 2022, patients attending our tertiary centers for expert fetal brain scan were recruited for the purpose of the study. A 3D volume of the fetal head, starting from the sagittal plane, was acquired in apparently normal fetuses transabdominally or transvaginally. Stored volume datasets were then independently evaluated by two expert operators. Two measurements (longitudinal diameter or D1 and transverse diameter or D2) of the GE in the coronal view were taken twice by each operator. Intra- and interobserver variation was calculated. Normal reference ranges for GE measurements were calculated in the normal population. Previously stored volume dataset of 60 cases with MCD were also independently analyzed by the two operators using the same method, in order to assess if GE abnormalities (cavitation or enlargement) were present. Postnatal follow-up was obtained in all cases. Results: In the study period, 160 normal fetuses between 19 and 22 weeks of gestation were included in the study. The GE was visible in the coronal plane at 3D ultrasound in 144 (90%) cases, not clearly visible in the remaining 16 cases. The intra- and interobserver agreement were almost perfect for D1, with an ICC of 0.90 (95% CI, 0.83-0.93) and an ICC of 0.90 (95% CI, 0.86-0.92), respectively, and substantial for D2, with an ICC of 0.80 (95% CI, 0.70-0.87) and an ICC of 0.64 (95% CI, 0.53-0.72), respectively. A retrospective analysis of 50 cases with MCD in the second trimester showed that GE enlargement was bilaterally present in 14 cases and GE cavitation in four cases. Conclusions: A systematic assessment of the GE in fetuses at 19-22 weeks is feasible at 3D brain ultrasound with good reproducibility in normal cases. Cavitations or enlargement of the GE can be demonstrated in fetuses with MCD. This article is protected by copyright. All rights reserved

    Pd-Based Hybrid Nanoparticles As Multimodal Theranostic Nanomedicine

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    A nanodelivery system based on palladium nanoparticles (PdNP) and cisplatin (CisPt) was developed by physisorption of the drug onto the PdNP synthesized via a green redox process, using d-glucose and polyvinylpyrrolidone (PVP) as reducing and stabilizing/capping agents, respectively. UV-vis analysis and H2-evolution measurements were carried out to prove the nanoparticles’ capability to act as bimodal theranostic nanomedicine, i.e., having both plasmonic and photocatalytic properties. XPS, XRD, and TEM allowed light to be shed on the chemical composition and morphology of the PdNP. The analysis of the UV-visible spectra evidenced plasmonic peak changes for the hybrid nanoparticle-drug assembly (Pd@CisPt), which pointed to a significant interaction of CisPt with the NP surface. The drug loading was quantitatively estimated by ICP-OES measurements, while DLS and AFM confirmed the strong association of the drug with the nanoparticle surface. The test of SOD-like activity in a cell-free environment proved the maintenance of the antioxidant capability of PdNP also in the Pd@CisPt systems. Finally, Pd@CisPt tested in prostate cancer cells (PC-3 line) unveiled the antitumoral action of the developed nanomedicine, related to reactive oxygen species (ROS) generation, with a condition of protein misfolding/unfolding and DNA damage, as evidenced by cytotoxicity and MitoSOX assays, as well as Raman microspectroscopy, respectively. Cell imaging by confocal microscopy evidenced cellular uptake of the nanoparticles, as well as dynamic processes of copper ion accumulation at the level of subcellular compartments. Finally, cell migration studies upon treatment with Pd@CisPt evidenced a tunable response between the inhibitory effect of CisPt and the enhanced rate of cell migration for the metal NP alone, which pointed out the promising potential of the developed theranostic nanomedicine in tissue regeneration. © 2023 The Authors. Published by American Chemical Societ

    Antihypertensive treatment changes and related clinical outcomes in older hospitalized patients

