Search

International research attention on evacuation issues has increased significantly following the human and natural disasters at the turn of the century, such as 9/11, Hurricane Katrina, Cyclones Idai and Kenneth, the Black Saturday forest fires and tsunamis in Japan. The main problem concerning when a disaster can occur involves studying the risk reduction. Risk, following all the theoretical and experimental studies, is determined by the product of three components: occurrence, vulnerability and exposure. Vulnerability can be improved over time through major infrastructure actions, but absolute security cannot be achieved. When the event will occur with certainty, only exposure remains to reduce the risk to people before the effect hits them. Exposure can be improved, under fixed conditions of occurrence and vulnerability, by improving evacuation. The main problem in terms of evacuating the population from an area is the available transport system, which must be used to its fullest. So, if the system is well managed, the evacuation improves (shorter times), meaning the exposure is reduced, and therefore, the risk is reduced. A key factor in the analysis of transport systems under emergency conditions is the behavior of the user, and therefore, the study of demand. This work identifies the main research lines that are useful for studying demand under exposure-related risk conditions. The classification of demand models that simulate evacuation conditions in relation to the effect on the transportation system is summarized. The contribution proposes a model for updating choice in relation to emergency conditions and utility. The contribution of emerging ICTs to actualization is formally introduced into the models. Intelligent technologies make it possible to improve user decisions, reducing exposure and therefore risk. The proposed model moves within the two approaches of the literature: it is an inter-period dynamic model with the probability expressed within the discrete choice theory; furthermore, it is a sequential dynamic model with the probability dependent on the previous choices. The contribution presents an example of application of the model, developing a transition matrix considering the case of choice updating under two extreme conditions.

Abstract Background The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. Results We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p

AbstractActivating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are among the most common genetic causes of Parkinson's disease (PD). The mechanistic path from LRRK2 mutations to PD is not established, but several lines of data suggest that LRRK2 modulation of lysosomal function is involved. It has previously been shown that LRRK2 is recruited to lysosomes upon lysosomal damage leading to increased phosphorylation of its RAB GTPase substrates in macrophage-derived RAW 264.7 cells. Here, we find that LRRK2 kinase inhibition reduces cell death induced by the lysosomotropic compound LLOMe in RAW 264.7 cells showing that lysosomal damage and LRRK2 functionally interacts in both directions: lysosomal damage can lead to activation of LRRK2 signaling and LRRK2 inhibition can attenuate LLOMe-induced cell death. The effect is lysosome specific, as only lysosomal stressors and not a variety of other cell death inducers could be modulated by LRRK2 kinase inhibition. We show with timing and Lysotracker experiments that LRRK2 inhibition does not affect the immediate lysosomal permeabilization induced by LLOMe, but rather modulates the subsequent cellular response to lysosomal damage. siRNA-mediated knockdown of LRRK2 and its main substrates, the RAB GTPases, showed that LRRK2 and RAB8A knockdown could attenuate LLOMe-induced cell death, but not other RAB GTPases tested. An RNA sequencing study was done to identify downstream pathways modulated by LLOMe and LRRK2 inhibition. The most striking finding was that almost all cholesterol biosynthesis genes were strongly downregulated by LLOMe and upregulated with LRRK2 inhibition in combination with LLOMe treatment. To explore the functional relevance of the transcriptional changes, we pretreated cells with the NPC1 inhibitor U18666A that can lead to accumulation of lysosomal cholesterol. U18666A-treated cells were less sensitive to LLOMe-induced cell death, but the attenuation of cell death by LRRK2 inhibition was strongly reduced suggesting that LRRK2 inhibition and lysosomal cholesterol reduces cell death by overlapping mechanisms. Thus, our data demonstrates a LRRK2- and RAB8A-mediated attenuation of RAW 264.7 cell death induced by lysosomal damage that is modulated by lysosomal cholesterol.

Abstract Large deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes. Here, we used targeted metabolomics to compare neonatal dried blood spot samples from 203 individuals clinically identified as carriers of a deletion at chromosome 22q11.2 with 203 unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers. We found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%), and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength. Targeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis.

Abstract Partial wave decomposition is one of the main tools within the modern S-matrix studies. We present a method to compute partial waves for 2 → 2 scattering of spinning particles in arbitrary spacetime dimension. We identify partial waves as matrix elements of the rotation group with definite covariance properties under a subgroup. This allows to use a variety of techniques from harmonic analysis in order to construct a novel algebra of weight-shifting operators. All spinning partial waves are generated by the action of these operators on a set of known scalar seeds. The text is accompanied by a Mathematica notebook to automatically generate partial waves. These results pave the way to a systematic studies of spinning S-matrix bootstrap and positivity bounds.

Abstract Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.

Helicobacter pylori (H. pylori) antibiotic resistance is the leading cause for unsuccessful eradication therapy. After one or more failures, the chance of encountering secondary antibiotic resistance increases. The aim of this study was to characterize genotypic secondary resistance in a cohort of southern Italian H. pylori patients with at least one previous failure. Such patients collected stool samples using a dedicated kit (THD fecal testTM), and bacterial DNA was extracted and amplified using RT-PCR. Resistance to clarithromycin, amoxicillin, metronidazole, levofloxacin, and tetracycline was assessed using a high-resolution melting curve. We enrolled 50 patients. A total of 72% of patients failed one previous antibiotic course, 16% failed two, 10% failed three, and 2% failed four. The rate of secondary antibiotic resistance was 16% for clarithromycin, 18% for metronidazole, 14% for amoxicillin, 14% for levofloxacin, and 2% for tetracycline. Among the eight clarithromycin-resistant patients, five (62.5%) previously received a clarithromycin-based regimen. The same rate was 33.3% (3/9) for metronidazole. The only tetracycline-resistant patient had received Pylera. In conclusion, our data seem to show that, even though secondary resistance is not very high, resistance to clarithromycin could be very likely related to previous exposure to this antibiotic.

