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Vincenzo Vestuto,1,* Marisa Conte,1,* Mariapia Vietri,1,* Francesca Mensitieri,2 Valentina Santoro,1,3 Anna Di Muro,1 Mariaevelina Alfieri,4 Maria Moros,5,6 Maria Rosaria Miranda,1,3 Chiara Amante,1 Matteo Delli Carri,1 Pietro Campiglia,1 Fabrizio Dal Piaz,2,7 Pasquale Del Gaudio,1 Nunziatina De Tommasi,1,3 Antonietta Leone,1 Ornella Moltedo,1 Giacomo Pepe,1,3 Elisa Cappetta,1 Alfredo Ambrosone1 1Department of Pharmacy, University of Salerno, Fisciano, 84084, Italy; 2Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081, Italy; 3National Biodiversity Future Center (NBFC), Palermo, 90133, Italy; 4Clinical Pathology, Santobono-Pausilipon Children’s Hospital, AORN, Naples, 80122, Italy; 5Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza, Spain; 6Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; 7Operative Unit of Clinical Pharmacology, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy*These authors contributed equally to this workCorrespondence: Alfredo Ambrosone; Elisa Cappetta, Department of Pharmacy, University of Salerno, Fisciano, 84084, Italy, Email aambrosone@unisa.it; ecappetta@unisa.itPurpose: Extracellular vesicles (EVs) are promising tools for nanomedicine and nanobiotechnology. The purification of mammalian-derived EVs involves intensive processes, and their therapeutic application raises multiple safety and regulatory issues. Plants have the potential to serve as nonconventional sources of therapeutically relevant EVs. In this context, we recently identified hairy roots (HRs) of medicinal plants as a novel biotechnological platform to produce EVs for human health.Methods: Herein, we report the purification, omics profiling, and bioactivity of EVs isolated from HRs of the medicinal plants S. sclarea and S. dominica. EVs were isolated from conditioned media of HR cultures using differential ultracentrifugation (dUC) and size exclusion chromatography (SEC). The isolated EVs were characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The proteomic and metabolomic profiles of the EVs were determined using mass spectrometry. Uptake studies and bioactivity assays, including confocal microscopy, MTT, flow cytometry, ROS quantification, and untargeted metabolomics analyses, were conducted in SH-SY5Y cells treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to evaluate the therapeutic potential of EVs in an in vitro model of Parkinson’s disease.Results: S. sclarea HRs released nanosized round-shaped EVs with a distinctive molecular signature. HR EVs from S. sclarea and S. dominica revealed conserved cargo of secondary metabolites, predominantly triterpenoids, which are known for their antioxidant properties. We showed that HR EVs are safe, enter the cells, and strongly inhibit apoptosis in a cellular model of Parkinson’s disease. Cellular metabolomics revealed that EVs preserved metabolic homeostasis and mitigated cellular oxidative stress when co-administered with 6-OHDA. Mechanistically, HR EVs inhibited 6-OHDA autoxidation and substantially reduced the accumulation of its oxidative products, which are responsible for 6-OHDA-induced toxicity.Conclusion: Collectively, our findings provide compelling evidence that EVs isolated from the hairy roots of Salvia species are promising, non-mammalian alternative for the design of novel therapies targeting neurological disorders. Keywords: non-mammalian EV source, Salvia extracellular vesicles, hairy roots, nanomedicine, neuroprotection, Parkinson’s disease

Posterior lateral meniscal root (PLMR) tears are commonly observed in conjunction with anterior cruciate ligament (ACL) injuries. The presence of PLMR tears exacerbates knee instability, increasing stress on ACL grafts and accelerating joint degeneration if left untreated. Anatomical repair of PLMR tears is therefore crucial for restoring native knee kinematics and reducing tibiofemoral contact pressures, thereby safeguarding the ACL graft. However, the standard use of a single medial tunnel approach for concomitant PLMR and revision ACL reconstruction may require reconsideration to prevent the potential risks of tunnel overlapping, which could undermine graft anatomical integrity. This article, to prevent the risk of tunnel overlapping, introduces a surgical approach that employs an additional lateral tibial tunnel for PLMR repair, instead of the typically used single medial one, for PLMR repair during simultaneous revision ACL reconstruction.

