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The preparation of planetary missions as well as the analysis of their data require a wide use of planetary simulants. They are very important for both testing mission operations and payloads, and for interpreting remote sensing data. In this work, a detailed analysis of three commercially available simulants of Martian dust and regolith is presented. Indeed, up to date, a complete data set related to their chemical, mineralogical, granulometric and spectral characters is not fully provided by their distribution and sales companies. Our dataset regards the Mars Global (MGS-1) High-Fidelity Martian Dirt Simulant [1], the Mojave Mars Simulant MMS-1 [2] and the Enhanced Mars Simulant (MMS-2) [2]. Being essential for ensuring consistency and enabling data comparison, all the chosen Martian simulants underwent the same analytical process. Grainsize data were collected using a Laser Diffraction Particle Size Analyzer. Chemical analysis was performed by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). Mineralogical analysis was carried out by X-Ray powder Diffractometry (XRD). Moreover, the largest particles of MGS-1 simulant were analyzed with the Scanning Electron Microscope (SEM-EDS) in order to confirm their chemical composition. Finally, the spectral acquisitions in the VNIR-SWIR range were taken by two Headwall Photonics hyperspectral imaging cameras. This complete series of data integrating pre-existing ones (e.g., Cannon et al. [1] and Karl et al. [2]) can in the future be used to allow a straightful choice of the right simulant for biological and life-support experiments and potential testing of mission instruments, to help inferring the composition of the Martian surface from remote sensing data, and to create new simulants or adjust the existing ones in order to get closer to the known Martian regolith variability and eventually new compositional information provided by future missions.

Summary: Background: Globally, fall-related injuries are a substantial problem, and 80% of fatal falls occur in low-income and middle-income countries. We aimed to measure time from injury to hip-fracture surgery in people aged 50 years or older living in low-income and middle-income regions, as well as to measure the proportion of patients with surgical stabilisation of their hip fracture within 72 h of admission to hospital and to identify risk factors associated with surgical delay. Methods: For this secondary analysis, we analysed data collected from Africa, Latin America, China, India, and Asia (excluding China and India) for the International Orthopaedic Multicentre Study in Fracture Care (INORMUS) between March 29, 2014, and June 15, 2022. Patients from INORMUS were included in this analysis if they were aged 50 years or older and had an isolated, primary hip fracture sustained from a ground-level fall. Staff at participating hospitals identified patients with musculoskeletal injury and referred them for assessment of eligibility. We report time from injury to surgery as three distinct time periods: time from injury to hospital admission, time from admission to surgery, and a total time from injury to surgery. Date and time of injury were self-reported by patients at the time of study recruitment. If time to hospital admission after injury exceeded 24 h, patients reported the primary reason for delayed admission. Reasons for surgery, no surgery, and surgical delay were reported by the treating team. For patients undergoing surgery, multivariable regression analyses were used to identify risk factors for surgical delay. Findings: 4486 adults aged 50 years or older with an isolated, primary hip fracture were enrolled in INORMUS from 55 hospitals in 24 countries. Countries were grouped into five regions: Africa (418 [9·3%] of 4486), Latin America (558 [12·4%]), China (1680 [37·4%]), India (1059 [23·6%]) and Asia (excluding China and India; 771 [17·2%]). Of 4486 patients, 3805 (84·8%) received surgery. The rate of surgery was similar in all regions except in Africa, where only 193 (46·3%) of 418 patients had surgery. Overall, 2791 (62·2%) of 4486 patients were admitted to hospital within 24 h of injury. However, 1019 (22·7%) of 4486 patients had delayed hospital admission of 72 h or more from injury. The two most common reasons for delayed admission of more than 24 h were transfer from another hospital (522 [36·2%] of 1441) and delayed care-seeking because patients thought the injury would heal on its own (480 [33·3%]). Once admitted to hospital, 1451 (38·1%) of 3805 patients who received surgery did so within 72 h (median 4·0 days [IQR 1·7–6·0]). Regional variation was seen in the proportion of patients receiving surgery within 72 h of hospital admission (92 [17·9%] of 514 in Latin America, 53 [27·5%] of 193 in Africa, 454 [30·9%] of 1471 in China, 318 [44·4%] of 716 in Asia [excluding China and India], and 534 [58·6%] of 911 in India). Of all 3805 patients who received operative treatment, 2353 (61·8%) waited 72 h or more from hospital admission. From time of injury, the proportion of patients who were surgically stabilised within 72 h was 889 (23·4%) of 3805 (50 [9·7%] of 517 in Latin America, 31 [16·1%] of 193 in Africa, 277 [18·8%] of 1471 in China, 189 [26·4%] of 716 in Asia [excluding China and India], and 342 [37·5%] of 911 in India). Interpretation: Access to surgery within 72 h of hospital admission was poor, with factors that affected time to surgery varying by region. Data are necessary to understand existing pathways of hip-fracture care to inform the local development of quality-improvement initiatives. Funding: The National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, McMaster Surgical Associates, Hamilton Health Sciences, and the US National Institutes of Health.

