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Abstract E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.

Abstract Laser-driven dynamic compression experiments of plastic materials have found surprisingly fast formation of nanodiamonds (ND) via X-ray probing. This mechanism is relevant for planetary models, but could also open efficient synthesis routes for tailored NDs. We investigate the release mechanics of compressed NDs by molecular dynamics simulation of the isotropic expansion of finite size diamond from different P-T states. Analysing the structural integrity along different release paths via molecular dynamic simulations, we found substantial disintegration rates upon shock release, increasing with the on-Hugnoiot shock temperature. We also find that recrystallization can occur after the expansion and hence during the release, depending on subsequent cooling mechanisms. Our study suggests higher ND recovery rates from off-Hugoniot states, e.g., via double-shocks, due to faster cooling. Laser-driven shock compression experiments of polyethylene terephthalate (PET) samples with in situ X-ray probing at the simulated conditions found diamond signal that persists up to 11 ns after breakout. In the diffraction pattern, we observed peak shifts, which we attribute to thermal expansion of the NDs and thus a total release of pressure, which indicates the stability of the released NDs.

Abstract Data standardization promotes a common framework through which researchers can utilize others’ data and is one of the leading methods neuroimaging researchers use to share and replicate findings. As of today, standardizing datasets requires technical expertise such as coding and knowledge of file formats. We present ezBIDS, a tool for converting neuroimaging data and associated metadata to the Brain Imaging Data Structure (BIDS) standard. ezBIDS contains four major features: (1) No installation or programming requirements. (2) Handling of both imaging and task events data and metadata. (3) Semi-automated inference and guidance for adherence to BIDS. (4) Multiple data management options: download BIDS data to local system, or transfer to OpenNeuro.org or to brainlife.io. In sum, ezBIDS requires neither coding proficiency nor knowledge of BIDS, and is the first BIDS tool to offer guided standardization, support for task events conversion, and interoperability with OpenNeuro.org and brainlife.io.

IntroductionDelayed discharge represents the difficulty in proceeding with discharge of patients who do not have any further benefit from prolonged stay. A quota of this problem is related to organizational issues. In the Lazio region in Italy, a macro service re-organization in on the way, with a network of hospital and territorial centers engaged in structuring in- and out- of hospital patient pathways, with a special focus on intermediate care structures. Purpose of this study is to quantify the burden of delayed discharge on a single hospital structure, in order to estimate costs and occurrence of potential resource misplacement.Material and methodsObservational Retrospective study conducted at the Santo Spirito Hospital in Rome, Italy. Observation period ranged from 1/09/2022, when the local database was instituted, to 1/03/2023 (6 months). Data from admissions records was anonymously collected. Data linkage with administrative local hospital database was performed in order to identify the date a discharge request was fired for each admission. Surgical discharges and Intensive Care Unit (ICU) discharges were excluded from this study. A Poisson hierarchical regression model was employed to investigate for the role of ward, Severity of Disease (SoD) and Risk of Mortality (RoM) on elongation of discharge time.Results1222 medical ward admissions were recorded in the timeframe. 16% of them were considered as subject to potentially elongated stay, and a mean Delay in discharge of 6.3 days (SD 7.9) was observed.Discussion and conclusionsDelayed discharge may cause a "bottleneck" in admissions and result in overcrowded Emergency Department, overall poor performance, and increase in overall costs. A consisted proportion of available beds can get inappropriately occupied, and this inflates both direct and indirect costs. Clinical conditions on admission are not a good predictor of delay in discharge, and the root causes of this phenomenon likely lie in organizational issues (on structure\system level) and social issues (on patient's level).

Abstract Gut microbiota is an emerging editable cardiovascular risk factor. We aim to investigate gut and coronary plaque microbiota, using fecal samples and angioplasty balloons from patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS) and control subjects. We examined bacterial communities in gut and coronary plaques by 16S rRNA sequencing and we performed droplet digital PCR analysis to investigate the gut relative abundance of the bacterial genes CutC/CntA involved in trimethylamine N-oxide synthesis. Linear discriminant analysis effect size (LEfSe) at the genus and species levels displayed gut enrichment in Streptococcus, Granulicatella and P. distasonis in ACS compared with CCS and controls; Roseburia, C. aerofaciens and F. prausnitzii were more abundant in controls than in patients. Principal component analysis (PCA) of 41 differentially abundant gut taxa showed a clustering of the three groups. In coronary plaque, LEfSe at the genus level revealed an enrichment of Staphylococcus and Streptococcus in ACS, and Paracoccus in CCS, whereas PCA of 15 differentially abundant plaque taxa exhibited clustering of ACS and CCS patients. CutC and CntA genes were more abundant in ACS and CCS than in controls while no significant difference emerged between ACS and CCS. Our results indicate that ACS and CCS exhibit a different gut and plaque microbial signature, suggesting a possible role of these microbiotas in coronary plaque instability.

Abstract Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury.