IntroductionBacterial infection of the central nervous system (CNS) poses a clinical challenge and is a leading cause of neurological disorders in cattle. Human studies have demonstrated an increase in cerebrospinal fluid (CSF) L-lactate levels in bacterial meningitis. The aims of this study were to establish a Reference Interval (RI) for L-lactate in bovine CSF and assess its potential as a biomarker for detecting infectious-inflammatory disorders.MethodsCSF L-lactate was measured in the field using a commercially available lactate monitor. The RI for CSF L-lactate was calculated on healthy animals; univariate and receiver operating characteristic (ROC) analyses were performed to disclose an association between CSF L-lactate levels and interpretation of CSF in sick animals.ResultsTwenty-seven healthy cattle and 86 sick cattle with either CNS infectious-inflammatory disorders (47/86) or CNS disorders of other etiology (39/86) were included in this prospective study. The RI for CSF L-lactate was 1.1–2.4 mmol/L. The concentration was higher in the cattle with neutrophilic pleocytosis and the area under the ROC curve was 0.92 compared to other animals. Based on a cut-off of 3.15 mmol/L, CSF L-lactate had diagnostic sensitivity and specificity for neutrophilic pleocytosis of 93 and 80%, respectively.DiscussionThis is the first study to determine a RI for CSF L-lactate in cattle. Elevated CSF L-lactate levels indicated neutrophilic pleocytosis, which is often manifested in acute bacterial infection. The present findings may aid in diagnosis and correct use of antimicrobial drugs.

El estudiante que ingresa a la Educación Superior requiere manejar su conocimiento y aprendizaje de forma estratégica. En la medida en que este dispone de recursos metacognitivos para regular los procesos asociados al hecho de aprender, le permitirá tener mayor conciencia cognitiva. En esta investigación, se determinó el perfil metacognitivo de 532 estudiantes inscritos en el primer semestre de diferentes carreras que oferta la Universidad Nacional Experimental del Táchira, a través de las dimensiones que este constructo involucra: metamemoria, metalenguaje, metaatención y metacomprensión. Su identificación contribuye a conocer las necesidades diagnosticadas en los estudiantes, a fin de desarrollar nuevas estrategias de aprendizaje o fortalecer aquellas que conlleven a un proceso de formación integral de los futuros Ingenieros de la UNET. Los resultados indican que los estudiantes de nuevo ingreso presentan un perfil metacognitivo entre “moderado” y “alto”, por lo que se aprecia una adecuada habilidad metacognitiva para manejar y controlar el conocimiento que poseen.

Antimicrobial resistance is a growing concern for the scientific community and the public, so many countries have stepped up monitoring to tackle it and promote correct antimicrobial use. The welfare assessment protocol for dairy cows used by the Italian National Reference Centre for Animal Welfare (CReNBA) recommends lowering the use of antibiotics, so this study assessed the effects of the introduction of the welfare score on antimicrobial use and animal welfare between 2015 and 2018. For this study, 23 dairy farms in northern Italy (Piedmont) were enrolled. Data on animal categories (calf, heifer and cow) and antimicrobial use were extrapolated from mandatory farm registers. The antimicrobial animal-defined daily dose (ADDD) and the ADDD per year (ADDD/year) were calculated. Each farm was evaluated with the CReNBA welfare assessment protocol for dairy cows. An increase was recorded for 2018 regarding the number of reared animals (especially adult cows) and in the welfare (2015: 71.44% ± 7.84% vs. 2018: 76.18% ± 6.40%; p

Loss-, gain-of-function and mixed variants in SCN1A (Nav1.1 voltage-gated sodium channel) have been associated with a spectrum of neurologic disorders with different severity and drug-responsiveness. Most SCN1A variants are heterozygous changes occurring de novo or dominantly inherited; recessive inheritance has been reported in a few cases. Here, we report a family in which the biallelic inheritance of two novel SCN1A variants, N935Y and H1393Q, occurs in two siblings presenting with drug-responsive developmental and epileptic encephalopathy and born to heterozygous asymptomatic parents. To assess the genotype–phenotype correlation and support the treatment choice, HEK 293 cells were transfected with different combinations of the SCN1A WT and mutant cDNAs, and the resulting sodium currents were recorded through whole-cell patch-clamp. Functional studies showed that the N935Y and H1393Q channels and their combinations with the WT (WT + N935Y and WT + H1393Q) had current densities and biophysical properties comparable with those of their respective control conditions. This explains the asymptomatic condition of the probands’ parents. The co-expression of the N935Y + H1393Q channels, mimicking the recessive inheritance of the two variants in siblings, showed ~20% reduced current amplitude compared with WT and with parental channels. This mild loss of Nav1.1 function may contribute in part to the disease pathogenesis, although other mechanisms may be involved.