This study monitored the process and investigated the quality of compost obtained from different biomasses. Five blends of agri-food waste were composted by a laboratory pilot plant named COMPOSTER, that is designed to optimize biodegradation, and produce compost efficiently. The COMPOSTER consists of two 35-liter nearly adiabatic, aerated bioreactors that simulate an industrial process involving the typical sequence of mesophilic-thermophilic-mesophilic phases. It continuously monitors and records temperature, internal pressure, and biomass weight, while controlling and quantifying oxygen consumption and carbon dioxide emissions resulting from aerobic biodegradation. All composts were characterized for their main chemical, physical, and molecular features, as well as their suppressiveness against Fusarium oxysporum f.sp. lycopersici (FOL), tested on tomato seedlings. Optimized biodegradation yielded 50–60 % mature compost with a cumulative oxygen consumption ranging from 282 to 456 gO2 per kg of dry matter, with peaks of 2.55 gO2 per kg of volatile solids per hour, and carbon dioxide emissions of 22–36 % of the initial carbon content, with peaks of 5.89 g CO2 per kg of volatile solids per hour. Blends containing more ligno-cellulosic ingredients showed higher yields and lower CO2 emissions. Most of the nitrogen present initially was retained in the final compost; indeed, all mixtures exhibited an apparent nitrogen concentration increase due to carbon loss. Composting determined deep modifications in the molecular structure of the organic matter. 13C CPMAS-NMR and off-line thermochemolysis GC-MS analyses highlighted decomposition degree of polysaccharides and peptidic moieties, selective preservation of aliphatic and aromatic recalcitrant compounds, and optimal ongoing humification. All composts were non-phytotoxic, except for that including pepper crop residues, and all resulted rich in macro- and micro-elements for plant nutrition and proved to be active in controlling FOL disease. Compost comprising 81.2 % tomato crop waste exhibited the best growth performance and pathogen control on tomato. Mature, non-phytotoxic, nutrient-rich, and suppressive composts represent promising by-products that can be successfully recycled in agriculture, including high-value applications, leading to lower use of fertilizers and pesticides.

Antimicrobial Resistance (AMR) is a global health emergency that threatens modern medicine and incurs great cost to human health. The World Health Organization as part of a quadripartite joint initiative with the Food and Agriculture Organization of the United Nations, World Organisation for Animal Health, and United Nations Environment Programme, has recently published a One Health Priority Research Agenda for AMR. In this article we present a multidisciplinary approach, proposed by behavioural science experts, One Health experts and AMR experts to support the implementation of the Priority Research Agenda. We review, using specific examples of complex interventions designed to tackle AMR in which behavioural science has been embedded, five main steps: Define – what behaviours are a priority in each context; Diagnose - What are the barriers and enablers to the behaviours prioritised? Design - what interventions exist and what new or enhanced interventions could work to tackle the barriers identified? and, Implement and Evaluate the intervention(s). The approach presented will be useful for funders and researchers who wish to incorporate methods, frameworks and insights from the behavioural sciences into research plans, proposals and protocols in relation to a multisectoral One Health agenda and produce findings that are more relevant to policymakers.

Boron neutron capture therapy exploits 10B(n,α)7Li reactions for targeted tumor destruction. In this work, we aimed at developing a dose monitoring system based on the detection of 478keV gamma rays emitted by the reactions, which is very challenging due to the severe background present. We investigated a compact gamma-ray detector with a pinhole collimator and shielding housing. Experimental nuclear reactor measurements involved varying boron concentrations and artificial shifts of the sources. The system successfully resolved the 478keV photopeak and detected 1cm lateral displacements, confirming its suitability for precise boron dose monitoring.

Background: The COVID-19 pandemic and its impact on hospitals' activity and organization has imposed a vast change in standard neurosurgical oncology practice to accommodate for shifting resources. Aims: This investigation aims to analyse the nationwide capability in reorganizing the surgical neuro-oncological activity during the COVID-19 pandemic to evaluate whether COVID-19-pandemic influenced the surgical management in these patients. Method: A web-based dataset model organized by the Italian Neurosurgical Society (SINCh) was sent to all the Italian neurosurgical departments in May 2021, requesting to report the types and numbers of surgical procedures performed in the pre-pandemic period (from March 9th 2019 to March 9th 2020) compared to the pandemic period (from March 10th 2020 to March 10th 2021). Results: This multicentre investigation included the surgical activity of 35 Italian Neurosurgical Departments in a pre-pandemic year versus a pandemic year. During the COVID period, 699 fewer neuro-oncological patients were operated on than in the pre-COVID period. We noted a slight increase in urgency and a more severe decrease in elective and benign pathology. None of these differences was statistically significant. Surgically treated patients who tested positive for SARS-CoV-2 were 36, of which 11 died. Death was found to be COVID-related only in 2 cases. Conclusion: The reorganization of the Italian Neurosurgical Departments was able to guarantee a redistribution of the CNS tumors during the inter-pandemic periods, demonstrating that patients even in the pandemic era could be treated without compromising the efficacy and safety of the surgical procedure.