Abstract Prehistoric monuments often constitute evident landmarks and sometimes, after falling into disuse, fascinated local people enough to stimulate speculations about their origin over time. According to legend, the Hill of Udine (NE Italy) was built by Attila the Hun’s soldiers, but its origin (natural or anthropogenic) has been debated until now. Our research analyzed five new 40-m long stratigraphic cores, investigating for the first time the total thickness of the hill and compared the data with the available archaeological information. Moreover, we considered other hills and mounds in northern Italy and other European regions where folklore traditions relate their origin to Attila. The geoarchaeological and ethnographic data prove that the Hill of Udine is a Bronze Age anthropogenic mound erected between 1400 and 1150 BCE and that, later, folklore has transformed the ancestral memory of its origin into legend. By measuring 30 m in height and over 400,000 m3 in volume, the flat-topped hill is the largest prehistoric mound in Europe. This discovery reveals unprecedented skills in earth construction and confirms significant anthropogenic modifications of the environment during Bronze Age.

Abstract Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D‐associated single nucleotide polymorphisms (SNPs) are located in non‐coding regions of the human genome. Interestingly, SNPs in long non‐coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus‐induced T1D‐associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the promoter and enhancer regions of IFNβ and interferon‐stimulated genes, promoting their transcriptional activation in an allele‐specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic β cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D‐related SNPs in lncRNAs influence pathogenesis at the pancreatic β cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic β cell inflammation in T1D.

IntroductionLow Molecular Weight Heparins (LMWHs) and Fondaparinux have been widely used as anticoagulants. Mass prescription may lead to prescriptive inappropriateness, which causes Heparin-induced thrombocytopenia and other side effects.ObjectivesThe study investigates the appropriate prescription of LMWHs and Fondaparinux in Tuscany. We aim to validate the crude measure of prescription appropriateness of the Key Performance Indicator (KPI) "Patients treated with LMWHs and Fondaparinux every hundred residents in Tuscany" as a proxy for monitoring prescription appropriateness.MethodsTo compare a crude KPI based only on drug consumption with a refined KPI based on exclusions listed in the clinical guidelines, a retrospective observational cohort study was carried out, using the RECORD guidelines for the year 2019. The refined indicator is computed via record linkage of different datasets regarding (a) pharmaceutical services; (b) hospital discharge records; (c) outpatient services; and (d) birth certificates. We apply exclusion criteria to identify the cohort of patients. Values of the KPI are compared, by ranking, with those obtained from its refined version. A Spearman test was performed to validate the use of the crude KPI as a proxy.Results208,717 LMWH and Fondaparinux users are identified, of which 103,299 fall within the study's inclusion criteria. 16,817 (16%) of LMWHs and Fondaparinux users are classified as high consumption. The refined version of the KPI produces the same ranking results in terms of local health districts (rho = 0.98 pConclusionsAlthough the crude KPI is less refined and detailed than the adjusted indicator computed by our study, it has proven capable to provide an accurate snapshot of the use of these drugs across the region. This analysis is useful to enable regional and local managers to run rapid and simple indicators to monitor the appropriateness of LMWHs and Fondaparinux. This analysis should be reviewed periodically to confirm its accuracy.

Abstract We present structure and equation of state (EOS) measurements of biaxially orientated polyethylene terephthalate (PET, $$({\hbox {C}}_{10} {\hbox {H}}_8 {\hbox {O}}_4)_n$$ ( C 10 H 8 O 4 ) n , also called mylar) shock-compressed to ( $$155 \pm 20$$ 155 ± 20 ) GPa and ( $$6000 \pm 1000$$ 6000 ± 1000 ) K using in situ X-ray diffraction, Doppler velocimetry, and optical pyrometry. Comparing to density functional theory molecular dynamics (DFT-MD) simulations, we find a highly correlated liquid at conditions differing from predictions by some equations of state tables, which underlines the influence of complex chemical interactions in this regime. EOS calculations from ab initio DFT-MD simulations and shock Hugoniot measurements of density, pressure and temperature confirm the discrepancy to these tables and present an experimentally benchmarked correction to the description of PET as an exemplary material to represent the mixture of light elements at planetary interior conditions.

Turbulence effects explored use macroscale systems in general. Here the authors generate a turbulent plasma using laser irradiation of a solid target and study the dynamics of the plasma flow at the micron-scale by using scattering of an XFEL beam.

Abstract Patients requiring diagnostic testing for coronavirus disease 2019 (COVID-19) are routinely assessed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) amplification of Sars-CoV-2 virus RNA extracted from oro/nasopharyngeal swabs. Despite the good specificity of the assays certified for SARS-CoV-2 molecular detection, and a theoretical sensitivity of few viral gene copies per reaction, a relatively high rate of false negatives continues to be reported. This is an important challenge in the management of patients on hospital admission and for correct monitoring of the infectivity after the acute phase. In the present report, we show that the use of digital PCR, a high sensitivity method to detect low amplicon numbers, allowed us to correctly detecting infection in swab material in a significant number of false negatives. We show that the implementation of digital PCR methods in the diagnostic assessment of COVID-19 could resolve, at least in part, this timely issue.

Mass outflow is a common process in astrophysical objects. Here the authors investigate in which conditions an astrophysically-scaled laser-produced plasma flow can be collimated and evolves in the presence of a misaligned external magnetic field.