Abstract Background Atypical Haemolytic Uremic Syndrome is an acute life-threatening condition, characterized by the clinical triad of microangiopathic hemolytic anaemia, thrombocytopenia, kidney injury. Management of pregnants affected by Atypical Haemolytic Uremic Syndrome can be a serious concern for obstetric anesthesiologist in the delivery room and in the intensive care unit. Case presentation A 35-year-old primigravida with a monochorionic diamniotic twin pregnancy, presented with an acute haemorrhage due to retained placenta after elective caesarean section and underwent surgical exploration. In the postoperative period, the patient progressively developed hypoxemic respiratory failure and, later on, anaemia, severe thrombocytopenia, and acute kidney injury. A timely diagnosis of Atypical Haemolytic Uremic Syndrome was made. Non-invasive ventilation and high-flow nasal cannula oxygen therapy sessions were initially required. Hypertensive crisis and fluid overload were aggressively treated with a combination of beta and alpha adrenergic blockers (labetalol 0,3 mg/kg/h by continuous intravenous infusion for the first 24 hours, bisoprolol 2,5 mg twice daily for the first 48 hours, doxazosin 2 mg twice daily), central sympatholytics (methyldopa 250 mg twice daily for the first 72 hours, transdermal clonidine 5 mg by the third day), diuretics (furosemide 20 mg three times daily), calcium antagonists (amlodipine 5 mg twice daily). Eculizumab 900 mg was administered via intravenous infusion once per week, attaining hematological and renal remissions. The patient also received several blood transfusion units and anti- meningococcal B, anti-pneumococcal, anti-haemophilus influenzae type B vaccination. Her clinical condition progressively improved, and she was finally discharged from intensive care unit 5 days after admission. Conclusions The clinical course of this report underlines how crucial it is for the obstetric anaesthesiologist to promptly identify Atypical Haemolytic Uremic Syndrome, since early initiation of eculizumab, together with supportive therapy, has a direct effect on patient outcome.

Abstract Background Central nervous system (CNS) infections in cattle are a major cause of economic loss and mortality. Machine learning (ML) techniques are gaining widespread application in solving predictive tasks in both human and veterinary medicine. Objectives Our primary aim was to develop and compare ML models that could predict the likelihood of a CNS disorder of infectious or inflammatory origin in neurologically‐impaired cattle. Our secondary aim was to create a user‐friendly web application based on the ML model for the diagnosis of infection and inflammation of the CNS. Animals Ninety‐eight cattle with CNS infection and 86 with CNS disorders of other origin. Methods Retrospective observational study. Six different ML methods (logistic regression [LR]; support vector machine [SVM]; random forest [RF]; multilayer perceptron [MLP]; K‐nearest neighbors [KNN]; gradient boosting [GB]) were compared for their ability to predict whether an infectious or inflammatory disease was present based on demographics, neurological examination findings, and cerebrospinal fluid (CSF) analysis. Results All 6 methods had high prediction accuracy (≥80%). The accuracy of the LR model was significantly higher (0.843 ± 0.005; receiver operating characteristic [ROC] curve 0.907±0.005) than the other models and was selected for implementation in a web application. Conclusion and Clinical Importance Our findings support the use of ML algorithms as promising tools for veterinarians to improve diagnosis. The open‐access web application may aid clinicians in achieving correct diagnosis of infectious and inflammatory neurological disorders in livestock, with the added benefit of promoting appropriate use of antimicrobials.

The “Fani Maoré” eruption off the coasts of Mayotte has been intensively monitored by applying methods similar to those used for subaerial eruptions. Repeated high-resolution bathymetric surveys and dredging, coupled with petrological analyses of time-constrained samples, allowed tracking the evolution of magma over the whole submarine eruptive sequence. Indeed, after one year of direct ascent (Phase 1), basanitic magma switched to a different pathway that sampled a tephri-phonolitic subcrustal reservoir (Phase 2). Later, the magma pathway shifted again in the crust resulting in a new eruption site located 6 km northwest of the main edifice (Phase 3). The petrological signature of lava flows reveals both an evolution by fractional crystallization and syn-eruptive mixing with a tephri-phonolitic magma.We demonstrate that high-flux eruption of large volumes of basanitic magma from a deep-seated reservoir can interact with shallower reservoirs and remobilize eruptible magma. This has significant hazards implications with respect to the capacity of such large eruptions to reactivate shallow-seated inactive reservoirs from a transcrustal magmatic system that could be located potentially at a distance from the high-flux eruptive site.