Wetlands are of great importance for biodiversity as they support a rich variety of plant and animal species, and the presence of endemic and migratory species is frequent. It is therefore necessary to protect and monitor such areas. The work conducted, reported in the present paper, aimed to verify the quality of soil in most wetlands in eastern Sicily. Specifically, four areas were studied: three Oriented Nature Reserves (RNO), the Saline di Priolo, with the adjacent Penisola di Magnisi, the Saline di Siracusa, and the Faunistic Oasis of Vendicari11 The Oasis takes the overall name of Vendicari, in reality it is made up of various localities that take on different names: Vendicari, Marianelli, Cittadella, Calamosche., and one Special Protection Area (SPA), the Biviere di Lentini. The study areas were sampled in 12 different sites, in spring and in autumn, to monitor soil fauna and assess the soil biological quality through the calculation of the QBS-ar. The results represent the first data relating to the QBS-ar in Sicily and, in particular, relating to wetlands.The QBS-ar values recorded were all higher, for both seasons, than the averages reported for land use by Menta et al., 2018. The statistical analysis regarding annual QBS-ar divides the sites into two groups: Saline di Priolo1, Marianelli1, Cittadella1, Vendicari1, Biviere di Lentini2 with a QBS-ar > 200 and Biviere di Lentini1, Saline di Priolo2, Penisola di Magnisi1, Penisola di Magnisi2, Saline di Siracusa1 and Saline di Siracusa2 with QBS-ar

Summary: Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to tumor subclonal properties is debated. In this study, we describe the systematic derivation, propagation, and characterization of multiple distinct GSCs from single, treatment-naive GBMs (GSC families). The tumorigenic potential of each GSC better correlates with its transcriptional profile than its genetic make-up, with classical GSCs being inherently more aggressive and mesenchymal more dependent on exogenous growth factors across multiple GBMs. These GSCs can segregate and recapitulate different histopathological aspects of the same GBM, as shown in a paradigmatic tumor with two histopathologically distinct components, including a conventional GBM and a more aggressive primitive neuronal component. This study provides a resource for investigating how GSCs with distinct genetic and/or phenotypic features contribute to individual GBM heterogeneity and malignant escalation.

Objectives: Aedes-borne viruses (ABV) affect humans on every inhabited continent and frequently cause epidemics. Recent epidemics of chikungunya and Zika viruses (ZIKV) highlight that preparedness for future epidemics requires assessment of susceptibility, particularly among high-risk groups. We sought to determine immunity against the three major circulating ABV among pregnant women in an ABV-endemic area of Colombia. Methods: A cross-sectional seroprevalence study was performed, enrolling women presenting to Labor and Delivery. Cord blood and maternal peripheral blood samples were obtained. IgG seroprevalence to flaviviruses and chikungunya was determined by ELISA. An abbreviated neutralization test was used to estimate the frequency and magnitude of immunity to Zika and four dengue serotypes. Cluster analyses explored epidemiologic factors associated with seroprevalence. Results: Most women exhibited high levels of neutralizing antibodies to one or more ABV; however, nearly 20% were seronegative for flaviviruses. Our research took place after the epidemic peak of the ZIKV outbreak in Colombia in 2016. However, only 20% of pregnant women had high levels of Zika-neutralizing antibodies consistent with likely protective immunity to ZIKV. Conclusion: Hence, a high proportion of pregnant women in Risaralda remain susceptible to one or more ABV including the teratogenic ZIKV, indicating a risk for future epidemics in this region.

Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model’s original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell’s adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model’s original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p

In light of the importance of helium production in influencing the behaviour of fast reactor fuels, in this work we present a burn-up module with the objective to calculate the production of helium in both in-pile and out-of-pile conditions tracking the evolution of 23 alpha-decaying actinides. This burn-up module relies on average microscopic cross-section look-up tables generated via SERPENT high-fidelity calculations and involves the solution of the system of Bateman equations for the selected set of actinide nuclides. The results of the burn-up module are verified in terms of evolution of actinide and helium concentrations by comparing them with the high-fidelity ones from SERPENT, considering two representative test cases of (U,Pu)O2 fuel in fast reactor conditions. In addition, a code-to-code comparison is made with the independent state-of-the-art module TUBRNP (implemented in the TRANSURANUS fuel performance code) for the same test cases. The herein presented burn-up module is available in the SCIANTIX code, designed for coupling with fuel performance codes.