Warm dense silica is a key component in rocky planets’ mantles, but reproducing the relevant conditions in experiments is challenging. Here the authors use a double-shock technique to achieve such conditions and measure the reflectivity in situ, providing insight into the conductivity and its possible impact on dynamo processes in super-Earths’ mantles.

Taking informed decisions, namely acting rationally, is an individual attitude of paramount relevance in nature and human societies. In this work, we study how rationality spreads in a community. To this end, through an agent-based model, we analyse the dynamics of a population whose individuals, endowed with a rational attitude controlled by a numerical parameter, play a simple game. The latter consists of multiple strategies, each associated with a given reward. The proposed model is then used as a benchmark for studying the behaviour of Bitcoin users, inferred by analysing transactions recorded in the Blockchain. Remarkably, a population undergoing a sharp transition from irrational to rational attitudes shows a behavioural pattern similar to that of Bitcoin users, whose rationality showed up as soon as their cryptocurrency became worth just a few cents (USD). To conclude, a behavioural analysis that relies on an entropy measure combined with a simple agent-based model allows us to detect the rise of rationality across a community. Although further investigations are essential to corroborate our results, we deem the proposed approach could also get used for studying other social phenomena and behaviours.

The behaviour of Bitcoin owners is reflected in the structure and the number of bitcoin transactions encoded in the Blockchain. Likewise, the behaviour of Bitcoin traders is reflected in the formation of bullish and bearish trends in the crypto market. In light of these observations, we wonder if human behaviour underlies some relationship between the Blockchain and the crypto market. To address this question, we map the Blockchain to a spin-lattice problem, whose configurations form ordered and disordered patterns, representing the behaviour of Bitcoin owners. This novel approach allows us to obtain time series suitable to detect a causal relationship between the dynamics of the Blockchain and market trends of the Bitcoin and to find that disordered patterns in the Blockchain precede Bitcoin panic selling. Our results suggest that human behaviour underlying Blockchain evolution and the crypto market brings out a fascinating connection between disorder and panic in Bitcoin dynamics.

Knowledge of tree size is of great importance for the precision management of a hazelnut orchard. In fact, it has been shown that site-specific crop management allows for the best possible management and efficiency of the use of inputs. Generally, measurements of tree parameters are carried out using manual techniques that are time-consuming, labor-intensive and not very precise. The aim of this study was to propose, evaluate and validate a simple and innovative procedure using images acquired by an unmanned aerial vehicle (UAV) for canopy characterization in an intensive hazelnut orchard. The parameters considered were the radius (Rc), the height of the canopy (hc), the height of the tree (htree) and of the trunk (htrunk). Two different methods were used for the assessment of the canopy volume using the UAV images. The performance of the method was evaluated by comparing manual and UAV data using the Pearson correlation coefficient and root mean square error (RMSE). High correlation values were obtained for Rc, hc and htree while a very low correlation was obtained for htrunk. The method proposed for the volume calculation was promising.

Diffusion weighted imaging (DWI) with multiple, high b-values is critical for extracting tissue microstructure measurements; however, high b-value DWI images contain high noise levels that can overwhelm the signal of interest and bias microstructural measurements. Here, we propose a simple denoising method that can be applied to any dataset, provided a low-noise, single-subject dataset is acquired using the same DWI sequence. The denoising method uses a one-dimensional convolutional neural network (1D-CNN) and deep learning to learn from a low-noise dataset, voxel-by-voxel. The trained model can then be applied to high-noise datasets from other subjects. We validated the 1D-CNN denoising method by first demonstrating that 1D-CNN denoising resulted in DWI images that were more similar to the noise-free ground truth than comparable denoising methods, e.g., MP-PCA, using simulated DWI data. Using the same DWI acquisition but reconstructed with two common reconstruction methods, i.e. SENSE1 and sum-of-square, to generate a pair of low-noise and high-noise datasets, we then demonstrated that 1D-CNN denoising of high-noise DWI data collected from human subjects showed promising results in three domains: DWI images, diffusion metrics, and tractography. In particular, the denoised images were very similar to a low-noise reference image of that subject, more than the similarity between repeated low-noise images (i.e. computational reproducibility). Finally, we demonstrated the use of the 1D-CNN method in two practical examples to reduce noise from parallel imaging and simultaneous multi-slice acquisition. We conclude that the 1D-CNN denoising method is a simple, effective denoising method for DWI images that overcomes some of the limitations of current state-of-the-art denoising methods, such as the need for a large number of training subjects and the need to account for the rectified noise floor.

