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Alu retrotransposons, which form the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase, EP400 chromatin remodeler and YAP1 and FOS transcription factors. The physical interaction of e1a with EP400 was critical for Alu derepression, which was abrogated upon EP400 ablation. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, which requires EP400 and is mediated by the e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenoviruses.

Topical chlormethine (CL) gel formulation was approved by the EMA in 2017 for the treatment of adult patients with mycosis fungoides (MF). To expand the knowledge on the management of patients with MF, this paper provides an overview of clinical practice evidence about the MF diagnostic phase and a collection of clinical experiences to better characterize the use of CL gel in daily practice. Collected cases underline the importance of the concomitant biopsy and clinical evaluation in the diagnostic phase, with the contribution of a multidisciplinary team and support the use of CL gel as a first-line or adjuvant treatment in selected patients.

Abstract Time-varying metamaterials rely on large and fast changes of the linear permittivity. Beyond the linear terms, however, the effect of a non-perturbative modulation of the medium on harmonic generation remains largely unexplored. In this work, we study second harmonic generation at an optically pumped time-varying interface between air and a 310 nm Indium Tin Oxide film. We observe a modulation contrast at the second harmonic wavelength up to 93% for a pump intensity of 100 GW/cm2, leading to large frequency broadening and shift. We experimentally demonstrate that a significant contribution to the enhancement comes from the temporal modulation of the second order nonlinear susceptibility. Moreover, we show the frequency-modulated spectra resulting from single and double-slit time diffraction could be exploited for enhanced optical computing and sensing, enabling broadband time-varying effects on the harmonic signal and extending the application of Epsilon-Near-Zero materials to the visible range.

Abstract Huntington’s disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and the 4th leading cause of renal replacement therapy in the world. ADPKD is a systemic disorder as cysts may develop in several organs. Liver cysts are the most common extrarenal manifestations and are often incidentally detected. Even though cysts do not influence liver function, they can grow to a very great size and can significantly enlarge liver volume, causing structural distortion of the biliary tree and patient discomfort due to the mass effect. Nephrectomy is frequently considered in preparation for renal transplantation in patients with remarkable kidneys’ enlargement. There are currently no globally recognized clinical guidelines for nephrectomy. Although cysts do not normally affect liver function in ADPKD, after nephrectomy cases of liver fibrosis and Budd-Chiari have been reported. These are uncommon disorders due to the obstruction of the blood flow in the hepatic venous causing spleen and liver volume enlargement, portal hypertension, and hepatic cirrhosis. Case Presentation: We present a case of hepatic fibrosis with splenomegaly and severe pancytopenia as a tardive complication after bilateral nephrectomy in 47-year-old ADPKD patient. Conclusion: This finding underscores the critical significance of meticulously examining the anatomical relationship between polycystic kidneys and the liver before performing nephrectomy. Additionally, it highlights the importance of assessing liver involvement and associated complications. By integrating liver assessment into the criteria, we can significantly enhance patient care and improve the overall management of ADPKD before kidney transplantation.

Background: This study evaluates the repeatability and reproducibility of fat-fraction percentage (FF%) in whole-body magnetic resonance imaging (WB-MRI) of prostate cancer patients with bone metastatic hormone naive disease. Methods: Patients were selected from the database of a prospective phase-II trial. The treatment response was assessed using the METastasis Reporting and Data System for Prostate (MET-RADS-P). Two operators identified a Small Active Lesion (SAL,

Studying the origin of rivers, the development of drainage through geological time, and the multiple processes that affect the composition of the sediment is a fascinating scientific adventure. This article probes into modern sedimentary processes in the Orange River catchment, which covers much of South Africa, and monitors changes in petrographic, mineralogical, geochemical, and geochronological signatures along the ∼4000 km-long fluvial and coastal conveyor belt that transferred pyroxene-rich and diamond-bearing sand from Lesotho to Angola.The Orange River, established as early as the Early Jurassic as a classic example of dome-flank drainage, is perhaps the oldest river on our planet. A quarter of Orange sand is supplied by the erosion of Lesotho basaltic highlands, reaching 3482 m a.s.l. and representing a remnant of one of the most extensive magmatic effusions of Phanerozoic history, the Lower Jurassic Karoo lavas. Basaltic lavas, dolerite sills and dykes shed rock fragments and clinopyroxenes that constitute the unique fingerprint of Orange River sand. Only a tenth of the sediment is supplied by the Vaal River, the longest Orange tributary that drains siliciclastic and volcanic units ranging in age from Neoarchean in the Transvaal to early Mesozoic in the Karoo Basin. In the arid middle and lower reaches, the Orange River carves its course into the Namaqua Belt and receives the Molopo River flowing only episodically across the vast Kalahari Desert and the Fish River draining sedimentary rocks of the Nama Group and Karoo Supergroup. Fragile sedimentary rock fragments do not survive high-energy wave transport, but basaltic rock fragments and pyroxenes do, allowing us to trace sand transport for ∼1800 km all along the Atlantic coast of Namibia to as far as southern Angola. Understanding sediment mass transfer has scientific as well as practical interest, being a prerequisite for effective fluvial and coastal management, with particular economic significance in the special case of diamond-bearing Orange sand.