Nearshore water quality can be highly impacted by anthropogenic activities ongoing along the coast, the effects of which on natural environments can be permanent and irreversible, with consequences for ecosystem biodiversity and functioning, as well as for associated services. Benthic filter feeders (e.g., mussels) provide several services for coastal regions, including improving water quality by reducing eutrophication, being a major source of food for humans, and as a habitat-forming species. Here, we seek to understand the role of benthic filter feeders in enhancing water quality in an urban coastal system in order to assess their role as ecosystem service providers and how they should be included in ecosystem-based evaluations. Using as a model False Bay, South Africa’s largest natural bay and a socio-economic hotspot, this multidisciplinary study was designed to identify possible pollution sources to a highly-urbanised coastal region, assess their effects on several biological and biogeochemical parameters, and evaluate the role of mussels in mitigating these anthropogenic inputs. We consider several sources of pollution, including nutrient loading from wastewater and river outflows, heavy metals, and aerosol deposition. We find that pollutant inputs are largely attenuated by the circulation of the bay and by the presence of filter feeders that bioaccumulate contaminants, thereby removing them from coastal waters. Our work thus emphasizes the potential for mussels and natural abiotic processes to ameliorate anthropogenic impacts, although these mitigation strategies are not without environmental risk. We recommend that such information should be included in national assessments used to develop appropriate strategies and policies for coastal environmental management and conservation.

Background & Aims: Patients with hepatocellular carcinoma (HCC) are selected for liver transplantation (LT) based on pre-LT imaging ± alpha-foetoprotein (AFP) level, but discrepancies between pre-LT tumour assessment and explant are frequent. Our aim was to design an explant-based recurrence risk reassessment score to refine prediction of recurrence after LT and provide a framework to guide post-LT management. Methods: Adult patients who underwent transplantation between 2000 and 2018 for HCC in 47 centres were included. A prediction model for recurrence was developed using competing-risk regression analysis in a European training cohort (TC; n = 1,359) and tested in a Latin American validation cohort (VC; n=1,085). Results: In the TC, 76.4% of patients with HCC met the Milan criteria, and 89.9% had an AFP score of ≤2 points. The recurrence risk reassessment (R3)-AFP model was designed based on variables independently associated with recurrence in the TC (with associated weights): ≥4 nodules (sub-distribution of hazard ratio [SHR] = 1.88, 1 point), size of largest nodule (3–6 cm: SHR = 1.83, 1 point; >6 cm: SHR = 5.82, 5 points), presence of microvascular invasion (MVI; SHR = 2.69, 2 points), nuclear grade >II (SHR = 1.20, 1 point), and last pre-LT AFP value (101–1,000 ng/ml: SHR = 1.57, 1 point; >1,000 ng/ml: SHR = 2.83, 2 points). Wolber’s c-index was 0.76 (95% CI 0.72–0.80), significantly superior to an R3 model without AFP (0.75; 95% CI 0.72–0.79; p = 0.01). Four 5-year recurrence risk categories were identified: very low (score = 0; 5.5%), low (1–2 points; 15.1%), high (3–6 points; 39.1%), and very high (>6 points; 73.9%). The R3-AFP score performed well in the VC (Wolber’s c-index of 0.78; 95% CI 0.73–0.83). Conclusions: The R3 score including the last pre-LT AFP value (R3-AFP score) provides a user-friendly, standardised framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials for HCC not limited to the Milan criteria. Clinical Trials Registration: NCT03775863. Lay summary: Considering discrepancies between pre-LT tumour assessment and explant are frequent, reassessing the risk of recurrence after LT is critical to further refine the management of patients with HCC. In a large and international cohort of patients who underwent transplantation for HCC, we designed and validated the R3-AFP model based on variables independently associated with recurrence post-LT (number of nodules, size of largest nodule, presence of MVI, nuclear grade, and last pre-LT AFP value). The R3-AFP model including last available pre-LT AFP value outperformed the original R3 model only based on explant features. The final R3-AFP scoring system provides a robust framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials, irrespective of criteria used to select patients with HCC for LT.

Insulinomas are considered rare indolent neuroendocrine neoplasms in human medicine, however when metastases occur no curative treatment is available thus, novel therapies are needed. Recently advances have been made in unraveling the pathophysiology of malignant insulinoma still major challenges hinder the development of a functional model to study them. Canine malignant insulinoma have similar recurrence and a poor prognosis as human malignant insulinoma. Additionally, both human and canine patients share extensively the same environment, tend to develop insulinoma seemingly spontaneously with an etiological role for hormones, at a similar incidence and stage of lifespan, with metastasis commonly to liver and regional lymph nodes, which are unresponsive to current therapies. However, the occurrence of metastases in dogs is as high as 95% compared with only 5–16% in human studies. From a comparative oncology perspective, the shared features with human insulinoma but higher incidence of metastasis in canine insulinoma suggests the latter as a model for human malignant insulinomas. With the common purpose of increasing survival rates of human and veterinary patients, in this review we are going to compare and analyze clinical, pathological and molecular aspects of canine and human insulinomas to evaluate the suitability of the canine model for future translational clinical studies.