Diffusion weighted imaging (DWI) with multiple, high b-values is critical for extracting tissue microstructure measurements; however, high b-value DWI images contain high noise levels that can overwhelm the signal of interest and bias microstructural measurements. Here, we propose a simple denoising method that can be applied to any dataset, provided a low-noise, single-subject dataset is acquired using the same DWI sequence. The denoising method uses a one-dimensional convolutional neural network (1D-CNN) and deep learning to learn from a low-noise dataset, voxel-by-voxel. The trained model can then be applied to high-noise datasets from other subjects. We validated the 1D-CNN denoising method by first demonstrating that 1D-CNN denoising resulted in DWI images that were more similar to the noise-free ground truth than comparable denoising methods, e.g., MP-PCA, using simulated DWI data. Using the same DWI acquisition but reconstructed with two common reconstruction methods, i.e. SENSE1 and sum-of-square, to generate a pair of low-noise and high-noise datasets, we then demonstrated that 1D-CNN denoising of high-noise DWI data collected from human subjects showed promising results in three domains: DWI images, diffusion metrics, and tractography. In particular, the denoised images were very similar to a low-noise reference image of that subject, more than the similarity between repeated low-noise images (i.e. computational reproducibility). Finally, we demonstrated the use of the 1D-CNN method in two practical examples to reduce noise from parallel imaging and simultaneous multi-slice acquisition. We conclude that the 1D-CNN denoising method is a simple, effective denoising method for DWI images that overcomes some of the limitations of current state-of-the-art denoising methods, such as the need for a large number of training subjects and the need to account for the rectified noise floor.

BackgroundCerebral arteriovenous malformations (AVMs) are challenging lesions, often requiring multimodal interventions; however, data on the efficacy of stereotactic radiosurgery for cerebral AVMs are limited. This study aimed to evaluate the clinical and radiographic results following robotic radiosurgery, alone or in combination with endovascular treatment, and to investigate factors associated with obliteration and complications in patients with AVM.MethodsWe retrospectively analyzed the clinical and imaging characteristics of 123 patients with AVMs of all Spetzler-Martin grades treated at two institutions by robotic radiosurgery in single-fraction doses (CyberKnife). Embolization was performed before radiosurgery in a subset of patients to attempt to downgrade the lesions. Factors associated with AVM obliteration and complications (toxicity) were identified via univariate and multivariate analyses.ResultsThe median follow-up time was 48.1 months (range, 3.6-123 months). Five patients were lost to follow-up. The obliteration rate in the 59 patients with a follow-up period exceeding four years was 72.8%. Complete obliteration and partial remission were achieved in 67 (56.8%) and 31 (26.3%) cases, respectively, whereas no change was observed in 20 cases (17.8%). Embolization was performed in 54/123 cases (43.9%). Complete and partial obliteration were achieved in 29 (55.7%) and 14 (26.9%) embolized patients, respectively. In the multivariate analysis, the factors associated with obliteration were age (p = .018) and the Spetzler-Martin grade (p = .041). Treatment-induced toxicity (radiation necrosis and/or edema) was observed in 15 cases (12.7%), rebleeding occurred in three cases (2.5%), and the rate of mortality associated with rebleeding was 1.7%.ConclusionsCyberKnife radiosurgery is a valid approach for treating AVMs of all Spetzler-Martin-grades, with satisfactory obliteration rates, low toxicity, and a relatively rare incidence of rebleeding.

ObjectivesCaregivers of allogeneic hematopoietic stem cell transplant (HCT) cancer patients experience high caregiver burden and carry a significant amount of responsibility. Mindfulness has the potential to lessen caregiver burden by aiding in stress management. To date, no studies have examined the efficacy of mindfulness in reducing caregiver burden in this population. Based on our pilot study demonstrating initial feasibility and acceptability of FOCUS (Focusing On mindfulness for Caregivers Under Stress), this 3-arm randomized controlled trial aims to examine the efficacy of a 6-week mindfulness-based stress management program for allogeneic HCT caregivers. Hypotheses include that the FOCUS condition will have lower post-treatment caregiver burden and that patients of these caregivers will have better patient health outcomes compared to other treatment conditions.MethodEligible caregivers will be randomly assigned to one of three treatment conditions: FOCUS, Healthy Living (HL; active control), and Enhanced Care (EC; usual care). Caregivers in FOCUS and HL will participate in 6-week weekly individual treatment sessions and will be sent brief daily momentary interventions/messages. Caregivers in all conditions will complete daily diaries over the course of treatment. Patients of enrolled caregivers will be enrolled for assessments only. Participants will complete assessments at baseline, end of treatment, 2- and 6-months post-treatment. Biomarker data will be collected via hair cortisol concentrations from caregivers at baseline and 6 months post-treatment.ResultsRecruitment is ongoing.ConclusionsThe data collected from this study will provide evidence on the efficacy of mindfulness in alleviating HCT caregiver stress and impacting patient health outcomes.Trial registrationThe current study is registered in clinicaltrials.gov (NCT05078229); see https://clinicaltrials.gov/ct2/show/NCT05078229?term=christine+vinci&draw=2&rank=1.

[This corrects the article DOI: 10.1371/journal.pone.0266316.].