Concomitant therapy (CT) and bismuth quadruple therapy (BQT) are recommended in geographical areas with high clarithromycin resistance for Helicobacter pylori (H. pylori) eradication. We compared CT and BQT as the first lines of treatment in a randomized controlled trial. Consecutive patients with H. pylori diagnosed by concordance of both a urea breath test and histology were recruited. For BQT, patients received 3 PyleraTM capsules q.i.d.; for CT, 1000 mg of amoxicillin b.i.d, 500 mg of clarithromycin b.i.d and 500 mg of metronidazole b.i.d. As a proton pump inhibitor, 40 mg of pantoprazole b.i.d was administered. Both regimens lasted 10 days. In total, 46 patients received CT and 38 BQT. Both groups were comparable for age (p = 0.27) and sex (p = 0.36). We did not record any drop outs; therefore, the intention to treat and per protocol rates coincided. The most common symptoms were heartburn and post-prandial fullness, which were equally present in both groups. The success rate was 95.6% for CT and 100% for BQT (p = 0.56). Side effects were recorded in 23.9% and 31.6% of patients in the CT and BQT arms, respectively (p = 0.47). The most common ones were abdominal pain (8) and diarrhea (6). In conclusion, CT and BQT are equally effective in our area with high clarithromycin resistance, southern Italy, and showed comparable safety.

The paper presents the study on the existence and uniqueness (strong and in law) of a class of non-Markovian SDEs whose drift contains the derivative in the sense of distributions of a continuous function.

Abstract We consider Bekenstein-Hawking entropy and attractors in extremal BPS black holes of N $$ \mathcal{N} $$ = 2, D = 4 ungauged supergravity obtained as reduction of minimal, matter-coupled D = 5 supergravity. They are generally expressed in terms of solutions to an inhomogeneous system of coupled quadratic equations, named BPS system, depending on the cubic prepotential as well as on the electric-magnetic fluxes in the extremal black hole background. Focussing on homogeneous non-symmetric scalar manifolds (whose classification is known in terms of L(q, P, Ṗ) models), under certain assumptions on the Clifford matrices pertaining to the related cubic prepotential, we formulate and prove an invertibility condition for the gradient map of the corresponding cubic form (to have a birational inverse map which is given by homogeneous polynomials of degree four), and therefore for the solutions to the BPS system to be explicitly determined, in turn providing novel, explicit expressions for the BPS black hole entropy and the related attractors as solution of the BPS attractor equations. After a general treatment, we present a number of explicit examples with Ṗ = 0, such as L(q, P), 1 ⩽ q ⩽ 3 and P ⩾ 1, or L(q, 1), 4 ⩽ q ⩽ 9, and one model with Ṗ = 1, namely L(4, 1, 1). We also briefly comment on Kleinian signatures and split algebras. In particular, we provide, for the first time, the explicit form of the BPS black hole entropy and of the related BPS attractors for the infinite class of L(1, P) P ⩾ 2 non-symmetric models of N $$ \mathcal{N} $$ = 2, D = 4 supergravity.

Abstract MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase .

Of the approximately 100,000 km of High-Speed Rail (HSR) lines in the world today, half are in operation and half are planned or under construction. The implementation of HSRs are planned in various countries with different characteristics to pursue different objectives. Today, the results are known, and therefore, the differences between the planned and achieved objectives can be verified. Italy is one of the countries that first built an HSR, and now, at the national planning level, Italy has decided to implement an HSR in Southern Italy. The problem is therefore not “whether” to realize an HSR but “which” type of HSR to realize. Italy is an important case study at the international level because it is possible to extend the HSR network in three different ways: upgrading existing lines by increasing the speed to 200 km/h, building a new line with speeds of 300 km/h with heavy freight trains, and building a new line with speeds of 300 km/h without heavy freight trains. The problem is how to find the best alternative in order to pursue sustainable development while considering national planning. To solve this problem, at the intermediate level between planning and design, the theoretical Lean, Agile, Resilient, Green (LARG) paradigm is proposed and applied. This approach can be extended to all countries that are launching massive and expensive programs to construct HSR lines or to upgrade existing lines.

Coeliac disease is a very common autoimmune disease estimated to affect 1 in 100 people worldwide. It occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine, and it is accurately diagnosticated through duodenal biopsy, an invasive diagnostic method. The liquid biopsy, generally used for monitoring cancer, is an appealing alternative even for autoimmune pathology such as coeliac disease, allowing for detecting disease progression or resistance to treatment. For this reason, an electrochemical peptide nucleic acid (PNA) device combined with a smartphone‐assisted potentiostat for non‐invasive coeliac disease diagnosis is proposed, by measuring the selected overexpressed miRNA‐486‐5p in serum, enlarging the application of liquid biopsy in nontumor pathologies. For highly sensitive detection, the polyester‐based printed sensor is nanomodified with gold nanoparticles and a synthetic customized PNA probe. The designed sensor can detect the target analyte in the range of 10–100 nm with a limit of detection of 0.7 nm by measuring the variation of the response of the electrochemical mediator hexaammineruthenium in the presence of PNA–miRNA duplex on the nanostructured working electrode surface. The analyses testing serum samples are found in agreement with ones obtained by real‐time quantitative polymerase chain reaction (RT‐qPCR), demonstrating the reliability of this innovative electrochemical chip developed.