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, −8 and −13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC50 of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.

Prior exposure to variable environmental conditions is predicted to influence the resilience of marine organisms to global change. We conducted complementary 4-month field and laboratory experiments to understand how a dynamic, and sometimes extreme, environment influences growth rates of a tropical reef-building crustose coralline alga and its responses to ocean acidification (OA). Using a reciprocal transplant design, we quantified calcification rates of the Caribbean coralline Lithophyllum sp. at sites with a history of either extreme or moderate oxygen, temperature, and pH regimes. Calcification rates of in situ corallines at the extreme site were 90% lower than those at the moderate site, regardless of origin. Negative effects of corallines originating from the extreme site persisted even after transplanting to more optimal conditions for 20 weeks. In the laboratory, we tested the separate and combined effects of stress and variability by exposing corallines from the same sites to either ambient (Amb: pH 8.04) or acidified (OA: pH 7.70) stable conditions or variable (Var: pH 7.80-8.10) or acidified variable (OA-Var: pH 7.45–7.75) conditions. There was a negative effect of all pH treatments on Lithophyllum sp. calcification rates relative to the control, with lower calcification rates in corallines from the extreme site than from the moderate site in each treatment, indicative of a legacy effect of site origin on subsequent response to laboratory treatment. Our study provides ecologically relevant context to understanding the nuanced effects of OA on crustose coralline algae, and illustrates how local environmental regimes may influence the effects of global change.

Background & Aims: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and ‘all-comers’. Methods: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000–2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. Results: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8–55.8) and 38.2% (CI 25.4–52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p

Summary: Changes in mitochondrial size, shape, and subcellular position, a process collectively known as mitochondrial dynamics, are exploited for various cancer traits. Modulation of subcellular mitochondrial trafficking and accumulation at the cortical cytoskeleton has been linked to the machinery of cell movements, fueling cell invasion and metastatic spreading. Here, we detail a technique to track changes in mitochondrial volume using a commercial CellLight™ Mitochondria-RFP/GFP reporter and live confocal microscopy. This allows a real-time study of mitochondrial dynamics in live cells.For complete details on the use and execution of this protocol, please refer to Bertolini et al. (2020).

Background: Mitochondrial functions are exploited in cancer and provide a validated therapeutic target. However, how this process is regulated has remained mostly elusive and the identification of new pathways that control mitochondrial integrity in cancer is an urgent priority. Methods: We studied clinically-annotated patient series of primary and metastatic prostate cancer, representative cases of multiple myeloma (MM) and publicly available genetic databases. Gene regulation studies involved chromatin immunoprecipitation, PCR amplification and Western blotting of conditional Myc-expressing cell lines. Transient or stable gene silencing was used to quantify mitochondrial functions in bioenergetics, outer membrane permeability, Ca2+ homeostasis, redox balance and cell death. Tumorigenicity was assessed by cell proliferation, colony formation and xenograft tumour growth. Findings: We identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancer, compared to normal tissues. Biochemically, MFF isoforms, MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel-1 (VDAC1) at the mitochondrial outer membrane, in vivo. Disruption of this complex by MFF silencing induces general collapse of mitochondrial functions with increased outer membrane permeability, loss of inner membrane potential, Ca2+ unbalance, bioenergetics defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice. Interpretation: An MFF-VDAC1 complex is a novel regulator of mitochondrial integrity and actionable therapeutic target in cancer. Keywords: Mitochondria, MFF, Cell death, Tumour metabolism, VDAC1, Cancer therapy

This paper focused on the evaluation of Ultrasound effect on the growth patterns (3–6% of salt and 45 °C), acidification (pH-decrease), interactions with microorganisms, and membrane permeability of nine strains of Lactiplantibacillus plantarum. Ultrasound treatment was applied at 20% of net power by modulating duration (2–10 min) and pulses (2–10 s).Viable count (7.15–8.16 log CFU/mL) was never affected by Ultrasound, while the treatment increased the extent of pH decrease of at least three strains (109, 162 and c19). L. plantarum c19 was the best performer, as a low intensity treatment was able to increase its acidification, without affecting its growth. The effects could be attributed to an increased permeability of the cellular membrane, as suggested by the increase of released intracellular components. Other factors should be further assessed (e.g. possible changes in the metabolism) and the performances of Ultrasound-treated strains in real brines.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative condition with phenotypic and genetic heterogeneity. It is characterized by the selective vulnerability and the progressive loss of the neural population. Here, an induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of an individual carrying the p.G376D mutation in the TDP-43 protein. Fibroblasts were reprogrammed using non-integrating episomal plasmids. There were no karyotype abnormalities, and iPSCs successfully differentiated into all three germ layers. This cell line may prove useful in the study of the pathogenic mechanisms that underpin ALS syndrome.