Abstract Water, methane, and ammonia are commonly considered to be the key components of the interiors of Uranus and Neptune. Modelling the planets’ internal structure, evolution, and dynamo heavily relies on the properties of the complex mixtures with uncertain exact composition in their deep interiors. Therefore, characterising icy mixtures with varying composition at planetary conditions of several hundred gigapascal and a few thousand Kelvin is crucial to improve our understanding of the ice giants. In this work, pure water, a water-ethanol mixture, and a water-ethanol-ammonia “synthetic planetary mixture” (SPM) have been compressed through laser-driven decaying shocks along their principal Hugoniot curves up to 270, 280, and 260 GPa, respectively. Measured temperatures spanned from 4000 to 25000 K, just above the coldest predicted adiabatic Uranus and Neptune profiles (3000–4000 K) but more similar to those predicted by more recent models including a thermal boundary layer (7000–14000 K). The experiments were performed at the GEKKO XII and LULI2000 laser facilities using standard optical diagnostics (Doppler velocimetry and optical pyrometry) to measure the thermodynamic state and the shock-front reflectivity at two different wavelengths. The results show that water and the mixtures undergo a similar compression path under single shock loading in agreement with Density Functional Theory Molecular Dynamics (DFT-MD) calculations using the Linear Mixing Approximation (LMA). On the contrary, their shock-front reflectivities behave differently by what concerns both the onset pressures and the saturation values, with possible impact on planetary dynamos.

Improved genome engineering methods that enable automation of large and precise edits are essential for systematic investigations of genome function. We adapted peel-1 negative selection to an optimized Dual-Marker Selection (DMS) cassette protocol for CRISPR-Cas9 genome engineering in Caenorhabditis elegans and observed robust increases in multiple measures of efficiency that were consistent across injectors and four genomic loci. The use of Peel-1-DMS selection killed animals harboring transgenes as extrachromosomal arrays and spared genome-edited integrants, often circumventing the need for visual screening to identify genome-edited animals. To demonstrate the applicability of the approach, we created deletion alleles in the putative proteasomal subunit pbs-1 and the uncharacterized gene K04F10.3 and used machine vision to automatically characterize their phenotypic profiles, revealing homozygous essential and heterozygous behavioral phenotypes. These results provide a robust and scalable approach to rapidly generate and phenotype genome-edited animals without the need for screening or scoring by eye.

Bioluminescence imaging (BLI) is ubiquitous in scientific research for the sensitive tracking of biological processes in small animal models. However, due to the attenuation of visible light by tissue, and the limited set of near-infrared bioluminescent enzymes, BLI is largely restricted to monitoring single processes in vivo. Here we show, that by combining stabilised colour mutants of firefly luciferase (FLuc) with the luciferin (LH2) analogue infraluciferin (iLH2), near-infrared dual BLI can be achieved in vivo. The X-ray crystal structure of FLuc with a high-energy intermediate analogue, 5’-O-[N-(dehydroinfraluciferyl)sulfamoyl] adenosine (iDLSA) provides insight into the FLuc-iLH2 reaction leading to near-infrared light emission. The spectral characterisation and unmixing validation studies reported here established that iLH2 is superior to LH2 for the spectral unmixing of bioluminescent signals in vivo; which led to this novel near-infrared dual BLI system being applied to monitor both tumour burden and CAR T cell therapy within a systemically induced mouse tumour model.

Marine data are needed for many purposes: for acquiring a better scientific understanding of the marine environment, but also, increasingly, as marine knowledge for decision making as well as developing products and services supporting economic growth. Data must be of sufficient quality to meet the specific users' needs. It must also be accessible in a timely manner. And yet, despite being critical, this timely access to known-quality data proves challenging. Europe's marine data have traditionally been collected by a myriad of entities with the result that much of our data are scattered throughout unconnected databases and repositories. Even when data are available, they are often not compatible, making the sharing of the information and data aggregation particularly challenging. In this paper, we present how the European Marine Observation and Data network (EMODnet) has developed over the last decade to tackle these issues. Today, EMODnet is comprised of more than 150 organizations which gather marine data, metadata, and data products and make them more easily accessible for a wider range of users. EMODnet currently consists of seven sub-portals: bathymetry, geology, physics, chemistry, biology, seabed habitats, and human activities. In addition, Sea-basin Checkpoints have been established to assess the observation capacity in the North Sea, Mediterranean, Atlantic, Baltic, Artic, and Black Sea. The Checkpoints identify whether the observation infrastructure in Europe meets the needs of users by undertaking a number of challenges. To complement this, a Data Ingestion Service has been set up to tackle the problem of the wealth of marine data that remain unavailable, by reaching out to data holders, explaining the benefits of sharing their data and offering a support service to assist them in releasing their data and making them available through EMODnet. The EMODnet Central Portal (www.emodnet.eu) provides a single point of access to these services, which are free to access and use. The strategic vision of EMODnet in the next decade is also presented, together with key focal areas toward a more user-oriented service, including EMODnet for business, internationalization for global users, and stakeholder engagement to connect the diverse communities across the marine knowledge value chain.