Recently, the evolution of emerging information and communication technologies (e-ICTs) has opened the road for developing and implementing new integrated and dynamic city logistics solutions and subsequently for identifying new frontiers of intelligent transport systems (ITSs). The study evolves pointing out the different city logistics groups of actors and their reciprocal interactions in relation to the considered new technologies (i.e., internet of things, block chain, big data, and artificial intelligence), which allow actors to increase their utility exploiting the advancement of current intelligent transport systems. The changes in the generalized path costs supported by each stakeholder are explored, and the modifications guided by e-ICTs are analyzed. The learning process due to the update for within-day and day-to-day dynamics is detailed and formalized. In this way, the current formulation of the classical transport problem (vehicle routing and scheduling) and the new one (pushed from the growth of ecommerce, i.e., courier routing) are explored under the light of the new knowledge derived from the use of e-ICTs. Novelty of the study mainly comprises the analysis of each emerging ICT group and of the formalization, in the classical transport system models (TSM), of the new knowledge for each actor group.

Abstract Background Irritable bowel syndrome (IBS) is characterised by gastrointestinal (GI) and psychological symptoms (e.g., depression, anxiety, and somatization). Depression and anxiety, but not somatization, have already been associated with altered intestinal barrier function, increased LPS, and dysbiosis. The study aimed to investigate the possible link between somatization and intestinal barrier in IBS with diarrhoea (IBS-D) patients. Methods Forty-seven IBS-D patients were classified as having low somatization (LS = 19) or high somatization (HS = 28) according to the Symptom Checklist-90-Revised (SCL-90-R), (cut-off score = 63). The IBS Severity Scoring System (IBS-SSS) and the Gastrointestinal Symptom Rating Scale (GSRS) questionnaires were administered to evaluate GI symptoms. The intestinal barrier function was studied by the lactulose/mannitol absorption test, faecal and serum zonulin, serum intestinal fatty-acid binding protein, and diamine oxidase. Inflammation was assessed by assaying serum Interleukins (IL-6, IL-8, IL-10), and tumour necrosis factor-α. Dysbiosis was assessed by the urinary concentrations of indole and skatole and serum lipopolysaccharide (LPS). All data were analysed using a non-parametric test. Results The GI symptoms profiles were significantly more severe, both as a single symptom and as clusters of IBS-SSS and GSRS, in HS than LS patients. This finding was associated with impaired small intestinal permeability and increased faecal zonulin levels. Besides, HS patients showed significantly higher IL-8 and lowered IL-10 concentrations than LS patients. Lastly, circulating LPS levels and the urinary concentrations of indole were higher in HS than LS ones, suggesting a more pronounced imbalance of the small intestine in the former patients. Conclusions IBS is a multifactorial disorder needing complete clinical, psychological, and biochemical evaluations. Trial registration: https://clinicaltrials.gov/ct2/show/NCT03423069 .

Celiac disease (CD) is an inflammatory autoimmune disorder triggered by the ingestion of gluten from wheat and other cereals. Nowadays, its positive diagnosis is based on invasive approaches such as the histological examination of intestinal biopsies and positive serology screening of antibodies. After proven diagnosis, the only admissible treatment for CD individuals is strict life-long adherence to gluten-free diet (GFD), although it is not a conclusive therapy. Acting by different mechanisms and with different etiologies, both CD and GFD have a great impact on gut microbiota that result in a different taxa composition. Altered production of specific metabolites reflects these microbiota changes. In this light, the currently available literature reports some suggestions about the possible use of specific metabolites, detected by meta-omics analyses, as potential biomarkers for a CD non-invasive diagnosis. To highlight insights about metabolomics application in CD study, we conducted a narrative dissertation of selected original articles published in the last decade. By applying a systematic search, it clearly emerged how the metabolomic signature appears to be contradictory, as well as poorly investigated.

Abstract Background Studies on tumor-secreted microRNAs point to a functional role of these in cellular communication and reprogramming of the tumor microenvironment. Uptake of tumor-secreted microRNAs by neighboring cells may result in the silencing of mRNA targets and, in turn, modulation of the transcriptome. Studying miRNAs externalized from tumors could improve cancer patient diagnosis and disease monitoring and help to pinpoint which miRNA-gene interactions are central for tumor properties such as invasiveness and metastasis. Methods Using a bioinformatics approach, we analyzed the profiles of secreted tumor and normal interstitial fluid (IF) microRNAs, from women with breast cancer (BC). We carried out differential abundance analysis (DAA), to obtain miRNAs, which were enriched or depleted in IFs, from patients with different clinical traits. Subsequently, miRNA family enrichment analysis was performed to assess whether any families were over-represented in the specific sets. We identified dysregulated genes in tumor tissues from the same cohort of patients and constructed weighted gene co-expression networks, to extract sets of co-expressed genes and co-abundant miRNAs. Lastly, we integrated miRNAs and mRNAs to obtain interaction networks and supported our findings using prediction tools and cancer gene databases. Results Network analysis showed co-expressed genes and miRNA regulators, associated with tumor lymphocyte infiltration. All of the genes were involved in immune system processes, and many had previously been associated with cancer immunity. A subset of these, BTLA, CXCL13, IL7R, LAMP3, and LTB, was linked to the presence of tertiary lymphoid structures and high endothelial venules within tumors. Co-abundant tumor interstitial fluid miRNAs within this network, including miR-146a and miR-494, were annotated as negative regulators of immune-stimulatory responses. One co-expression network encompassed differences between BC subtypes. Genes differentially co-expressed between luminal B and triple-negative breast cancer (TNBC) were connected with sphingolipid metabolism and predicted to be co-regulated by miR-23a. Co-expressed genes and TIF miRNAs associated with tumor grade were BTRC, CHST1, miR-10a/b, miR-107, miR-301a, and miR-454. Conclusion Integration of IF miRNAs and mRNAs unveiled networks associated with patient clinicopathological traits, and underlined molecular mechanisms, specific to BC sub-groups. Our results highlight the benefits of an integrative approach to biomarker discovery, placing secreted miRNAs within a biological context.