Since May 2018, an unexpected long and intense seismic crisis started offshore Mayotte (Indian Ocean, France). This ongoing seismic sequence is associated with the birth of a newly discovered submarine volcano 50 km east of Petite Terre. Here, we investigate the indirect impact of this crisis on the stability of an atypical ecosystem located in Mayotte, the Dziani Dzaha Lake. This lacustrine system presented physical, chemical and biogeochemical characteristics that were distinct from those classically observed in modern lakes or seawater, e.g. high salinity (up to 70 psu), lack of nitrate, sulfate content below 3 mM, and permanent water column anoxia below ca. 1.5 m depth (2012–2017 period). Based on three surveys conducted in 2020 and 2021, we documented an episode of water column oxygenation, a significant pH decrease and an impressive change in the carbon isotope signatures. These preliminary data suggest that the functioning of biogeochemical cycles in the Dziani Dzaha Lake is impacted by increased CO2 inputs and the changes in the lake mixing dynamics, which is an indirect consequence of the ongoing seismo-volcanic crisis.

IntroductionConstant rate infusion (CRI) of benzodiazepines or propofol (PPF) is a therapeutic option for cluster seizures (CS) and status epilepticus (SE) in canine patients non-responding to first-line benzodiazepines or non-anesthetics. However, specific indications for optimal duration of CRI are lacking. The aim of this study was to determine the effect of duration of anesthetic CRI on outcome and length of hospital stay in dogs with refractory seizure activity of different etiology.Study designOpen-label non-randomized clinical trial.Materials and methodsSeventy-three client-owned dogs were enrolled. Two groups [experimental (EXP) vs. control (CTRL)] were compared. The EXP group received diazepam (DZP) or PPF CRI for 12 h (±1 h) and the CTRL group received DZP or PPF CRI for 24 h (±1 h) in addition to a standardized emergency treatment protocol identical for both study groups. The historical control group was made up of a population of dogs already reported in a previously published paper by the same authors. Favorable outcome was defined as seizure cessation after CRI, no seizure recurrence, and clinical recovery. Poor outcome was defined as seizure recurrence, death in hospital or no return to acceptable clinical baseline. Univariate statistical analysis was performed.ResultsThe study sample was 73 dogs: 45 (62%) received DZP CRI and 28 (38%) received PPF CRI. The EXP group was 39 dogs (25 DZP CRI and 14 PPF CRI) and the CTRL group 34 dogs (20 DZP CRI and 14 PPF CRI). We found no statistically significant difference in outcomes between the groups. The median length of stay was 56 h (IQR, 40–78) for the ALL EXP group and 58.5 h (IQR, 48–74.5) for the ALL CTRL group (p = 0.8).ConclusionEven though a shorter DZP or PPF CRI duration was not associated with a worse outcome, the study failed to identify a clear superiority of shorter CRI duration on outcome or length of hospital stay in dogs with refractory seizure activity of different etiology.

The Comoros archipelago is an active geodynamic region located in the Mozambique Channel between East continental Africa and Madagascar. The archipelago results from intra-plate volcanism, the most recent eruptions having occurred on the youngest island of Grande Comore and on the oldest one of Mayotte. Since 2018, the eastern submarine flank of Mayotte has been the site of one of the largest recent eruptive events on Earth in terms of erupted lava volume. On land, the most recent volcanic activity occurred in Holocene on the eastern side of Mayotte, corresponding to the small Petite Terre Island, where two main and persistent gas seep areas are present (Airport Beach, namely BAS, and Dziani Dzaha intracrateric lake). The large submarine eruption at the feet of Mayotte (50 km offshore; 3.5 km b.s.l.) is associated with deep (mantle level) seismic activity closer to the coast (5–15 km offshore) possibly corresponding to a single and large magmatic plumbing system. Our study aims at characterizing the chemical and isotopic composition of gas seeps on land and assesses their potential link with the magmatic plumbing system feeding the Mayotte volcanic ridge and the recent submarine activity. Data from bubbling gases collected between 2018 and 2021 are discussed and compared with older datasets acquired between 2005 and 2016 from different research teams. The relation between $\mbox {}^{3}\mathrm{He}/\mbox {}^{4}\mathrm{He}$ and $\delta ^{13}\mathrm{C}$-$\mathrm{CO}_{2}$ shows a clear magmatic origin for Mayotte bubbling gases, while the variable proportions and isotopic signature of $\mathrm{CH}_{4}$ is related to the occurrence of both biogenic and abiogenic sources of methane. Our new dataset points to a time-decreasing influence of the recent seismo-volcanic activity at Mayotte on the composition of hydrothermal fluids on land, whose equilibrium temperature steadily decreases since 2018. The increased knowledge on the gas-geochemistry at Mayotte makes the results of this work of potential support for volcanic and environmental monitoring programs.