AimsTo assess the impact of the introduction of direct oral anticoagulants upon the outcomes from elective electrical cardioversion for atrial fibrillation.MethodsThis is a retrospective comparison of delay to elective cardioversion with different anticoagulants. The data was gathered from a large regional hospital from January 2013 to September 2017. There were 3 measured outcomes: 1) the time in weeks from referral to the date of attempted electrical cardioversion; 2) the proportion of patients who were successfully cardioverted; and 3) the proportion of patients who remained in sinus rhythm by the 12 week follow-up. Time-to-cardioversion was non-parametrically distributed so was analysed with Kruskal-Wallis testing and Mann-Whitney-U testing. Maintenance of sinus rhythm was analysed using z-testing.Results1,374 patients were submitted to cardioversion. The referrals for cardioversion were either from primary care or from cardiologists. At the time of cardioversion, 789 cases were anticoagulated on warfarin (W), 215 on apixaban (A) and 370 on rivaroxaban (R). All 3 cohorts were initially compared independently using Kruskal-Wallis testing. This demonstrated a significant difference in the delay (measured in weeks) between the A and W group (A = 7, W = 9, PConclusionDOACs appear to significantly shorten the latency between the decision to cardiovert and the cardioversion procedure by at least 2 weeks compared to warfarin in a real-world setting. In this study, patients who had not previously been cardioverted who were anticoagulated with warfarin had a significantly lower probability of conversion to sinus rhythm and a significantly lower probability to remain in sinus rhythm at the 12 week follow-up compared to the combined apixaban and rivaroxaban group.

The seafloor covers some 70% of the Earth’s surface and has been recognised as a major sink for marine litter. Still, litter on the seafloor is the least investigated fraction of marine litter, which is not surprising as most of it lies in the deep sea, i.e. the least explored ecosystem. Although marine litter is considered a major threat for the oceans, monitoring frameworks are still being set up. This paper reviews current knowledge and methods, identifies existing needs, and points to future developments that are required to address the estimation of seafloor macrolitter. It provides background knowledge and conveys the views and thoughts of scientific experts on seafloor marine litter offering a review of monitoring and ocean modelling techniques. Knowledge gaps that need to be tackled, data needs for modelling, and data comparability and harmonisation are also discussed. In addition, it shows how research on seafloor macrolitter can inform international protection and conservation frameworks to prioritise efforts and measures against marine litter and its deleterious impacts.

The physical activity is an important aspect of good health for everyone; it is even more important for psychiatric patients who usually live an unhealthy lifestyle. The aim of this study was to investigate the effects of football practice on the self-reported health quality of life (SRHQL) and Wellbeing in schizophrenic subjects. A randomized controlled clinical trial was conducted to assess the effectiveness of the Psychosocial Rehabilitation Program performed by Daily Center Mazzacurati, Department of Mental Health Roma/D , for psychotic subjects that included weekly football activities for a period of 9 months. The results show that the model proved effective in the experimental group (SG) as regards the psychopathological dimensions, which are significantly improved (Median(IQR): 31(16) versus 53(18); p=0.001); in particular the negative symptomatology has been reduced, and this result is hardly achieved with the drug therapy (17(7) versus 25(15); p=0.003). This study increases the awareness of following this ap proach and improving the extension and the confirmation of the results achieved.

The ability of Trichoderma harzianum (strain OMG-08) as plant growth promoting fungus (PGPF), was tested on Zea mays plants grown in soil pots added with different inorganic (triple superphosphate and rock phosphate) and organic (cow and horse manure composts) P fertilizers. The effect of treatments was evaluated by following the variations of plants dry biomass and nutrient content, as well as the metabolic changes in plant leaves by both GC-MS and NMR spectroscopy. A synergic effect was observed in treatments with both composts and fungus inoculation, in which not only plant growth and P uptake were enhanced, but also the expression of different metabolites related to an improved photosynthetic activity. Conversely, the combination of Trichoderma with inorganic fertilizers was less effective and even showed a reduction of plants shoot biomass and N content. The corresponding plant metabolome revealed metabolic compounds typical of biotic or abiotic stresses, which may be attributed to a reduced capacity of inorganic fertilizers to provide a sufficient P availability during plant growth. Our findings also indicate that the molecular composition of compost differentiated the Trichoderma activity in sustaining plant growth. The positive effects of the combined Trichoderma and compost treatment suggest that it may become an alternative to the phosphorus mineral fertilization.

Sinkholes are a well-known geologic hazard but their past occurrence, useful for subsidence risk prediction, is difficult to define, especially for ancient historic times. Consequently, our knowledge about Holocene carbonate landscapes is often limited. A multidisciplinary study of Trieste Karst (Italy), close to early Roman military fortifications, led to the identification of possible ancient road tracks, cut by at least one sinkhole. Electrical Resistivity Tomography through the sinkhole has suggested the presence of a cave below its bottom, possibly responsible of the sinkhole formation, while Ground Penetrating Radar has detected no tectonic disturbances underneath the tracks. Additionally, archaeological surveys led to the discovery of over 200 Roman shoe hobnails within or close to the investigated route. According to these data, the tracks are interpreted as the remains of a main Roman road, whose itinerary has been reconstructed for more than 4 km together with other elements of ancient landscape. Our results provide the first known evidence of a Roman main road swallowed by sinkholes and suggest that Holocene karst landscapes could be much different from what previously believed. In fact, sinkholes visible nowadays in the investigated region could have been flat areas filled by sediments up to the Roman time.

