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Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies.

Abstract With his bicentennial breeding history based on athletic performance, the Thoroughbred horse can be considered the equine sport breed. Although genomic and transcriptomic tools and knowledge are at the state of the art in equine species, the epigenome and its modifications in response to environmental stimuli, such as training, are less studied. One of the major epigenetic modifications is cytosine methylation at 5′ of DNA molecules. This crucial biochemical modification directly mediates biological processes and, to some extent, determines the organisms' phenotypic plasticity. Exercise indeed affects the epigenomic state, both in humans and in horses. In this study, we highlight, with a genome-wide analysis of methylation, how the adaptation to training in the Thoroughbred can modify the methylation pattern throughout the genome. Twenty untrained horses, kept under the same environmental conditions and sprint training regimen, were recruited, collecting peripheral blood at the start of the training and after 30 and 90 days. Extracted leukocyte DNA was analyzed with the methylation content sensitive enzyme ddRAD (MCSeEd) technique for the first time applied to animal cells. Approximately one thousand differently methylated genomic regions (DMRs) and nearby genes were called, revealing that methylation changes can be found in a large part of the genome and, therefore, referable to the physiological adaptation to training. Functional analysis via GO enrichment was also performed. We observed significant differences in methylation patterns throughout the training stages: we hypothesize that the methylation profile of some genes can be affected early by training, while others require a more persistent stimulus.

Abstract Background Recently, two invasive Aedes mosquito species, Ae. japonicus and Ae. koreicus, are circulating in several European countries posing potential health risks to humans and animals. Vector control is the main option to prevent mosquito-borne diseases, and an accurate genome sequence of these mosquitoes is essential to better understand their biology and to develop effective control strategies. Methods A de novo genome assembly of Ae. japonicus (Ajap1) and Ae. koreicus (Akor1) has been produced based on a hybrid approach that combines Oxford Nanopore long-read and Illumina short-read data. Their quality was ascertained using various metrics. Masking of repetitive elements, gene prediction and functional annotation was performed. Results Sequence analysis revealed a very high presence of repetitive DNA and, among others, thermal adaptation genes and insecticide-resistance genes. Through the RNA-seq analysis of larvae and adults of Ae. koreicus and Ae. japonicus exposed to different temperatures, we also identified genes showing a differential temperature-dependent activation. Conclusions The assembly of Akor1 and Ajap1 genomes constitutes the first updated collective knowledge of the genomes of both mosquito species, providing the possibility of understanding key mechanisms of their biology such as the ability to adapt to harsh climates and to develop insecticide-resistance mechanisms. Graphical Abstract

Abstract The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD, N = 282) or β‐thalassemia (β‐Thal, N = 60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC). We identified 405 different HLA‐A‐B‐DRB1 haplotypes in SCD and 108 in β‐Thal patients. Using data from African and European populations of the “1000 Genomes Project” for comparison with SCD and β‐Thal, respectively, we found that the haplotypes HLA‐A*30‐B*14‐DRB1*15 (OR 7.87, 95% CI: 1.66–37.3, pb = 0.035), HLA‐A*23‐B*08 (OR 6.59, 95% CI: 1.8–24.13, pb = 0.023), and HLA‐B*14‐DRB1*15 (OR 10.74, 95% CI: 3.66–31.57, pb = 0.000) were associated with SCD, and the partial haplotypes HLA‐A*30‐B*13 and HLA‐A*68‐B*53 were associated with β‐Thal (OR 4.810, 95% CI: 1.55–14.91, pb = 0.033, and OR 17.52, 95% CI: 2.81–184.95, pb = 0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with β‐Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.

Abstract Introduction To understand factors leading to biologic switches and to develop a readily usable model with data collected in clinical care at preceding visits, with the overall aim to predict the probability of switching biologic at a subsequent clinic visit in patients with rheumatoid arthritis (RA). Methods Participants were adults with RA participating in the CorEvitas RA registry. The study matched patients who switched biologics or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) with control patients who had not switched biologics/tsDMARDs; the cohort was divided into a training and test set for prediction model development and validation. Using the training set, the best subset regression, lasso, and elastic net methods were used to determine the best potential models. Area under the ROC curve (AUC) was used for the final selection of the best model, and estimated coefficients of this model were applied to the test dataset to predict switching. Results A total of 5050 patients were included, of whom 3016 were in the training set and 2034 were in the test dataset. The average age was 59.6 years, the majority were female (3998, 79.2%), and the average duration of RA at the time of switch or control visit was 12.8 years. The final model included prior Clinical Disease Activity Index (CDAI) by category, prior patient pain measurement, change in CDAI from baseline, age group, and number of prior biologics, all of which were significantly associated with switching biologics. The AUC was 0.690 for this model with the training dataset. The model was then applied to the test data with similar performance; the AUC was 0.687. Conclusion We have developed a simple model to determine the probability of switching biologics for RA at the following clinic visit. This model could be used in practice to provide clinicians with more information about their patient’s trajectory and likelihood of switching to a new biologic.