PurposeTo evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD).MethodsWe investigated the electro-clinical longitudinal data and CSF Aβ42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families.ResultsThree progressive electro-clinical stages were identified. The early phase was characterized by rare, generalized tonic-clonic and focal visual seizures, followed by the occurrence of myoclonus after a period ranging from 2 to 12 months. The intermediate stage, usually occurring 2 years after the onset of epilepsy, is characterized by a worsening of epilepsy and myoclonus associated with progressive dementia and cerebellar signs. Finally, the late stage, evolving after a mean period of 7 ± 1.41 years from the onset of the disease, was characterized by gait ataxia resulting in bedriddenness, severe dementia, daily/pluri-daily myoclonus, drug-resistant epilepsy, clusters of seizures or status epilepticus, and medical complications. Amyloid (CSF Aβ42, amyloid PET) and neurodegenerative (CSF p-tau181 and t-tauAg, FDG-PET) biomarkers indicate a pattern of cognitive impairment of the non-Alzheimer's disease type. A total of 80% of the LD patients showed more severe hypometabolism in the second FDG-PET scan compared to the first scan performed in a lower phase; the lateral temporal lobe and the thalamus hypometabolism were associated with the presence of intermediate or late phase.ConclusionsThree electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the efficacy of new disease-modifying treatments. The combination of traditional CSF biomarkers improves the diagnostic accuracy of cognitive decline in LD patients, indicating a cognitive impairment of the non-Alzheimer's disease type.

IntroductionCluster seizures (CS) and status epilepticus (SE) in dogs are severe neurological emergencies that require immediate treatment. Practical guidelines call for constant rate infusion (CRI) of benzodiazepines or propofol (PPF) in patients with seizures not responding to first-line treatment, but to date only few studies have investigated the use of CRI in dogs with epilepsy.Study designRetrospective clinical study.MethodsDogs that received CRI of diazepam (DZP) or PPF for antiepileptic treatment during hospitalization at the Veterinary Teaching Hospital of the University of Turin for CS or SE between September 2016 and December 2019 were eligible for inclusion. Favorable outcome was defined as cessation of clinically visible seizure activity within few minutes from the initiation of the CRI, no seizure recurrence within 24 h after discontinuation of CRI through to hospital discharge, and clinical recovery. Poor outcome was defined as recurrence of seizure activity despite treatment or death in hospital because of recurrent seizures, catastrophic consequences of prolonged seizures or no return to an acceptable neurological and clinical baseline, despite apparent control of seizure activity. Comparisons between the number of patients with favorable outcome and those with poor outcome in relation to type of CRI, seizure etiology, reason for presentation (CS or SE), sex, previous AED therapy and dose of PPF CRI were carried out.ResultsA total of 37 dogs, with 50 instances of hospitalization and CRI administered for CS or SE were included in the study. CRI of diazepam (DZP) or PPF was administered in 29/50 (58%) and in 21/50 (42%) instances of hospitalization, respectively. Idiopathic epilepsy was diagnosed in 21/37 (57%), (13/21 tier I and 8/21 tier II); structural epilepsy was diagnosed in 6/37 (16%) of which 4/6 confirmed and 2/6 suspected. A metabolic or toxic cause of seizure activity was recorded in 7/37 (19%). A total of 38/50 (76%) hospitalizations were noted for CS and 12/50 (24%) for SE. In 30/50 (60%) instances of hospitalization, the patient responded well to CRI with cessation of seizure activity, no recurrence in the 24 h after discontinuation of CRI through to hospital discharge, whereas a poor outcome was recorded for 20/50 (40%) cases (DZP CRI in 12/50 and PPF CRI in 8/50). Comparison between the number of patients with favorable outcome and those with poor outcome in relation to type of CRI, seizure etiology, reason for presentation (CS or SE), sex and previous AED therapy was carried out but no statistically significant differences were found.ConclusionsThe present study is the first to document administration of CRI of DZP or PPF in a large sample of dogs with epilepsy. The medications appeared to be tolerated without major side effects and helped control seizure activity in most patients regardless of seizure etiology. Further studies are needed to evaluate the effects of CRI duration on outcome and complications.

Solid lipid nanoparticles promote skin hydration via stratum corneum occlusion, which prevents water loss by evaporation, and via the reinforcement of the skin’s lipid-film barrier, which occurs through the adhesion of the nanoparticles to the stratum corneum. The efficacy of both phenomena correlates with lower nanoparticle size and the increased skin permeation of loaded compounds. The so-called Polysorbate Sorbitan Phase-Inversion Temperature method has, therefore, been optimized in this experimental work, in order to engineer ultrasmall solid-lipid nanoparticles that were then loaded with α-tocopherol, as the anti-age ingredient for cosmetic application. Ultrasmall solid-lipid nanoparticles have been proven to be able to favor the skin absorption of loaded compounds via the aforementioned mechanisms.