In the past few years, increasing attention has been given to the pathologic role of specific foods in IBS, like wheat and other cereals. Recent literature describes IBS patients who may experience gastrointestinal (GI) and extra-GI symptoms precipitated by the ingestion of cereals. Tritordeum is a cereal of Spanish origin derived from the hybridization of durum wheat and wild barley. It is different from classic wheat for its gluten protein composition, with fewer carbohydrates and fructans and a higher content of proteins, dietary fibers, and antioxidants. This pilot study aimed to investigate the effects of a 12-week diet with Tritordeum-based foods in substitution of other cereals on the profile of GI symptoms (evaluated by appropriate questionnaire) and the health of the GI barrier (assessed by sugar absorption test and different markers of integrity and functions) in 16 diarrhea-predominant IBS (IBS-D) patients. The diet with Tritordeum-based foods (bread, bakery products, and pasta) significantly reduced IBS-D patients' symptoms. This amelioration appears to occur through an overall improvement of the GI barrier, as demonstrated by the reduced intestinal permeability and the decreased levels of markers of intestinal mucosal integrity, mucosal inflammation, and fermentative dysbiosis.

Between October 2020 and December 2020, 1,466 healthcare workers were screened for the presence of Sars-Cov-2 infection in a Local Health Department of the Piedmont region, North-Western Italy, using a Real-Time RT PCR based technique. Mean age was 46.1 ± 11.3 years and female were 77%. We found 234 positive cases (16%): mean age was 45.9 ± 11.1 years and 73% were female. The most common symptoms were cough, hyposmia and ageusia. Asymptomatic subjects were 57%. Our data further underline the importance of an active COVID-19 screening in the healthcare workers population regardless of symptoms or of a clear infection exposure.

Urban areas constitute one of the main issues of sustainability as defined by the United Nations with the Sustainable Development Goals (SDGs). The recent smart city concept represents a way for achieving the urban sustainability goals. The European Commission (EC) bases the smart city concept on three pillars: energy, transport and Information and Communication Technologies (ICT). The main objective of the paper is to investigate the European smart city process, by focusing on urban mobility and their interconnections with the other two pillars. The methodological approach of territorial planning is used by identifying the plan dimensions and then analyzing the processes at master and sectorial level. The applied processes are verified with a review of the European documents that constitute the rules for defining and implementing the smart city concept. European guidelines indicate the SUMP as the integrated master plan that contributes to reach the convergence among energy, transport and ICT processes. By focusing on people mobility sector, European cities are implementing the Mobility as a Service (MaaS) plan at the sectorial level. This implies the necessity to enhance the knowledge of mobility phenomenon, in relation to emerging ICT and their impact on energy consumptions. The contribution of the work is given by the identification of a planning and implementation path focused on smart city, in urban areas, which connects the general goals of Agenda 2030 with the daily implications for citizens and therefore with the specific results. The paper results are useful: from one side, for researchers that work on advancements of theories, and from another side, for planners and decision makers to explore the European attempts towards urban sustainability and the real implementations on urban mobility systems.

Background: Since hospital use of gene therapy requires close cooperation between doctors and pharmacists to ensure correct drug handling and administration, it is essential to define standard operating procedures (SOPs) for each phase of the process to ensure therapeutic success in compliance with the safety of patient and healthcare professionals. Among the available gene therapy medicines, voretigene neparvovec is used to treat hereditary dystrophy of the retina caused by biallelic mutations in the RPE65 gene. The aim of this article is to describe the experience of the Hospital Pharmacy unit of L. Vanvitelli university hospital in the management of treatment with voretigene neparvovec in the first two pediatric patients treated in Italy. Methods: SOPs were developed for all phases of gene therapy management process (procurement, receipt, storage, handling, transport of the finished product and waste disposal). Particular attention was paid to the training of personnel involved, to ensure maximum compliance with the procedures at all stages of the process. Results: SOPs were developed according to the European Association of Hospital Pharmacist (EAHP) policies and in full agreement with the operating procedures established by the manufacturer, ensuring correct storage and handling of the drug, as well as safe administration to patients. Conclusions: This example confirms the importance of close collaboration in a multidisciplinary team between hospital pharmacists, ophthalmologists experienced in the treatment of patients with hereditary retinal dystrophies and surgeons experienced in subretinal surgery to ensure the correct management of gene therapy with voretigene neparvovec, through compliance with shared operating procedures.

Geographical location, infrastructures, and services are the main consolidated pillars of a port in terms of its capacity to compete and cooperate with other ports. In the last years, a new pillar was identified: emerging technologies. Ports’ issues were initially solved with individual ICT solutions adopted by each decision-maker, which generated efficiencies in the three main port flows: cargo, information, and financial. However, new benefits and challenges are connected with the introduction of shared emerging ICT among decision-makers inside ports. The crucial issue concerns the fact that several decision-makers could share a decision about a single-port operation. Therefore, the effectiveness and efficiency of ports depend on how the interactions between the decision-makers are solved. Port operations are associated with movements (cargo) and transactions (information and financial) in a synchronic graph, which allows highlighting the role of emerging technologies in the modification of port operation generalized cost, considering the different decision-makers. The focal point concerns the building of a theoretical model using the formal equations of Transport System Models (TSMs) for the estimation of the cost for a Unit of Load (UL), e.g., a container traveling along a path, composed of a sequence of port operations, inside a port with and without emerging technologies. The proposed theoretical model provides the possibility of estimating ex ante the reduction of cost (port time of UL) given by introducing new technologies and a Port Community System (PCS). Different scenarios, considering some cases, ranging from the absence of ICT to the presence of a PCS, are compared, considering the different situations from a non-congested port to a congested one. The main results of the study and its novelty concern, on the one hand, the extension of TSMs to port systems, highlighting the problem of a non-single decision-maker (two or more) in some port operations and, on the other hand, the possibility of reducing the generalized cost (e.g., time) in the same operations in which there are concurrent decision-makers, through the use of an advanced PCS. The reported numerical example confirms the theoretical results. The work can be useful for researchers for port planners (e.g., port authorities) because it permits evaluating the utility for introducing shared emerging technologies using advanced PCS in a unified view.