Background Despite evidence showing that the intranasal and sublingual routes are safe and effective in providing analgesia, no data are available about their day-to-day use in the emergency department (ED). The aim of this study was to assess the frequency of the use of the intranasal and sublingual routes, and the clinical characteristics of the patients receiving analgesia through these routes.Methods A multicentre study was performed in the EDs participating in the Pain in Paediatric Emergency Room research group. It included a survey and a retrospective data collection in which the medical records of all patients who received analgesia from 1 April 2022 to 31 May 2022 were collected.Results 48 centres (91%) answered the survey. The intranasal and sublingual routes were used in 25 centres (52%). 13 centres (27%) used both routes, 9 centres (19%) used only the sublingual and 3 centres (6%) used only the intranasal route.12 centres (48%) participated in the retrospective study. Data about 3409 patients, median age 9 years (IQR 5–12), were collected. Among them, 337 patients (9.6%) received sublingual analgesia, and 87 patients (2.5%) received intranasal analgesia. The intranasal route was employed for injuries in 79 (90.8%) cases, and fentanyl was the drug delivered in 85 (97.7%) cases. The sublingual route was used mainly for injuries (57.3%), but also for abdominal pain (15.4%), musculoskeletal pain (14.5%) and headache (10.7%). Paracetamol, ketorolac and tramadol were administered through this route.Conclusions The use of the intranasal and sublingual routes for analgesia in the paediatric ED is still limited.

Nanoparticles composed of inorganic boron-containing compounds represent a promising candidate as 10B carriers for BNCT. This study focuses on the synthesis, characterization, and assessment of the biological activity of composite nanomaterials based on boron carbide (B4C). Boron carbide is a compelling alternative to borated molecules due to its high volumetric B content, prolonged retention in biological systems, and low toxicity. These attributes lead to a substantial accumulation of B in tissues, eliminating the need for isotopically enriched compounds. In our approach, B4C nanoparticles were included in composite nanostructures with ultrasmall superparamagnetic nanoparticles (SPIONs), coated with poly (acrylic acid), and further functionalized with the fluorophore DiI. The successful internalization of these nanoparticles in HeLa cells was confirmed, and a significant uptake of 10B was observed. Micro-distribution studies were conducted using intracellular neutron autoradiography, providing valuable insights into the spatial distribution of the nanoparticles within cells. These findings strongly indicate that the developed nanomaterials hold significant promise as effective carriers for 10B in BNCT, showcasing their potential for advancing cancer treatment methodologies.

Monte Amiata (305–231 ka; Italy) is an uncommon example of an entirely effusive silicic (mainly trachytic) composite volcano. A detailed geological map (1:25,000 scale) based on Unconformity Bounded Stratigraphic Unit criteria is presented accompanied by volcano-tectonic, stratigraphic relationship, and volcano evolution schemes. The volcanic facies analysis and structural analysis criteria have been applied to decipher Monte Amiata's geological evolution and structure, and to infer the relations between volcanism and regional tectonics. Based on the occurrence of a first-order geological unconformity representing a paleo-weathering surface of paleoclimatic significance, two major volcanic stratigraphic units and seven phases of activity are recognized.Highlights Monte Amiata is a volcano with the rare peculiarity of being completely silicic and effusiveThe produced, detailed, geological map has been the primary tool for the comprehension of the history of the volcano and will be the primary tool for land managementUsing of the Unconformity Bounded Stratigraphic Units hallowed us to reconsider Monte Amiata not as an isolated volcanic body but as a part of the geology of this portion of Southern Tuscany.At Monte Amiata, where the second largest Italian geothermal field is located, a complete geological picture means giving substantial help to geothermal resource development