Among the known causative genes of familial ALS, SOD1 mutation is one of the most common. It encodes for the ubiquitous detoxifying copper/zinc binding SOD1 enzyme, whose mutations selectively cause motor neuron death, although the mechanisms are not as yet clear. What is known is that mutant-mediated toxicity is not caused by loss of its detoxifying activity but by a gain-of-function. In order to better understand the pathogenic mechanisms of SOD1 mutation, a human induced pluripotent stem cell (hiPSC) line was generated from the somatic cells of a female patient carrying a missense variation in SOD1 (L145F).

Summary: Background: The Lancet Commission on Global Surgery established the Three Delays framework, categorising delays in accessing timely surgical care into delays in seeking care (First Delay), reaching care (Second Delay), and receiving care (Third Delay). Globally, knowledge gaps regarding delays for fracture care, and the lack of large prospective studies informed the rationale for our international observational study. We investigated delays in hospital admission as a surrogate for accessing timely fracture care and explored factors associated with delayed hospital admission. Methods: In this prospective observational substudy of the ongoing International Orthopaedic Multicenter Study in Fracture Care (INORMUS), we enrolled patients with fracture across 49 hospitals in 18 low-income and middle-income countries, categorised into the regions of China, Africa, India, south and east Asia, and Latin America. Eligible patients were aged 18 years or older and had been admitted to a hospital within 3 months of sustaining an orthopaedic trauma. We collected demographic injury data and time to hospital admission. Our primary outcome was the number of patients with open and closed fractures who were delayed in their admission to a treating hospital. Delays for patients with open fractures were defined as being more than 2 h from the time of injury (in accordance with the Lancet Commission on Global Surgery) and for those with closed fractures as being a delay of more than 24 h. Secondary outcomes were reasons for delay for all patients with either open or closed fractures who were delayed for more than 24 h. We did logistic regression analyses to identify risk factors of delays of more than 2 h in patients with open fractures and delays of more than 24 h in patients with closed fractures. Logistic regressions were adjusted for region, age, employment, urban living, health insurance, interfacility referral, method of transportation, number of fractures, mechanism of injury, and fracture location. We further calculated adjusted relative risk (RR) from adjusted odds ratios, adjusted for the same variables. This study was registered with ClinicalTrials.gov, NCT02150980, and is ongoing. Findings: Between April 3, 2014, and May 10, 2019, we enrolled 31 255 patients with fractures, with a median age of 45 years (IQR 31–62), of whom 19 937 (63·8%) were men, and 14 524 (46·5%) had lower limb fractures, making them the most common fractures. Of 5256 patients with open fractures, 3778 (71·9%) were not admitted to hospital within 2 h. Of 25 999 patients with closed fractures, 7141 (27·5%) were delayed by more than 24 h. Of all regions, Latin America had the greatest proportions of patients with delays (173 [88·7%] of 195 patients with open fractures; 426 [44·7%] of 952 with closed fractures). Among patients delayed by more than 24 h, the most common reason for delays were interfacility referrals (3755 [47·7%] of 7875) and Third Delays (cumulatively interfacility referral and delay in emergency department: 3974 [50·5%]), while Second Delays (delays in reaching care) were the least common (423 [5·4%]). Compared with other methods of transportation (eg, walking, rickshaw), ambulances led to delay in transporting patients with open fractures to a treating hospital (adjusted RR 0·66, 99% CI 0·46–0·93). Compared with patients with closed lower limb fractures, patients with closed spine (adjusted RR 2·47, 99% CI 2·17–2·81) and pelvic (1·35, 1·10–1·66) fractures were most likely to have delays of more than 24 h before admission to hospital. Interpretation: In low-income and middle-income countries, timely hospital admission remains largely inaccessible, especially among patients with open fractures. Reducing hospital-based delays in receiving care, and, in particular, improving interfacility referral systems are the most substantial tools for reducing delays in admissions to hospital. Funding: National Health and Medical Research Council of Australia, Canadian Institutes of Health Research, McMaster Surgical Associates, and Hamilton Health Sciences.

CHRNA7, encoding the neuronal alpha7 nicotinic acetylcholine receptor (a7nAChR), is highly expressed in the brain, particularly in the hippocampus. It is situated in the 15q13.3 chromosome region, frequently associated with a Copy Number Variation (CNV), which causes its duplication or deletion. The clinical significance of CHRNA7 duplications is unknown so far, but there are several research data suggesting that they may be pathogenic, with reduced penetrance. We have produced an iPS cell line from a single healthy donor's fibroblasts carrying a 15q13.3 CNV, including CHRNA7 in order to study the exact role of this CNV during the neurodevelopment.