Growth trends in passenger transport demand and gross domestic product have so far been similar. The increase in mobility in one area is connected with the increase in GDP in the same area. This increase is representative of the economic and social development of the area. At the same time, the increase in mobility produces one of the most negative environmental impacts, mainly determined by the growth of mobility of private cars. International attention is given to the possibilities of increasing mobility and, therefore, social and economic development without increasing environmental impacts. One of the most promising fields is that of MaaS: Mobility as a Service. MaaS arises from the interaction of new user behavioral models (demand) and new decision-making models on services (supply). Advanced interaction arises from the potentialities allowed by emerging ICT technologies. There is a delay in the advancement of transport system models that consider the updating of utility and choice for the user by means of updated information. The paper introduces sustainability as defined by Agenda 2030 with respect to urban passenger transport, then examines the role of ICT in the development of MaaS formalizing a dynamic model of demand–supply interaction explicating ICT. Finally, the advanced Sustainable MaaS, defined SMaaS, is analyzed, evidencing the contribution to achieving the goals of Agenda 2030.

Background: Based on data from the Ministry of Health, which highlighted the earlier onset of Covid-19 epidemic in Italy, compared with the Europe, we would like to present a statistical elaboration on the impact of measures taken by the Government, during the phase 1 and the start of phase 2. Methods: After the implementation of a Bayesian changepoint detection method, we looked for a best fit model, based on the first part of time series data, in order to observe the progress of the data in the presence and absence of the restriction measures introduced. Results: Both the implementation of changepoint detection method and the analysis of the curves showed that the decree that marked the start of lockdown has had the effect of slowing down the epidemic by allowing the start of a plateau between 21 and 25 March. Moreover, the decree that decided the beginning of phase 2 on 4 May did not have a negative impact. Conclusion: This statistical analysis supports the hypothesis that stringent measures decreased hospitalization, thanks to a slowing down in the evolution of the epidemic compared with what was expected.

The present study aimed to evaluate the effects of the probiotic Lactobacillus rhamnosus GG (L.GG) on the serotonergic pathway in an animal model of peptic tryptic digested gliadin (PTG)-induced enteropathy that mimics celiac disease (CD). The serotonin (5-HT) levels, the gene expression and the protein contents of 5-HT3B, 5-HTR4 receptors, SERT and TPH1 were evaluated in the duodenal tissue samples of control and treated Wistar rats.PTG caused an imbalance on both 5-HT receptors and SERT with a significant elevation of 5-HT levels, not due to increased synthesis by the TPH1. The L.GG counteracted the PTG-induced imbalance of the serotonergic system, reducing the 5-HTRs expression and increasing SERT without affecting TPH1 expression.Further research, also performed in clinical trials, is required to understand the precise link between 5-HT and CD. Notwithstanding, by decreasing 5-HT levels, LGG may be a potential strategy for helping improve clinical symptoms of CD.

The eradication of Helicobacter pylori (H. pylori) may be difficult due to antibiotic resistance. Indeed, after one failure, a second-line therapy is needed and a bismuth containing quadruple therapy (BQT) with a three-in-one capsule formulation is becoming very popular. Therefore, we aimed to evaluate effectiveness and safety of BQT as a second-line therapy. We recruited consecutive patients with one therapy failure. For ten days patients received the three-in-one BQT Pylera® therapy, in combination with a proton-pump inhibitor (PPI), decided at the choice of the investigator, at full dose bid. The eradication rate was calculated by intention-to-treat (ITT) and per-protocol (PP)analyses and 95% confidence intervals (CI) were calculated. Seventy-three patients were recruited, 41 females and 32 males (mean age 53.0±13.1 years). Fifty-five patients failed triple therapy with amoxicillin and clarithromycin and the remaining 18 received sequential therapy. Seventy-two patients consumed at least 90% of the capsules, while only one did not complete the therapy due to adverse events (nausea and diarrhea). By ITT analysis, BQT was successful in 62 subjects (eradication rate 84.9%, 95%CI 76.7–93.1%). By PP analysis, the eradication rate was 86.1% (95%CI 78.1–94.1%).Adverse events were observed in 14 subjects (20.5%).In conclusion, our report confirmed that BQT is effective as an empiric second-line regimen.