Abstract A maternal vaccine to protect neonates against Group B Streptococcus invasive infection is an unmet medical need. Such a vaccine should ideally be offered during the third trimester of pregnancy and induce strong immune responses after a single dose to maximize the time for placental transfer of protective antibodies. A key target antigen is the capsular polysaccharide, an anti-phagocytic virulence factor that elicits protective antibodies when conjugated to carrier proteins. The most prevalent polysaccharide serotypes conjugated to tetanus or diphtheria toxoids have been tested in humans as monovalent and multivalent formulations, showing excellent safety profiles and immunogenicity. However, responses were suboptimal in unprimed individuals after a single shot, the ideal schedule for vaccination during the third trimester of pregnancy. In the present study, we obtained and optimized self-assembling virus-like particles conjugated to Group B Streptococcus capsular polysaccharides. The resulting glyco-nanoparticles elicited strong immune responses in mice already after one immunization, providing pre-clinical proof of concept for a single-dose vaccine.

Musculoskeletal Disorders (MSDs) stand as a prominent cause of injuries in modern agriculture. Scientific research has highlighted a causal link between MSDs and awkward working postures. Several methods for the evaluation of working postures, and related risks, have been developed such as the Rapid Upper Limb Assessment (RULA). Nevertheless, these methods are generally applied with manual measurements on pictures or videos. As a consequence, their applicability could be scarce, and their effectiveness could be limited. The use of wearable sensors to collect kinetic data could facilitate the use of these methods for risk assessment. Nevertheless, the existing system may not be usable in the agricultural and vine sectors because of its cost, robustness and versatility to the various anthropometric characteristics of workers. The aim of this study was to develop a technology capable of collecting accurate data about uncomfortable postures and repetitive movements typical of vine workers. Specific objectives of the project were the development of a low-cost, robust, and wearable device, which could measure data about wrist angles and workers’ hand positions during possible viticultural operations. Furthermore, the project was meant to test its use to evaluate incongruous postures and repetitive movements of workers’ hand positions during pruning operations in vineyard. The developed sensor had 3-axis accelerometers and a gyroscope, and it could monitor the positions of the hand–wrist–forearm musculoskeletal system when moving. When such a sensor was applied to the study of a real case, such as the pruning of a vines, it permitted the evaluation of a simulated sequence of pruning and the quantification of the levels of risk induced by this type of agricultural activity.

Background: Degenerative aortic valve stenosis (AS) is the most common valvular heart disease among the elderly. Once cardiac symptoms occur, current guidelines recommend aortic valve replacement. Progressive degeneration/calcification reduces leaflet mobility with gradual cardiac output (CO) impairment. Low CO might induce abnormal brain-aging with cognitive impairment and increased risk of dementia, such as Alzheimer’s disease or vascular dementia. On the contrary, cognitive improvement has been reported in patients in whom CO was restored. Transcatheter aortic valve implantation (TAVI) has proven to be a safe alternative to conventional surgery, with a similar mid-term survival and stroke risk even in low-risk patients. TAVI is associated with an immediate CO improvement, also effecting the cerebrovascular system, leading to an increased cerebral blood flow. The correlation between TAVI and cognitive improvement is still debated. The present study aims at evaluating this relationship in a cohort of AS patients where cognitive assessment before and after TAVI was available. Methods: a total of 47 patients were retrospectively selected. A transcranial Doppler ultrasound (TCD) before and after TAVI, a quality of life (QoL) score, as well as a mini-mental state examination (MMSE) at baseline and up to 36 months, were available. Results: TAVI was associated with immediate increase in mean cerebral flow at TCD. MMSE slowly increase at 36-months follow-up with improved QoL mainly for symptoms, emotions and social interactions. Conclusions: this proof-of-concept study indicates that TAVI might induce cognitive improvement in the long-term as a result of multiple factors, such as cerebral flow restoration and a better QoL.

Organisations heavily dependent on paper documents still spend a significant amount of time managing a large volume of documents. An intelligent document management system (DMS) is presented to automate the processing of tax and administrative documents. The proposed system fills a gap in the landscape of practical tools in the field of DMS and advances the state of the art. This system represents a complex process of integrated AI-powered technologies that creates an ontology, extracts information from documents, defines profiles, maps the extracted data in RDF format, and applies inference through a reasoning engine. The DMS was designed to help all those companies that manage their clients’ tax and administrative documents daily. Automation speeds up the management process so that companies can focus more on value-added services. The system was tested in a case study that focused on the preparation of tax returns. The results demonstrated the efficacy of the system in providing document management service.