The data presented here are related to the research paper entitled “Thrombin induces protease-activated receptor 1 signaling and activation of human atrial fibroblasts and dabigatran prevents these effects” (Altieri et al., 2018) [1]. Data show that silencing of protease-activated receptor 1 (PAR1) prevents the activation of Fib isolated from atrial appendages of patients without atrial fibrillation (AF), as assessed by immunofluorescence for α-smooth muscle actin (αSMA) and Picro-Sirius red staining. Moreover, it is reported that primary atrial Fib obtained from two subjects with permanent AF express PAR1 and PAR2 and display enhanced αSMA immunoreactivity and collagen synthesis in response to thrombin, but not to dabigatran-bound thrombin, alike Fib from non-fibrillating atria.

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay, behavioural problems and circadian rhythm dysregulation. About 90% of SMS cases are due to a 17p11.2 deletion containing retinoic acid induced1 (RAI1) gene, 10% are due to heterozygous mutations affecting RAI1 coding region. Little is known about RAI1 role.

Joubert Syndrome (JS) is a rare autosomal recessive or X-linked condition characterized by a peculiar cerebellar malformation, known as the molar tooth sign (MTS), associated with other neurological phenotypes and multiorgan involvement. JS is a ciliopathy, a spectrum of disorders whose causative genes encode proteins involved in the primary cilium apparatus. In order to elucidate ciliopathy-associated molecular mechanisms, human induced pluripotent stem cells (hiPSCs) were derived from a patient affected by JS carrying a homozygous missense mutation in the AHI1 gene (p.H896R) that encodes a protein named Jouberin.

Dentato-Rubral-pallidoluysian atrophy (DRPLA) is a rare autosomal, dominant, progressive neurodegenerative disease that causes involuntary movements, mental and emotional problems. DRPLA is caused by a mutation in the ATN1 gene that encodes for an abnormal polyglutamine stretch in the atrophin-1 protein. DRPLA is most common in the Japanese population, where it has an estimated incidence of 2 to 7 per million people. This condition has also been seen in families from North America and Europe. We obtained a reprogrammed iPSC line from a Caucasian patient with a juvenile onset of the disease, carrying 64 CAG repeat expansion in the ATN1 gene.

Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.

Reprogramming of metabolic pathways contributes to human disease, especially cancer, but the regulators of this process are unknown. Here, we have generated a mouse knockout for the mitochondrial chaperone TRAP-1, a regulator of bioenergetics in tumors. TRAP-1−/− mice are viable and showed reduced incidence of age-associated pathologies, including obesity, inflammatory tissue degeneration, dysplasia, and spontaneous tumor formation. This was accompanied by global upregulation of oxidative phosphorylation and glycolysis transcriptomes, causing deregulated mitochondrial respiration, oxidative stress, impaired cell proliferation, and a switch to glycolytic metabolism in vivo. These data identify TRAP-1 as a central regulator of mitochondrial bioenergetics, and this pathway could contribute to metabolic rewiring in tumors.

Increased cortisol levels in humans are often observed in patients suffering from mood disorders. In this study human fetal brain aggregates were exposed to cortisol at 500 nM for 3 weeks, as an in-vitro model of chronic cortisol exposure. Microarray analysis on extracted mRNA using the Affymetrix U133A platform was then performed. Our results demonstrated a significant effect of cortisol on 1648 transcripts; 736 up-regulated and 912 down-regulated genes. The most differentially regulated biological categories were: RNA processing, protein metabolism, and cell growth. Within these categories we observed a down-regulation of fibroblast growth factor 2 (FGF2) (−1.5-fold) and aquaporin4 (AQP4) (−1.7-fold), alongside an up-regulation of fibroblast growth factor 9 (FGF9) (+1.7-fold) and vesicle associated membrane protein2 (VAMP2) (+1.7-fold). FGF2, FGF9, AQP4 and VAMP2 changes were confirmed at the protein level by immunohistochemistry. Alterations in FGF transcripts are in keeping with recent literature demonstrating such effects in patients with mood disorders.