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    Background: Hypertension management in older patients represents a challenge, particularly when hospitalized.Objective: The objective of this study is to investigate the determinants and related outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients.Methods: A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in-patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines [an angiotensin-converting-enzyme-inhibitor (ACE-I) or an angiotensin-receptorblocker (ARB) with a calcium- channel-blocker (CCB) and/or a thiazide diuretic; if > 80 years old, an ACE I or ARB or CCB or thiazide diuretic]. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all cause death, cardiovascular (CV) hospitalization/death, CV death, non CV death, evaluated according to the presence of MT at discharge.Results: Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all cause death, all cause death/hospitalization, CV death, CV death/hospitalization and non-CV death. Conclusions: Guidelines-suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in anti hypertensive treatment still occur in a significant proportion of older hospitalized patients


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    We study the separation property for Cahn-Hilliard type equations with constant mobility and (physically relevant) singular potentials in two dimensions. That is, any solution with initial finite energy stays uniformly away from the pure phases +/- 1 from a certain time on. Beyond its physical interest, this property plays a crucial role to achieve high order Sobolev and analytic regularity of the solutions and to analyze their longtime behavior. In the local case, we streamline known arguments by exploiting the Sobolev inequality to obtain direct entropy estimates. In the nonlocal case, we provide a new proof based on De Giorgi estimates rather than the Alikakos-Moser type argument. Finally, in the spectral-fractional case, we prove nonlinear estimates and the separation property for any fractional index s is an element of (0,1) filling the gap between first-order (local) and zero-order (nonlocal) energy cases. In all of the aforementioned cases, our new proofs neither make use of the Trudinger-Moser inequality nor of any assumptions involving the third derivative of the entropy, as in the previous contributions. In particular, they apply for a more general class of singular potentials than the Flory-Huggins (Boltzmann-Gibbs) logarithmic density. Besides, the new methods present a series of technical advantages, which can be useful to the analysis of important physical systems that couple Cahn-Hilliard equations with other equations (e.g., reaction-diffusion equations and/or Navier-Stokes type systems) as well as their stochastic counterparts

    Raman Microspectroscopy evidence of microplastics in human semen

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    : The presence of microplastics (MPs) in human fluids and organs is a great concern, since, as highlighted by recent studies on animal models, they could cause alterations of several physiological functions, including reproduction. In this study, semen samples collected from men living in a polluted area of the Campania Region (Southern Italy), were analyzed to assess the presence of MPs. N. 16 pigmented microplastic fragments (ranging from 2 to 6 Îźm in size) with spheric or irregular shapes were found in six out of ten samples. All the detected MPs were characterized in terms of morphology (size, colour, and shape) and chemical composition by Raman Microspectroscopy. Chemical composition showed the presence of polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), polystyrene (PS), polyvinylchloride (PVC), polycarbonate (PC), polyoxymethylene (POM) and acrylic, suggesting ingestion and/or inhalation as a route of exposure to environmental MPs. In this work, we propose for the first time a mechanism by which MPs pass into the semen most likely through the epididymis and seminal vesicles, which are the most susceptible to inflammation

    Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2

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    Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results

    Self-Supervised Category-level 6D Object Pose Estimation With Optical Flow Consistency

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    Category-level 6D object pose estimation aims at determining the pose of an object of a given category. Most current state-of-the-art methods require a significant amount of real training data to supervise their models. Moreover, annotating the 6D pose is very time consuming, error-prone, and it does not scale well to a large amount of object classes. Therefore, a handful of methods have recently been proposed to use unlabelled data to establish weak supervision. In this letter we propose a self-supervised method that leverages the 2D optical flow as a proxy for supervising the 6D pose. To this purpose, we estimate the 2D optical flow between consecutive frames based on the pose estimation. Then, we harness an off-the-shelf optical flow method to enable weak supervision using a 2D-3D optical flow based consistency loss. Experiments show that our approach for self-supervised learning yields state-of-the-art performance on the NOCS benchmark, and it reaches comparable results with some fully-supervised approaches
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