Abstract Background Alterations of the small-intestinal permeability (s-IP) might play an essential role in both diarrhoea-predominant IBS (D-IBS) and celiac disease (CD) patients. Our aims were to analyse in D-IBS patients the symptom profile along with the levels of urinary sucrose (Su), lactulose (La), mannitol (Ma), and circulating biomarkers (zonulin, intestinal fatty acid binding protein - I-FABP, and diamine oxidase - DAO) of the gastrointestinal (GI) barrier function. The pro-inflammatory interleukins 6 and 8 (IL-6 and IL-8), the plasma values of lipopolysaccharide (LPS), and Toll-like receptor 4 (TLR-4) were also investigated. Besides, these biomarkers were compared with those in CD and healthy controls (HC). Finally, comparisons were performed between D-IBS patients with [D-IBS(+)] and without [D-IBS(−)] increased s-IP according to normal or altered La/Ma ratio. Methods The study included 39 D-IBS patients, 32 CD patients, and 20 HC. GI permeability was assayed by high-performance liquid chromatography determination in the urine of Su and La/Ma ratio. ELISA kits assayed circulating concentrations of zonulin, I-FABP, DAO, IL-6, IL-8, LPS, and TLR-4. The Mann–Whitney or the Kruskal–Wallis with Dunn’s post-test was used to assess differences among the groups. Results As for the La/Ma ratio, %Su, and I-FABP levels, D-IBS patients were significantly different from CD, but not HC. IL-6 levels were significantly higher in CD than HC, whereas IL-8 levels were significantly higher in both D-IBS and CD patients than HC. By opposite, LPS, and TLR-4 concentrations did not differ significantly among the groups. When D-IBS patients were categorised according to normal or altered s-IP, D-IBS(+) patients had %La, %Su, I-FABP, and DAO levels significantly higher than D-IBS(−) ones. The inflammatory parameters and markers of bacterial translocation (namely, IL-6 and LPS) were significantly higher in D-IBS(+) patients than D-IBS(−) ones. Conclusions The present study suggests that two distinct D-IBS subtypes could be identified. The investigation of possible s-IP alterations (i.e., considering the La/Ma ratio) might be useful to assess better and categorise this heterogeneous D-IBS population. Trial registration NCT01574209. Registered March 2012. First recruitment started in April 2012.

Celiac disease (CD) is an immune-mediated enteropathy characterized by an increase in paracellular permeability. The improvements in barrier integrity have been related to changes in tight junction (TJ) structure as a consequence of modifications in TJ protein expression. Recently, also polyamines have been suggested to play a part in the control of intestinal permeability by modulating TJ and adherens junction (AJ) expressions.The present work investigated the protective role of Lactobacillus rhamnosus GG (L.GG) towards alterations of the paracellular permeability induced by Pepsin-Trypsin digested Gliadin (PTG) in Caco-2 cells.The results from this study clearly indicate that L.GG protects Caco-2 cells from PTG induced damage and, interestingly, the presence of cellular polyamines seems to be essential in the modulation of TJ and AJ protein expression exerted by this probiotic. On these bases, a role for L.GG as a dietary supplement to promote health also for CD patients could be hypothesized.

Stem cell plasticity is crucial for early embryo development and the differentiation of stem cells. Here, the authors show that the extracellular protein Cripto sustains mouse ESC self-renewal and maintains mouse EpiSC as well as human ESC pluripotency and controls the metabolic reprogramming in ESCs to EpiSC transition.

Antibiotic resistance has become an emerging problem for treating Helicobacter pylori (H. pylori) infection. Clarithromycin and levofloxacin are two key antibiotics used for its eradication. Therefore, we reviewed our experience with genotypic resistance analysis in stools to both clarithromycin and levofloxacin in the last four years to evaluate time trends, both in naive and failure patients. Patients collected a fecal sample using the THD fecal test device. Real-time polymerase chain reaction was performed to detect point mutations conferring resistance to clarithromycin (A2142C, A2142G, and A2143G in 23S rRNA) and levofloxacin (substitutions at amino acid position 87 and 91 of gyrA). One hundred and thirty-five naive patients were recruited between 2017–2020. Clarithromycin resistance was detected in 37 (27.4%). The time trend did not show any significant variation from 2017 to 2020 (p = 0.33). Primary levofloxacin resistance was found in 26 subjects (19.2%), and we observed a dramatic increase in rates from 2017 (10%) to 2018 (3.3%), 2019 (20%), and 2020 (37.8%). Ninety-one patients with at least one eradication failure were recruited. Secondary resistance to clarithromycin and levofloxacin was found in 59 (64.8%) and 45 patients (59.3%), respectively. In conclusion, our geographic area has a high risk of resistance to clarithromycin. There is also a progressive spreading of levofloxacin-resistant strains.

Formaldehyde (FA) is a general living and occupational pollutant, classified as carcinogenic for humans. Although genotoxicity is recognized as a FA mechanism of action, a potential contribution of epigenetic effects cannot be excluded. Therefore, aim of this review is to comprehensively assess possible epigenetic alterations induced by FA exposure in humans, animals, and cellular models. A systematic review of Pubmed, Scopus, and Isi Web of Science databases was performed. DNA global methylation changes were demonstrated in workers exposed to FA, and also in human bronchial cells. Histone alterations, i.e., the reduction in acetylation of histone lysine residues, in human lung cells were induced by FA. Moreover, a dysregulation of microRNA expression in human lung adenocarcinoma cells as well as in the nose, olfactory bulb and white blood cells of rodents and nonhuman primates was reported. Although preliminary, these findings suggest the role of epigenetic modifications as possible FA mechanisms of action that need deeper qualitative and quantitative investigation. This may allow to define the role of such alterations as indicators of early biological effect and the opportunity to include such information in future risk assessment and management strategies for public and occupationally FA-exposed populations.

miR-28-5p is downregulated in some tumor tissues in which it has been demonstrated to have tumor suppressor (TS) activity. Here, we demonstrate that miR-28-5p acts as a TS in prostate cancer (PCa) cells affecting cell proliferation/survival, as well as migration and invasion. Using the miRNA pull out assay and next generation sequencing, we collected the complete repertoire of miR-28-5p targets, obtaining a data set (miR-28-5p targetome) of 191 mRNAs. Filtering the targetome with TargetScan 7, PITA and RNA22, we found that 61% of the transcripts had miR-28-5p binding sites. To assign a functional value to the captured transcripts, we grouped the miR-28-5p targets into gene families with annotated function and showed that six transcripts belong to the transcription factor category. Among them we selected SREBF2, a gene with an important role in PCa. We validated miR-28-5p/SREBF2 interaction, demonstrating that SREBF2 inhibition affects almost all the tumor processes altered by miR-28-5p re-expression, suggesting that SREBF2 is an important mediator of miR-28-5p TS activity. Our findings support the identification of the targetome of cancer-related miRNAs as a tool to discover genes and pathways fundamental for tumor development, and potential new targets for anti-tumor therapy.