The term spondyloarthritis (SpA) encompasses a group of interrelated disorders characterised by the involvement of the musculoskeletal system as well as extra-articular manifestations like acute anterior uveitis, psoriasis and inflammatory bowel diseases (IBD). Likewise, IBD may present with various extra-intestinal manifestations among which those involving the musculoskeletal system, namely peripheral and axial SpA are the most common. The identification of patients with both SpA and IBD is of paramount importance in clinical practice since the coexistence of these two entities has been associated with great disability and decreased quality of life. In order to achieve an early diagnosis of IBD-SpA it is instrumental that rheumatologists seek for gastrointestinal symptoms in SpA patients and likewise that gastroenterologists seek for inflammatory musculoskeletal symptoms in patients with IBD. This narrative review aims at critically appraising the available evidence about SpA occurring in IBD patients versus IBD occurring in patients with SpA and at highlighting similarities and differences between the two scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: Excess body weight (EBW) is the most prevalent nutritional disorder among adolescents worldwide. Identifying determinants of EBW may help find new intervention strategies. Behavioral, socio-economic, educational and demographic correlates of EBW were examined in a population of Italian adolescents, separately for males and females., Methods and Results: As many as 1039 male and 2052 female students (aged 16-19 ys) attending the last three years of different types of high-school of the Emilia-Romagna region in Italy were offered participation, with 552 males and 841 females being finally evaluated. The prevalence of EBW was 21.0% in males and 14.1% in females. Step-wise multivariate logistic regression analyses were performed showing that EBW was negatively related to energy intake in males (odds ratio for 100 kcal/day (OR) = 0.94, 95% confidence interval (CI): 0.89 to 0.98; P = 0.008), and to father's educational attainment (OR = 0.70, 95% CI: 0.52 to 0.95; P = 0.020), but positively related to parental obesity (OR = 2.80, 95% CI: 1.65 to 4.76; P < 0.001). In females, EBW was positively related to parental obesity (OR = 1.94, 95% CI: 1.15 to 3.29; P = 0.013), but negatively to mother's educational attainment (OR = 0.66, 95% CI: 0.45 to 0.97; P = 0.034) and type of attended school (OR = 0.66, 95% CI: 0.49 to 0.89; P = 0.007). Mother's occupation was also an independent determinant of EBW status in females (OR = 0.39, 95% CI: 0.18 to 0.85; P = 0.018 for being unemployed vs blue-collar)., Conclusion: Parental obesity is associated with EBW in male and female adolescents. Importantly, we found sex differences in socio-economic and educational factors impacting on EBW, supporting possible distinct area of investigation., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Data with animal cells and models suggest that thrombin activates cardiac fibroblasts (Fib) to myofibroblasts (myoFib) via protease-activated receptor 1 (PAR1) cleavage, and in this way promotes adverse atrial remodeling and, thereby, atrial fibrillation (AF)., Objective: Here, we explored the effects of thrombin on human atrial Fib and whether they are antagonized by the clinically available direct thrombin inhibitor, dabigatran., Methods: Fib isolated from atrial appendages of patients without AF undergoing elective cardiac surgery were evaluated for PAR expression and treated with thrombin with or without dabigatran. PAR1 cleavage, downstream signaling and myoFib markers were investigated by immunofluorescence and Western blot. Collagen synthesis, activity of matrix metalloprotease (MMP)-2 and proliferation were assessed by Picro-Sirius red staining, gelatinolytic zymography and BrdU incorporation, respectively. Fib function was studied as capability to contract a collagen gel and stimulate the chemotaxis of peripheral blood monocytes from healthy volunteers., Results: Primary human atrial Fib expressed PAR1, while levels of the other PARs were very low. Thrombin triggered PAR1 cleavage and phosphorylation of ERK1/2, p38 and Akt, elicited a switch to myoFib enriched for αSMA, fibronectin and type I collagen, and induced paracrine/autocrine transforming growth factor beta-1, cyclooxygenase-2, endothelin-1 and chemokine (C-C motif) ligand 2 (CCL2); conversely, MMP-2 activity decreased. Thrombin-primed cells displayed enhanced proliferation, formed discrete collagen-containing cellular nodules, and stimulated the contraction of a collagen gel. Furthermore, their conditioned medium caused monocytes to migrate. All these effects were prevented by dabigatran., Conclusion: These results with human cells complete the knowledge about thrombin actions on cardiac Fib and strengthen the translational potential of the emerging paradigm that pharmacological blockade of thrombin may counteract molecular and cellular events underlying AF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cell attachment is provided by cell-matrix and cell-cell bonds, and acts as a regulator of vascular smooth muscle cell (VSMC) survival, activity and homeostasis, as well as of VSMCs response to pathogenic stimuli. In this work we elicited an exclusive cell-cell contact by culturing A7r5 VSMCs on agarose-coated wells to form floating cell clusters, and we demonstrated that a steady state with a reduced response to the vasoactive peptide Angiotensin II (ATII) was induced. We found that clustered VSMCs showed subcortical stabilization of beta-catenin and Caveolin 1 (Cav1), unlike adherent confluent counterparts. We demonstrated that beta-catenin and Cav1 stabilization at the membrane level hampers the molecular cross-talk induced by ATII-activated AT1 receptor (AT1R), thereby impeding the phosphorylation of Cav1 and IGF1R, the NADPH oxidase activity, and counteracting ATII-dependent hypertrophy. Thus, elective cell-cell bond might modulate the proatherogenic activity of ATII, reducing the adverse vascular remodelling associated with AT1R activation.