Aqueous extracts from four different American hops varieties (Mosaic, Chinook, Citra, and Centennial) were produced using the Synergy Pure technique, an innovative extraction distillation process developed by Synergy Flavours, a global specialist in the manufacturing of flavors, extracts and essences. This process is able to preserve and maximize the aromatic characteristics without increasing the bitterness of the final product. Therefore, the aim of this work is to identify the volatile and sensory characteristics of these extracts, with the additional aim to assess their suitability for brewing. GC-MS and sensory analyses were carried out on the four different aqueous extracts. The results highlighted the presence of 33 volatile compounds in a quantity that allowed us to identify the characteristics of the varieties under investigation in each extract. Sensory analysis was carried out using the expert sensory profiling technique. The results regarding the olfactory analysis of the extracts allowed us to define the aroma profiles of the four extracts, highlighting their strong correspondence with the characteristic of the varieties under investigation. Finally, the results showed that the aqueous extracts produced using the Synergy Pure extraction technique had a richer aroma profile, highlighting its higher aptitude in beer production.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical–pathological factors.

Given its huge economic, nutritional, and social value, extra virgin olive oil (EVOO) is an essential food. This flagship product of the countries bordering the Mediterranean basin is one of the most frauded products worldwide. Although traditional chemical analyses have demonstrated to be reliable tools for olive drupes and EVOO quality assessment, they present several drawbacks; the urgent need for fast and non-destructive techniques thus motivated this review. Given the lack of comprehensive reviews in the literature, our first aim was to summarize the current knowledge regarding applying spectroscopies, imaging analyses, and other non-destructive techniques to olives and EVOO. The second aim was to highlight the most innovative and futuristic applications and outline the future research prospects within this strategic production chain. With respect to olive drupes, the most interesting results were obtained using RGB imaging and NIR spectroscopy, particularly using portable NIR devices and specific digital cameras for in-field or in-mill monitoring. Nevertheless, it is important to highlight that RGB imaging and NIR spectroscopy need to be integrated with flesh hardness measurements, given the higher reliability of this parameter compared to olive skin color. Finally, with respect to EVOO, although several useful applications of visible imagining, UV–Visible, NIR, and Mid-Infrared spectroscopies have been found, the online monitoring of EVOO quality using NIR spectroscopy strikes us as being the most interesting technique for improving the EVOO production chain in the near future.

The Cryogenic Underground Observatory for Rare Events (CUORE) is a large-scale cryogenic experiment searching for neutrinoless double-beta decay (0νββ) in Te130. The CUORE detector is made of natural tellurium, providing the possibility of rare event searches on isotopes other than Te130. In this work we describe a search for neutrinoless positron-emitting electron capture (β+EC) decay in Te120 with a total TeO2 exposure of 355.7 kg yr, corresponding to 0.2405 kg yr of Te120. Albeit 0νββ with two final-state electrons represents the most promising channel, the emission of a positron and two 511-keV γ's make 0νβ+EC decay signature extremely clear. To fully exploit the potential offered by the detector modularity we include events with different topology and perform a simultaneous fit of five selected signal signatures. Using blinded data we extract a median exclusion sensitivity of 3.4×1022 yr at 90% credibility interval (C.I.). After unblinding we find no evidence of 0νβ+EC signal and set a 90% C.I. Bayesian lower limit of 2.9×1022 yr on Te120 half-life. This result improves by an order of magnitude the existing limit from the combined analysis of CUORE-0 and Cuoricino.

The possibility that neutrinos may be their own antiparticles, unique among the known fundamental particles, arises from the symmetric theory of fermions proposed by Ettore Majorana in 19371. Given the profound consequences of such Majorana neutrinos, among which is a potential explanation for the matter-antimatter asymmetry of the universe via leptogenesis2, the Majorana nature of neutrinos commands intense experimental scrutiny globally; one of the primary experimental probes is neutrinoless double beta (0νββ) decay. Here we show results from the search for 0νββ decay of 130Te, using the latest advanced cryogenic calorimeters with the CUORE experiment3. CUORE, operating just 10 millikelvin above absolute zero, has pushed the state of the art on three frontiers: the sheer mass held at such ultralow temperatures, operational longevity, and the low levels of ionizing radiation emanating from the cryogenic infrastructure. We find no evidence for 0νββ decay and set a lower bound of the process half-life as 2.2 × 1025 years at a 90 per cent credibility interval. We discuss potential applications of the advances made with CUORE to other fields such as direct dark matter, neutrino and nuclear physics searches and large-scale quantum computing, which can benefit from sustained operation of large payloads in a low-radioactivity, ultralow-temperature cryogenic environment.