miR-28-5p is an intragenic miRNA which is underexpressed in several tumor types showing a tumor suppressor (TS) activity. Routinely, the known miR-28-5p targets are validated in specific tumor contexts but it is unclear whether these targets are also being regulated in other tumor types. To this end, we adopted the miRNA pull out assay to capture the miR-28-5p targets in DU-145 prostate cancer (PCa) cells. Firstly, we demonstrated that miR-28-5p acts as a TS-miRNA in PCa, affecting cell proliferation, survival, and apoptosis. Secondly, we evaluated the enrichment of the 10 validated miR-28-5p targets in the pull out sample. We showed that E2F6, TEX-261, MAPK1, MPL, N4BP1, and RAP1B but not BAG1, OTUB1, MAD2L1, and p21 were significantly enriched, suggesting that not all the miR-28-5p targets are regulated by this miRNA in PCa. We then verified whether the miR-28-5p-interacting targets were regulated by this miRNA. We selected E2F6, the most enriched target in the pull out sample, and demonstrated that miR-28-5p downregulated E2F6 at the protein level suggesting that our approach was effective. In general terms, these findings support the miRNA pull out assay as a useful method to identify context-specific miRNA targets.

microRNAs (miRNAs) are small non-coding RNAs that play an important role in the post- transcriptional regulation of gene expression. miRNAs are involved in the regulation of many biological processes such as differentiation, apoptosis and cell proliferation. miRNAs are expressed in embryonic, postnatal, and adult hearts and they have a key role in the regulation of gene expression during cardiovascular development and disease. Aberrant expression of miRNAs is associated with abnormal cardiac cell differentiation and dysfunction. Tbx5 is a member of the T-box gene family which acts as transcription factor involved in the vertebrate heart development. Alteration of Tbx5 level affects the expression of hundreds of genes. Haploinsufficiency and gene duplication of Tbx5 are at the basis of the cardiac abnormalities associated with Holt-Oram syndrome (HOS). Recent data indicate that miRNAs might be an important part of the regulatory circuit through which Tbx5 controls heart development. Using high-throughput technology we characterized genome-widely the miRNA and mRNA expression profiles in WT and Tbx5 depleted zebrafish embryos at two developmental time points, 24 and 48 hours post fertilization (hpf). We found that several miRNAs which are potential effectors of Tbx5 are differentially expressed, some of them are already known to be involved in cardiac development and functions, such as miR-30, miR-34, miR-190, miR-21. We performed an integrated analysis of miRNA expression data with gene expression profiles to refine computational target prediction approaches by means of the inversely correlation of miRNA-mRNA expressions. Interestingly these targets have roles in cardiac contractility, cardiomyocyte proliferation/apoptosis and valve formation which are crucial functions regulated by Tbx5. This approach allowed to discover complex regulatory circuits involving novel miRNAs and protein coding genes not considered before in the HOS such as miR-34a and miR-30 and their targets.

Since the establishment of commercial sharing economy services like Uber, Blablacar, Lyft, Airbnb, TaskRabbit, etc., the debate about the sharing economy and its effects on competition has generated lively discussions, which have too often dangerously departed from a debate based on objective (market) observation to evolve into a quarrel among the supporters and opponents of the online platforms. Undoubtedly, the peculiar features of these new firms’ business models create frictions with the traditional regulatory environment, which currently appears to be incapable of framing them into models and schemes typical of a previous economic phase, such as, for example, one-sided markets, no externalities, and competition mainly on price. Nevertheless, setting aside the more or less impromptu debate about the “social goodness” of these firms, we argue that competition enforcers should look at their effective market power. In fact, as the basic principles of competition law teach us, only when those firms have (more or less legitimate) significant market power, will they be subject to special responsibilities and to stringent restrictions and obligations. Toward this aim, it is first necessary to define the relevant market. And, immediately afterwards, to delimit firms’ market position. This, in turn, should help to assess their compliance with the competition rules and the obligations that they are – or rather that they should be – subjected to. This exercise is not an easy one because the traditional regulatory concepts and definitions do not seem to reflect the competition dynamics that characterise the new markets on which we are reflecting. In this paper we focus on a number of challenges that are posed by the sharing economy businesses, suggesting that they could be solved with the traditional competition instruments, although adapted to the peculiar features of the markets that are at stake. These include, among others, multi-sidedness and the presence of different externalities.

This paper focuses on the valuation and hedging of gas storage facilities, using a spot-based valuation framework coupled with a financial hedging strategy implemented with futures contracts. The contributions of this paper are two-fold. Firstly, we propose a model that unifies the dynamics of the futures curve and spot price, and accounts for the main stylized facts of the US natural gas market such as seasonality and the presence of price spikes in the spot market. Secondly, we evaluate the associated model risk, and show not only that the valuation is strongly dependent upon the dynamics of the spot price, but more importantly that the hedging strategy commonly used in the industry leaves the storage operator with significant residual price risk.