In 2023, an archaeological research project was initiated by the University of Udine, in cooperation with the Dohuk Directorate of Antiquities and Heritage of the Kurdistan Region of Iraq, on the site of Bazhera, on the eastern bank of the Nahr al-Khazir, in the Akre district. The site consists of a partially standing building, which would have played a role in the communication system of the region during the late Islamic period, as one of the stations in support of travellers. The main objective of the project is to reconstruct the functioning of this structure, its material culture and its relationship with other archaeological remains identified on the settlement and with the surrounding landscape, in order to provide new data regarding land management and protection of a frontier region of the Ottoman empire which has been neglected by archaeological research.

Sewage sludge (biosolids) management represents a worldwide issue. Due to its valuable properties, approximately one half of the EU production is recovered in agriculture. Nevertheless, growing attention is given to potential negative effects deriving from the presence of harmful pollutants. It is recognized that a (even very detailed) chemical characterization is not able to predict ecotoxicity of a mixture. However, this can be directly measured by bioassays. Actually, the choice of the most suitable tests is still under debate. This paper presents a multilevel characterization protocol of sewage sludge and other organic residues, based on bioassays and chemical-physical-microbiological analyses. The detailed description of the experimental procedure includes all the involved steps: the criteria for selecting the organic matrices to be tested and compared; the sample pre-treatment required before the analyses execution; the chemical, physical and microbiological characterisation; the bioassays, grouped in three classes (baseline toxicity; specific mode of action; reactive mode of action); data processing. The novelty of this paper lies in the integrated use of advanced tools, and is based on three pillars: • the direct ecosafety assessment of the matrices to be reused. • the adoption of innovative bioassays and analytical procedures. • the original criteria for data normalization and processing.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), a novel term for Non-Alcoholic Fatty Liver Disease (NAFLD), is associated with liver mitochondrial dysfunction. We previously demonstrated that mitochondrial respiratory capacity in peripheral blood mononuclear cells (PBMCs) was significantly reduced in patients with MASLD compared to non-MASLD controls. For MASLD treatment, guidelines recommend behavioral and dietary changes to reduce body weight. A recent 12-month clinical trial demonstrated that ameliorating patients’ lifestyles through improved adherence to the Mediterranean diet and encouraged physical activity results in MASLD remission or regression. Methods: As a sub-study of the 12-month clinical trial, we evaluated the effects of the Mediterranean diet-oriented intervention on PBMC mitochondrial DNA content and respiratory parameters and on various biomarkers associated with MASLD. Results: Contrary to what was found at the baseline, after twelve months of intervention, systemic inflammatory and bioenergetics parameters did not differ between MASLD patients (N = 15) and control subjects (N = 17). PBMCs from MASLD subjects showed rescued basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity. The observed recovery coincided with a significant increase in the patients’ adherence to the Mediterranean diet (Medscore). Conclusions: Our findings indicate that a Mediterranean diet-oriented intervention, without calorie reduction, preserves blood cell mitochondrial function in MASLD subjects. Thus, PBMC bioenergetics-based assays might be taken into account not only for diagnosing but also for monitoring therapeutic responses in MASLD.