Piton de la Fournaise, situated on La Réunion island (France), is one of the most active hot spot basaltic shield volcanoes worldwide, experiencing at least two eruptions per year since the establishment of the volcanological observatory in 1979. Eruptions are typically fissure-fed and form extensive lava flow fields. About 95 % of some ∼ 250 historical events (since the first confidently dated eruption in 1708) have occurred inside an uninhabited horseshoe-shaped caldera (hereafter referred to as the Enclos), which is open to the ocean on its eastern side. Rarely (12 times since the 18th century), fissures have opened outside of the Enclos, where housing units, population centers, and infrastructure are at risk. In such a situation, lava flow hazard maps are a useful way of visualizing lava flow inundation probabilities over large areas. Here, we present the up-to-date lava flow hazard map for Piton de la Fournaise based on (i) vent distribution, (ii) lava flow recurrence times, (iii) statistics of lava flow lengths, and (iv) simulations of lava flow paths using the DOWNFLOW stochastic numerical model. The map of the entire volcano highlights the spatial distribution probability of future lava flow invasion for the medium to long term (years to decades). It shows that the most probable location for future lava flow is within the Enclos (where there are areas with up to 12 % probability), a location visited by more than 100 000 visitors every year. Outside of the Enclos, probabilities reach 0.5 % along the active rift zones. Although lava flow hazard occurrence in inhabited areas is deemed to be very low (< 0.1 %), it may be underestimated as our study is only based on post-18th century records and neglects older events. We also provide a series of lava flow hazard maps inside the Enclos, computed on a multi-temporal (i.e., regularly updated) topography. Although hazard distribution remains broadly the same over time, some changes are noticed throughout the analyzed periods due to improved digital elevation model (DEM) resolution, the high frequency of eruptions that constantly modifies the topography, and the lava flow dimensional characteristics and paths. The lava flow hazard map for Piton de la Fournaise presented here is reliable and trustworthy for long-term hazard assessment and land use planning and management. Specific hazard maps for short-term hazard assessment (e.g., for responding to volcanic crises) or considering the cycles of activity at the volcano and different event scenarios (i.e., events fed by different combinations of temporally evolving superficial and deep sources) are required for further assessment of affected areas in the future – especially by atypical but potentially extremely hazardous large-volume eruptions. At such an active site, our method supports the need for regular updates of DEMs and associated lava flow hazard maps if we are to be effective in keeping up to date with mitigation of the associated risks.

The process of GPCR dimerization can have profound effects on GPCR activation, signaling, and intracellular trafficking. Somatostatin receptors (SSTs) are class A GPCRs abundantly expressed in pituitary tumors where they represent the main pharmacological targets of somatostatin analogs (SSAs), thanks to their antisecretory and antiproliferative actions. The cytoskeletal protein filamin A (FLNA) directly interacts with both somatostatin receptor type 2 (SST2) and 5 (SST5) and regulates their expression and signaling in pituitary tumoral cells. So far, the existence and physiological relevance of SSTs homo- and hetero-dimerization in the pituitary have not been explored. Moreover, whether octreotide or pasireotide may play modulatory effects and whether FLNA may participate to this level of receptor organization have remained elusive. Here, we used a proximity ligation assay (PLA)–based approach for the in situ visualization and quantification of SST2/SST5 dimerization in rat GH3 as well as in human melanoma cells either expressing (A7) or lacking (M2) FLNA. First, we observed the formation of endogenous SST5 homo-dimers in GH3, A7, and M2 cells. Using the PLA approach combined with epitope tagging, we detected homo-dimers of human SST2 in GH3, A7, and M2 cells transiently co-expressing HA- and SNAP-tagged SST2. SST2 and SST5 can also form endogenous hetero-dimers in these cells. Interestingly, FLNA absence reduced the basal number of hetero-dimers (-36.8 ± 6.3% reduction of PLA events in M2, P < 0.05 vs. A7), and octreotide but not pasireotide promoted hetero-dimerization in both A7 and M2 (+20.0 ± 11.8% and +44.1 ± 16.3% increase of PLA events in A7 and M2, respectively, P < 0.05 vs. basal). Finally, immunofluorescence data showed that SST2 and SST5 recruitment at the plasma membrane and internalization are similarly induced by octreotide and pasireotide in GH3 and A7 cells. On the contrary, in M2 cells, octreotide failed to internalize both receptors whereas pasireotide promoted robust receptor internalization at shorter times than in A7 cells. In conclusion, we demonstrated that in GH3 cells SST2 and SST5 can form both homo- and hetero-dimers and that FLNA plays a role in the formation of SST2/SST5 hetero-dimers. Moreover, we showed that FLNA regulates SST2 and SST5 intracellular trafficking induced by octreotide and pasireotide.