Genes and their expression regulation are among the key factors in the comprehension of the genesis and development of complex diseases. In this context, microRNAs (miRNAs) are post-transcriptional regulators that play an important role in gene expression since they are frequently deregulated in pathologies like cardiovascular disease and cancer. In vitro validation of miRNA--targets regulation is often too expensive and time consuming to be carried out for every possible alternative. As a result, a tool able to provide some criteria to prioritize trials is becoming a pressing need. Moreover, before planning in vitro experiments, the scientist needs to evaluate the miRNA-target genes interaction network. In this paper we describe the miRable method whose purpose is to identify new potentially relevant genes and their interaction networks associate to a specific pathology. To achieve this goal miRable follows a system biology approach integrating together general-purpose medical knowledge (literature, Protein-Protein Interaction networks, prediction tools) and pathology specific data (gene expression data). A case study on Prostate Cancer has shown that miRable is able to: 1) find new potential miRNA-targets pairs, 2) highlight novel genes potentially involved in a disease but never or little studied before, 3) reconstruct all possible regulatory subnetworks starting from the literature to expand the knowledge on the regulation of miRNA regulatory mechanisms.

See directly the article

The Italian journeys of Jean Mabillon (1685-1686) and Bernard de Montfaucon (1698-1701), monks of the Congregation of St. Maur and fathers of diplomatic and palaeography, had a significant role in the early modern advancement of studies on Medieval art and antiquities. As regards their acquisition of art-historical information and direct experience of monuments, the position of Italian erudites was relevant. This is particularly clear with Mabillon's surveys in churches, catacombs, archives and private collections made with the essential help of Italian scholars and through the exchanges of art-historical data between the French monks and several Italian colleagues, such as emerged from their correspondence. As a result, this article aims to illustrate this process and outline a context of mutual influences between French and Italian traditions of scholarship.

MicroRNAs are small noncoding RNAs that play an important role in the regulation of various biological processes through their interaction with cellular messenger RNAs. They are frequently dysregulated in cancer and have shown great potential as tissue-based markers for cancer classification and prognostication. microRNAs are also present in extracellular human body fluids such as serum, plasma, saliva, and urine. Most of circulating microRNAs are present in human plasma and serum cofractionate with the Argonaute2 (Ago2) protein. However, circulating microRNAs have been also found in membrane-bound vesicles such as exosomes. Since microRNAs circulate in the bloodstream in a highly stable, extracellular form, they may be used as blood-based biomarkers for cancer and other diseases. A knowledge base of extracellular circulating miRNAs is a fundamental tool for biomedical research. In this work, we present miRandola, a comprehensive manually curated classification of extracellular circulating miRNAs. miRandola is connected to miRò, the miRNA knowledge base, allowing users to infer the potential biological functions of circulating miRNAs and their connections with phenotypes. The miRandola database contains 2132 entries, with 581 unique mature miRNAs and 21 types of samples. miRNAs are classified into four categories, based on their extracellular form: miRNA-Ago2 (173 entries), miRNA-exosome (856 entries), miRNA-HDL (20 entries) and miRNA-circulating (1083 entries). miRandola is available online at: http://atlas.dmi.unict.it/mirandola/index.html.

Introduction: In addition to sterility testings for common bacteria, from 2006 on we have introduced in our laboratory sterility tests for mycobacteria on surgical instruments such as bronchoscope and lava-endoscope fluid used for their sterilization as well. Methods: Bronchology and Pneumology SUN departments, doing bronchoscopies, regularly send to our laboratory bronchoscopes washing fluids. Bronchology department also sends liquids used in lavaendoscopes. Our standard protocol consists of liquids inoculation directly on Lowenstein - Jensen (LJ) solid ground and on Middlebrook 7H9 liquid medium into Mgit test tubes, both produced by Becton Dickinson, within 42 days (1, 5, 6). Results: When growth of acid-alcohol resistant bacilli was detected, they were identified through probes or Accuprobe bioMérieux Inno- LIPA Mycobacteria by Innogenetics. All positivite results were related to M. Gordonae. As for the liquids examined, we found one positivite result in liquid medium in 2006 and none in 2007. On the contrary, in 2008 and the first 6 months of 2009, we have identified the following positive results: 2008 - 2009 (6m) LJ pos TOT 20 C. Lavaendoscope 8 V. 12 FBS We linked the positive findings on equipment with positivity for M. gordonae observed in patients undergoing bronchoscopy. Conclusions: Data analysis indicates within the period 2008-2009 we observed a recurring positivity for M. gordonae on equipment and therefore in some patients. On a careful evaluation, they showed no signs of clinical infection, also considering that this mycobacteria is usually a saprophyte (2, 3, 4). However, the protocol we adopted allowed us to recognize equipment contamination at birth and to urge fellow users to review sterilization protocols.

BACKGROUND: Chromosomal fragile sites are heritable specific loci especially prone to breakage. Some of them are associated with human genetic disorders and several studies have demonstrated their importance in genome instability in cancer. MicroRNAs (miRNAs) are small non-coding RNAs responsible of post-transcriptional gene regulation and their involvement in several diseases such as cancer has been widely demonstrated. The altered expression of miRNAs is sometimes due to chromosomal rearrangements and epigenetic events, thus it is essential to study miRNAs in the context of their genomic locations, in order to find significant correlations between their aberrant expression and the phenotype. PRINCIPAL FINDINGS: Here we use statistical models to study the incidence of human miRNA genes on fragile sites and their association with cancer-specific translocation breakpoints, repetitive elements, and CpG islands. Our results show that, on average, fragile sites are denser in miRNAs and also in protein coding genes. However, the distribution of miRNAs and protein coding genes in fragile versus non-fragile sites depends on chromosome. We find also a positive correlation between fragility and repeats, and between miRNAs and CpG islands. CONCLUSION: Our results show that the relationship between site fragility and miRNA density is far more complex than previously thought. For example, we find that protein coding genes seem to be following similar patterns as miRNAs, if considered their overall distribution. However, once we allow for differences at the chromosome level in our statistical analysis, we find that distribution of miRNA and protein coding genes in fragile sites is very different from that of miRNA. This is a novel result that we believe may help discover new potential correlations between the localization of miRNAs and their crucial role in biological processes and in the development of diseases.