Preterm birth is associated with altered angiogenesis and with increased risk of cardiovascular dysfunction and hypertension at adulthood. We previously demonstrated that in preterm newborns circulating cord blood endothelial progenitor cells (ECFC), responsible for angio/vasculogenesis, are reduced in number and display altered angiogenic properties. Altered angiogenic function was associated with a decreased expression of pro-angiogenic genes, among which the AMOT gene which is a strong positive regulator of angiogenesis. Such dysregulation may be related to epigenetic factors. In this study we analyse the methylation profiling of the AMOT gene during development, through a comparative analysis of the cord blood ECFC of preterm newborns and their term counterpart.We used both cloning-sequencing and pyrosequencing experiments to perform a comparative analysis of the DNA methylation profile of the promoter CpG island of AMOT gene in the cord blood ECFC of 16 preterm newborns (28-35 weeks gestational age-GA) and 15 term newborns (>37 weeks GA).Twenty nine clones (obtained from 2 term newborns) and forty clones (obtained from 3 preterm newborns) were sequenced. The AMOT gene methylation rate was significantly higher in preterm compared to term newborns (4.5% versus 2.5% respectively: χ2 = 3.84; P = 1.8 10-02). Bisulfite pyrosequencing identified four CpG dinucleotides with significantly higher methylation levels in preterm newborns. This CpG-targeted methylation significantly decreased with increasing gestational age.These findings highlight importance of pro-angiogenic AMOT gene methylation in ECFC, suggesting that epigenetic mechanisms may control the regulation of angiogenesis during development. Therefore they pave the way to specific short term and long term complications of preterm birth by altered angiogenesis.

The central idea of this work is that Sport may enhance the therapeutic effects of medical treatment. In particular football is an healthy activity stimulating the psychophysical wellness, the clinical stabilization and the social interaction. Starting from this background and from empirical experiences in roman environment we drown this pilot work with the aim of develop a standard training protocol for schizophrenic patients.

In this paper we study the causal relation between country Economic Fitness F c and its Gross Domestic Product per capita ( G D P ). Using the Takens’ theorem, as first suggested in (Sugihara, G. et al. 2012), we show that there exists a reasonable evidence of causal correlation between G D P and F c for relatively rich countries. This is not the case for relatively poor countries where F c and G D P do not show any significant causal relation. We also present some preliminary results to understand whether G D P or F c are driving factor for economic growth.

Saphenous vein graft disease is a timely problem in coronary artery bypass grafting. Indeed, after exposure of the vein to arterial blood flow, a progressive modification in the wall begins, due to proliferation of smooth muscle cells in the intima. As a consequence, the graft progressively occludes and this leads to recurrent ischemia. In the present study we employed a novel ex vivo culture system to assess the biological effects of arterial-like pressure on the human saphenous vein structure and physiology, and to compare the results to those achieved in the presence of a constant low pressure and flow mimicking the physiologic vein perfusion. While under both conditions we found an activation of Matrix Metallo-Proteases 2/9 and of microRNAs-21/146a/221, a specific effect of the arterial-like pressure was observed. This consisted in a marked geometrical remodeling, in the suppression of Tissue Inhibitor of Metallo-Protease-1, in the enhanced expression of TGF-β1 and BMP-2 mRNAs and, finally, in the upregulation of microRNAs-138/200b/200c. In addition, the veins exposed to arterial-like pressure showed an increase in the density of the adventitial vasa vasorum and of cells co-expressing NG2, CD44 and SM22α markers in the adventitia. Cells with nuclear expression of Sox-10, a transcription factor characterizing multipotent vascular stem cells, were finally found in adventitial vessels. Our findings suggest, for the first time, a role of arterial-like wall strain in the activation of pro-pathologic pathways resulting in adventitial vessels growth, activation of vasa vasorum cells, and upregulation of specific gene products associated to vascular remodeling and inflammation.

OBJECTIVE: Increments in red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) levels are reportedly associated with higher insulin resistance (IR). Obesity may cause IR, but underlying factors remain incompletely defined, and interactions between obesity, hematological parameters and IR are incompletely understood. We therefore determined whether: 1) BMI and obesity per se are independently associated with higher RBC, hemoglobin and hematocrit; 2) hematological parameters independently predict insulin resistance in obese individuals. DESIGN AND METHODS: We investigated the associations between BMI, hematological parameters and insulin resistance as reflected by homeostasis model assessment (HOMA) in a general population cohort from the North-East Italy MoMa epidemiological study (M/F = 865/971, age = 49 ± 1). RESULTS: In all subjects, age-, sex- and smoking-adjusted hematological parameters were positively associated with BMI in linear regression (P