During recent decades, model organisms such as Drosophila melanogaster have made it possible to study the effects of different environmental oxygen conditions on lifespan and oxidative stress. However, many studies have often yielded controversial results usually assigned to variations in Drosophila genetic background and differences in study design. In this study, we compared longevity and ROS levels in young, unmated males of three laboratory wild-type lines (Canton-S, Oregon-R and Berlin-K) and one mutant line (Sod1n1) as a positive control of redox imbalance, under both normoxic and hypoxic (2% oxygen for 24 h) conditions. Lifespan was used to detect the effects of hypoxic treatment and differences were analysed by means of Kaplan-Meier survival curves and log-rank tests. Electron paramagnetic resonance spectroscopy was used to measure ROS levels and analysis of variance was used to estimate the effects of hypoxic treatment and to assess ROS differences between strains. We observed that the genetic background is a relevant factor involved in D. melanogaster longevity and ROS levels. Indeed, as expected, in normoxia Sod1n1 are the shortest-lived, while the wild-type strains, despite a longer lifespan, show some differences, with the Canton-S line displaying the lowest mortality rate. After hypoxic stress these variances are amplified, with Berlin-K flies showing the highest mortality rate and most evident reduction of lifespan. Moreover, our analysis highlighted differential effects of hypoxia on redox balance/unbalance. Canton-S flies had the lowest increase of ROS level compared to all the other strains, confirming it to be the less sensitive to hypoxic stress. Sod1n1 flies displayed the highest ROS levels in normoxia and after hypoxia. These results should be used to further standardize future Drosophila research models designed to investigate genes and pathways that may be involved in lifespan and/or ROS, as well as comparative studies on specific mutant strains.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. It is characterized by the formation of cysts in kidneys. This condition has a significant impact on people’s lives. It causes not only physical suffering but also psychological suffering. People with ADPKD may experience psychological distress, depending on their personal and health conditions. The inability to accept or adapt to the disease and its resulting changes causes individuals difficulties that appear in different levels of their lives: intrapersonal, interpersonal, social, and occupational. In the context of ADPKD, the psychologist is involved both at clinical and research levels. The psychologist has a crucial role in supporting patients by assessing how they react to the disease, to its related limitations, and to the resulting disabilities. The proposal of psychological support, considered as an intervention instrument, is helpful both at the diagnostic stage and in follow-up, as the disease worsens. The support aims to encourage acceptance and adaptation to the disease, process changes, and physical and mental consequences.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetically inherited kidney disease and the fourth leading cause of renal replacement therapy worldwide. It is characterized by the development of multiple cysts in the kidneys and in other organs, the increase in renal volume and the progressive loss of renal function. ADPKD outcome seems to be sensitive to hormonal fluctuations, particularly those of sex hormones. Despite the limited literature available, this review presents the first comprehensive overview of contraception and hormonal replacement therapy in women with ADPKD, delving into the risks and benefits associated with different contraceptive methods, including hormonal, intrauterine devices, and non-hormonal approaches. It also explores personalized strategies for contraception based on the severity of renal disease and the presence of comorbidities. Although the protective role of female sex hormones in slowing the progression of renal failure is acknowledged, hormonal therapy in women with ADPKD remains intricate and challenging due to its potential impact on liver disease progression. Women with ADPKD typically experience a slower progression of renal disease compared to men, largely influenced by hormonal dynamics. This literature review underscores the importance of a multidisciplinary assessment and a thorough patient discussion to identify the most suitable contraceptive method for each woman affected by polycystic kidney disease.

Introduction: Diving decompression theory hypothesizes inflammatory processes as a source of micronuclei which could increase related risks. Therefore, we tested 10 healthy, male divers. They performed 6–8 dives with a maximum of two dives per day at depths ranging from 21 to 122 msw with CCR mixed gas diving.Methods: Post-dive VGE were counted by echocardiography. Saliva and urine samples were taken before and after each dive to evaluate inflammation: ROS production, lipid peroxidation (8-iso-PGF2), DNA damage (8-OH-dG), cytokines (TNF-α, IL-6, and neopterin).Results: VGE exhibits a progressive reduction followed by an increase (p < 0.0001) which parallels inflammation responses. Indeed, ROS, 8-iso-PGF2, IL-6 and neopterin increases from 0.19 ± 0.02 to 1.13 ± 0.09 μmol.min−1 (p < 0.001); 199.8 ± 55.9 to 632.7 ± 73.3 ng.mg−1 creatinine (p < 0.0001); 2.35 ± 0.54 to 19.5 ± 2.96 pg.mL−1 (p < 0.001); and 93.7 ± 11.2 to 299 ± 25.9 μmol·mol−1 creatinine (p = 0.005), respectively. The variation after each dive was held constant around 158.3% ± 6.9% (p = 0.021); 151.4% ± 5.7% (p < 0.0001); 176.3% ± 11.9% (p < 0.0001); and 160.1% ± 5.6% (p < 0.001), respectively.Discussion: When oxy-inflammation reaches a certain level, it exceeds hormetic coping mechanisms allowing second-generation micronuclei substantiated by an increase of VGE after an initial continuous decrease consistent with a depletion of “first generation” pre-existing micronuclei.

Summary: Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The oSVZ comprises progenitor cells expressing specific oRG markers such as GFAP, LIFR, and HOPX, closely matching human fetal oRG. Finally, incorporating neural crest-derived LIF-producing cortical pericytes into cortical organoids recapitulates the effects of LIF treatment. These data indicate that increasing the cellular complexity of the organoid microenvironment promotes the emergence of oRG and supports a platform to study oRG in hPSC-derived brain organoids routinely.