Piton de la Fournaise (PdF) is a basaltic volcano whose activity is characterized by effusive to mildly explosive eruptions. The geologic record preserves evidence of explosive eruptions associated with the seaward sliding of the steep east flank. Such eruptions formed calderas that are several km in diameter and their products have been emplaced as breccias. The breccias of PdF offer the opportunity to sample a wide range of different lithologies covering most of the stratigraphy of the edifice. Petrophysical measurements revealed a corresponding variability in density, porosity, P-wave velocity, and uniaxial compressive strength, confirming the petrophysical consequences of the lithological diversity. Different lithologies cannot simply be distinguished on the basis of their physical properties. We infer that volcano instability should not be interpreted solely in terms of altered rock units. The large heterogeneity of crustal rocks must be considered when interpreting monitoring data and assessing hazards related to volcano stability.

Kidney transplanted recipients (KTR) are at high risk of severe SARS-CoV-2 infection due to immunosuppressive therapy. Although several studies reported antibody production in KTR after vaccination, data related to immunity to the Omicron (B.1.1.529) variant are sparse. Herein, we analyzed anti-SARS-CoV-2 immune response in seven KTR and eight healthy controls after the second and third dose of the mRNA vaccine (BNT162b2). A significant increase in neutralizing antibody (nAb) titers were detected against pseudoviruses expressing the Wuhan-Hu-1 spike (S) protein after the third dose in both groups, although nAbs in KTR were lower than controls. nAbs against pseudoviruses expressing the Omicron S protein were low in both groups, with no increase after the 3rd dose in KTR. Reactivity of CD4+ T cells after boosting was observed when cells were challenged with Wuhan-Hu-1 S peptides, while Omicron S peptides were less effective in both groups. IFN-γ production was detected in KTR in response to ancestral S peptides, confirming antigen-specific T cell activation. Our study demonstrates that the 3rd mRNA dose induces T cell response against Wuhan-Hu-1 spike peptides in KTR, and an increment in the humoral immunity. Instead, humoral and cellular immunity to Omicron variant immunogenic peptides were low in both KTR and healthy vaccinated subjects.

Landslides pose significant risks to towns and villages in Southern Italy, including the San Marco dei Cavoti hamlet (Benevento, Campania), where settlements have expanded into areas threatened by landslides, leading to property damage, disruption to the social fabric and loss of life. This study aims to investigate the surface deformations in the area using Differential Interferometry SAR (DInSAR) analysis on COSMO-SkyMed radar imagery and to assess the potential implications for landslide activity. The DInSAR analysis methodology allowed us to obtain high-precision results presented as time series diagrams and maps of cumulative displacement for the study area. Furthermore, the displacement rates derived from the DInSAR analysis were decomposed into vertical and horizontal components to provide better insights into the slope processes and their potential impacts on the San Marco dei Cavoti hamlet. Our significant findings revealed active slope movements and the uphill enlargement of previously inventoried landslides threatening the San Marco dei Cavoti hamlet. These insights contribute to a better understanding of the landslide dynamics in the region and highlight the areas that may require further investigation or intervention measures. In conclusion, this study demonstrates the effectiveness of DInSAR analysis in providing valuable insights into landslide dynamics and informing potential mitigation measures for at-risk communities. This technique could be applied to other landslide-prone regions to support informed decision-making and enhance the safety and resilience of affected communities.

Volcanic plumes are common and far-reaching manifestations of volcanic activity during and between eruptions. Observations of the rate of emission and composition of volcanic plumes are essential to recognize and, in some cases, predict the state of volcanic activity. Measurements of the size and location of the plumes are important to assess the impact of the emission from sporadic or localized events to persistent or widespread processes of climatic and environmental importance. These observations provide information on volatile budgets on Earth, chemical evolution of magmas, and atmospheric circulation and dynamics. Space-based observations during the last decades have given us a global view of Earth's volcanic emission, particularly of sulfur dioxide (SO2). Although none of the satellite missions were intended to be used for measurement of volcanic gas emission, specially adapted algorithms have produced time-averaged global emission budgets. These have confirmed that tropospheric plumes, produced from persistent degassing of weak sources, dominate the total emission of volcanic SO2. Although space-based observations have provided this global insight into some aspects of Earth's volcanism, it still has important limitations. The magnitude and short-term variability of lower-atmosphere emissions, historically less accessible from space, remain largely uncertain. Operational monitoring of volcanic plumes, at scales relevant for adequate surveillance, has been facilitated through the use of ground-based scanning differential optical absorption spectrometer (ScanDOAS) instruments since the beginning of this century, largely due to the coordinated effort of the Network for Observation of Volcanic and Atmospheric Change (NOVAC). In this study, we present a compilation of results of homogenized post-analysis of measurements of SO2 flux and plume parameters obtained during the period March 2005 to January 2017 of 32 volcanoes in NOVAC. This inventory opens a window into the short-term emission patterns of a diverse set of volcanoes in terms of magma composition, geographical location, magnitude of emission, and style of eruptive activity. We find that passive volcanic degassing is by no means a stationary process in time and that large sub-daily variability is observed in the flux of volcanic gases, which has implications for emission budgets produced using short-term, sporadic observations. The use of a standard evaluation method allows for intercomparison between different volcanoes and between ground- and space-based measurements of the same volcanoes. The emission of several weakly degassing volcanoes, undetected by satellites, is presented for the first time. We also compare our results with those reported in the literature, providing ranges of variability in emission not accessible in the past. The open-access data repository introduced in this article will enable further exploitation of this unique dataset, with a focus on volcanological research, risk assessment, satellite-sensor validation, and improved quantification of the prevalent tropospheric component of global volcanic emission. Datasets for each volcano are made available at https://novac.chalmers.se (last access: 1 October 2020) under the CC-BY 4 license or through the DOI (digital object identifier) links provided in Table 1.