BackgroundThe pericardial tissue is commonly used to produce bio-prosthetic cardiac valves and patches in cardiac surgery. The procedures adopted to prepare this tissue consist in treatment with aldehydes, which do not prevent post-graft tissue calcification due to incomplete xeno-antigens removal. The adoption of fixative-free decellularization protocols has been therefore suggested to overcome this limitation. Although promising, the decellularized pericardium has not yet used in clinics, due to the absence of proofs indicating that the decellularization and cryopreservation procedures can effectively preserve the mechanical properties and the immunologic compatibility of the tissue.Principal findingsThe aim of the present work was to validate a procedure to prepare decellularized/cryopreserved human pericardium which may be implemented into cardiovascular homograft tissue Banks. The method employed to decellularize the tissue completely removed the cells without affecting ECM structure; furthermore, uniaxial tensile loading tests revealed an equivalent resistance of the decellularized tissue to strain, before and after the cryopreservation, in comparison with the fresh tissue. Finally, immunological compatibility, showed a minimized host immune cells invasion and low levels of systemic inflammation, as assessed by tissue transplantation into immune-competent mice.ConclusionsOur results indicate, for the first time, that fixative-free decellularized pericardium from cadaveric tissue donors can be banked according to Tissue Repository-approved procedures without compromising its mechanical properties and immunological tolerance. This tissue can be therefore treated as a safe homograft for cardiac surgery.

Molecular diagnostics of human cancers may increase accuracy in prognosis, facilitate the selection of the optimal therapeutic regimen, improve patient outcome, reduce costs of treatment and favour development of personalized approaches to patient care. Moreover sensitivity and specificity are fundamental characteristics of any diagnostic method. We developed a highly sensitive microarray for the detection of common KRAS and BRAF oncogenic mutations. In colorectal cancer, KRAS and BRAF mutations have been shown to identify a cluster of patients that does not respond to anti-EGFR therapies; the identification of these mutations is therefore clinically extremely important. To verify the technical characteristics of the microarray system for the correct identification of the KRAS mutational status at the two hotspot codons 12 and 13 and of the BRAF(V600E) mutation in colorectal tumor, we selected 75 samples previously characterized by conventional and CO-amplification at Lower Denaturation temperature-PCR (COLD-PCR) followed by High Resolution Melting analysis and direct sequencing. Among these samples, 60 were collected during surgery and immediately steeped in RNAlater while the 15 remainders were formalin-fixed and paraffin-embedded (FFPE) tissues. The detection limit of the proposed method was different for the 7 KRAS mutations tested and for the V600E BRAF mutation. In particular, the microarray system has been able to detect a minimum of about 0.01% of mutated alleles in a background of wild-type DNA. A blind validation displayed complete concordance of results. The excellent agreement of the results showed that the new microarray substrate is highly specific in assigning the correct genotype without any enrichment strategy.

Nutrient balance in the human body is maintained through systemic signaling between different cells and tissues. Breaking down this circuitry to its most basic elements and reconstructing the metabolic network in-vitro provides a systematic method to gain a better understanding of how cross-talk between the organs contributes to the whole body metabolic profile and of the specific role of each different cell type. To this end, a 3-way connected culture of hepatocytes, adipose tissue and endothelial cells representing a simplified model of energetic substrate metabolism in the visceral region was developed. The 3-way culture was shown to maintain glucose and fatty acid homeostasis in-vitro. Subsequently it was challenged with insulin and high glucose concentrations to simulate hyperglycaemia. The aim was to study the capacity of the 3-way culture to maintain or restore normal circulating glucose concentrations in response to insulin and to investigate the effects these conditions on other metabolites involved in glucose and lipid metabolism. The results show that the system's metabolic profile changes dramatically in the presence of high concentrations of glucose, and that these changes are modulated by the presence of insulin. Furthermore, we observed an increase in E-selectin levels in hyperglycaemic conditions and increased IL-6 concentrations in insulin-free-hyperglycaemic conditions, indicating, respectively, endothelial injury and proinflammatory stress in the challenged 3-way system.

BACKGROUND: It is known that primary sequences of enzymes involved in sterol biosynthesis are well conserved in organisms that produce sterols de novo. However, we provide evidence for a preservation of the corresponding genes in two animals unable to synthesize cholesterol (auxotrophs): Drosophila melanogaster and Caenorhabditis elegans. PRINCIPAL FINDINGS: We have been able to detect bona fide orthologs of several ERG genes in both organisms using a series of complementary approaches. We have detected strong sequence divergence between the orthologs of the nematode and of the fruitfly; they are also very divergent with respect to the orthologs in organisms able to synthesize sterols de novo (prototrophs). Interestingly, the orthologs in both the nematode and the fruitfly are still under selective pressure. It is possible that these genes, which are not involved in cholesterol synthesis anymore, have been recruited to perform different new functions. We propose a more parsimonious way to explain their accelerated evolution and subsequent stabilization. The products of ERG genes in prototrophs might be involved in several biological roles, in addition to sterol synthesis. In the case of the nematode and the fruitfly, the relevant genes would have lost their ancestral function in cholesterogenesis but would have retained the other function(s), which keep them under pressure. CONCLUSIONS: By exploiting microarray data we have noticed a strong expressional correlation between the orthologs of ERG24 and ERG25 in D. melanogaster and genes encoding factors involved in intracellular protein trafficking and folding and with Start1 involved in ecdysteroid synthesis. These potential functional connections are worth being explored not only in Drosophila, but also in Caenorhabditis as well as in sterol prototrophs.