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although males and females are at equivalent risk of infection, males are more prone to develop a higher severity disease, regardless of age. The factors that mediate susceptibility to SARS-CoV-2 and transmission are still under investigation. A potential role has been attributed to differences in the immune systems response to viral antigens between males and females as well as to different regulatory actions played by sex-related hormones on the two crucial molecular effectors for SARS-CoV-2 infection, TMPRSS2 and ACE2. While few and controversial data about TMPRSS2 transcript regulation in lung cells are emerging, no data on protein expression and activity of TMPRSS2 have been reported. Aim of the present study was to search for possible modulatory actions played by sex-related hormones on TMPRSS2 and ACE2 expression in Calu-3 cells, to test the effects of sex-steroids on the expression of the 32kDa C-term fragment derived from autocatalitic cleavage of TMPRSS2 and its impact on priming of transiently transfected spike protein. Cells were stimulated with different concentrations of methyltrienolone (R1881) or estradiol for 30 h. No difference in mRNA and protein expression levels of full length TMPRSS2 was observed. However, the 32 kDa cleaved serine protease domain was increased after 100 nM R1881 (+2.36 ± 1.13 fold-increase vs control untreated cells, p < 0.05) and 10 nM estradiol (+1.90 ± 0.64, fold-increase vs control untreated cells, p < 0.05) treatment. Both R1881 and estradiol significantly increased the activating proteolytic cleavage of SARS-CoV-2 Spike (S) transfected in Calu-3 cells (+1.76 ± 0.18 and +1.99±,0.76 increase in S cleavage products at R1881 100nM and 10 nM estradiol treatment, respectively, p < 0.001 and p < 0.05 vs control untreated cells, respectively). Finally, no significant differences in ACE2 expression were observed between hormones-stimulated cells and untreated control cells. Altogether, these data suggest that both male and female sex-related hormones are able to induce a proteolityc activation of TMPRSS2, thus promoting viral infection, in agreement with the observation that males and females are equally infected by SARS-CoV-2.

Abstract Background Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients. Case presentation In this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records. Conclusions Our study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.

IntroductionRemdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown.Materials and methodsProspective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality.ResultsWe included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, pConclusionsIn COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.

Background: Seizures are a common complication of cerebral venous thrombosis. In this study, we intended to define clinical and neuroradiological factors associated with early and late seizures and predictors for seizure recurrence. Methods: The database of our high-volume tertiary stroke center was screened for patients diagnosed with cerebral venous thrombosis between April 2006 and July 2021. Demographics, clinical, imaging, and instrumental data were collected. Results: Out of a total of 80 patients, 30 had seizures, either within the first week after onset (22 patients) or after (8 patients). Speech impairment and intracerebral bleeding were statistically associated with seizures in univariate analysis, but in a logistic regression model, only brain damage with hemorrhagic infarct and/or presence of brain hematoma [OR 6.051; 95% CI 1.881–19.468] (p = 0.003) were predicting factors for seizures. Late seizures were significantly more frequent in younger age [OR 0.864; 95% CI 0.763–0.978] (p = 0.020). Early seizures resulted as protective factors for recurrence; an altered state of consciousness at baseline and late seizures resulted as predictive factors for relapses (0.0% vs. 81.0%, p = 0.005, and 100.0% vs. 19.0%, p < 0.005, respectively). Conclusions: Our study confirms brain bleeding as the strongest risk factor for seizures after cerebral venous thrombosis. Recurrence is unusual after early seizures, while the presence of late seizures seems to raise the risk of recurrence.