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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.

Irritable bowel syndrome with diarrhea (IBS-D) is the most prevalent subtype of IBS, characterized by chronic gastrointestinal symptoms in the absence of identifiable pathological findings. This study aims to investigate the molecular mechanisms underlying IBS-D using transcriptomic data. By employing causal network inference methods, we identify key transcriptomic modules associated with IBS-D. Utilizing data from public databases and applying advanced computational techniques, we uncover potential biomarkers and therapeutic targets. Our analysis reveals significant molecular alterations that affect cellular functions, offering new insights into the complex pathophysiology of IBS-D. These findings enhance our understanding of the disease and may foster the development of more effective treatments.

Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD) affecting the gastrointestinal tract that can also cause extra-intestinal complications. Following exposure to the mRNA vaccine BNT162b2 (Pfizer-BioNTech) encoding the SARS-CoV-2 Spike (S) protein, some patients experienced a lack of response to the biological drug Adalimumab and a recrudescence of the disease. In CD patients in progression, resistant to considered biological therapy, an abnormal increase in intestinal permeability was observed, more often with a modulated expression of different proteins such as Aquaporin 8 (AQP8) and in tight junctions (e.g., ZO-1, Claudin1, Claudin2, Occludin), especially during disease flares. The aim of this study is to investigate how the SARS-CoV-2 vaccine could interfere with IBD therapy and contribute to disease exacerbation. We investigated the role of the SARS-CoV-2 Spike protein, transported by extracellular vesicles (EVs), and the impact of various EVs components, namely, exosomes (EXOs) and microvesicles (MVs), in modulating the expression of molecules involved in the exacerbation of CD, which remains unknown.

Many patients with irritable bowel syndrome (IBS) have a compromised intestinal barrier associated with low-grade inflammation. Polyunsaturated fatty acids (PUFAs) are potential mediators of inflammation: omega-6 PUFAs are pro-inflammatory, while omega-3 PUFAs are antioxidant and anti-inflammatory. Zonulin is a potential biomarker for small intestinal permeability (s-IP). This study investigated the relationship between PUFAs and gastrointestinal (GI) barrier integrity in IBS patients with predominant diarrhea (IBS-D). We evaluated GI barrier function indicators in the urine and bloodstream and erythrocyte membrane PUFA composition in 38 IBS-D patients (5 men, 33 women, 44.11 ± 1.64 years), categorized at baseline by fecal zonulin levels into high (≥107 ng/mL, H-FZ) and normal (n-3 PUFAs levels, and higher n-6/n-3 PUFAs and arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratios than N-FZ. After LFD, H-FZ patients showed significant increases in n-3 PUFAs levels; decreases in n-6 PUFAs, n-6/n-3 PUFAs and AA/EPA ratios; and improved s-IP. The n-6/n-3 PUFAs ratio positively correlated with fecal zonulin levels in all subjects. These findings highlight the relationship between PUFAs and the intestinal barrier, suggesting their role in IBS-D pathophysiology and confirming the positive effects of LFD in managing IBS-D.

Motor impairment is a common issue in stroke patients, often affecting the upper limbs. To this standpoint, robotic neurorehabilitation has shown to be highly effective for motor function recovery. Notably, Machine learning (ML) may be a powerful technique able to identify the optimal kind and intensity of rehabilitation treatments to maximize the outcomes. This retrospective observational research aims to assess the efficacy of robotic devices in facilitating the functional rehabilitation of upper limbs in stroke patients through ML models. Specifically, clinical scales, such as the Fugl-Meyer Assessment (A-D) (FMA), the Frenchay Arm Test (FAT), and the Barthel Index (BI), were used to assess the patients’ condition before and after robotic therapy. The values of these scales were predicted based on the patients’ clinical and demographic data obtained before the treatment. The findings showed that ML models have high accuracy in predicting the FMA, FAT, and BI, with R-squared (R2) values of 0.79, 0.57, and 0.74, respectively. The findings of this study suggest that integrating ML into robotic therapy may have the capacity to establish a personalized and streamlined clinical practice, leading to significant improvements in patients’ quality of life and the long-term sustainability of the healthcare system.

A stroke represents a significant medical condition characterized by the sudden interruption of blood flow to the brain, leading to cellular damage or death. The impact of stroke on individuals can vary from mild impairments to severe disability. Treatment for stroke often focuses on gait rehabilitation. Notably, assessing muscle activation and kinematics patterns using electromyography (EMG) and stereophotogrammetry, respectively, during walking can provide information regarding pathological gait conditions. The concurrent measurement of EMG and kinematics can help in understanding disfunction in the contribution of specific muscles to different phases of gait. To this aim, complexity metrics (e.g., sample entropy; approximate entropy; spectral entropy) applied to EMG and kinematics have been demonstrated to be effective in identifying abnormal conditions. Moreover, the conditional entropy between EMG and kinematics can identify the relationship between gait data and muscle activation patterns. This study aims to utilize several machine learning classifiers to distinguish individuals with stroke from healthy controls based on kinematics and EMG complexity measures. The cubic support vector machine applied to EMG metrics delivered the best classification results reaching 99.85% of accuracy. This method could assist clinicians in monitoring the recovery of motor impairments for stroke patients.

A very low calorie ketogenic diet (VLCKD) impacts host metabolism in people marked by an excess of visceral adiposity, and it affects the microbiota composition in terms of taxa presence and relative abundances. As a matter of fact, there is little available literature dealing with microbiota differences in obese patients marked by altered intestinal permeability. With the aim of inspecting consortium members and their related metabolic pathways, we inspected the microbial community profile, together with the set of volatile organic compounds (VOCs) from untargeted fecal and urine metabolomics, in a cohort made of obese patients, stratified based on both normal and altered intestinal permeability, before and after VLCKD administration. Based on the taxa relative abundances, we predicted microbiota-derived metabolic pathways whose variations were explained in light of our cohort symptom picture. A totally different number of statistically significant pathways marked samples with altered permeability, reflecting an important shift in microbiota taxa. A combined analysis of taxa, metabolic pathways, and metabolomic compounds delineates a set of markers that is useful in describing obesity dysfunctions and comorbidities.

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.

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with EGFR–tyrosine kinase inhibitors (TKIs) inevitably develop resistance through several biological mechanisms. However, little is known on the molecular mechanisms underlying acquired resistance to suboptimal EGFR-TKI doses, due to pharmacodynamics leading to inadequate drug exposure. To evaluate the effects of suboptimal EGFR-TKI exposure on resistance in NSCLC, we obtained HCC827 and PC9 cell lines resistant to suboptimal fixed and intermittent doses of gefitinib and compared them to cells exposed to higher doses of the drug. We analyzed the differences in terms of EGFR signaling activation and the expression of epithelial–mesenchymal transition (EMT) markers, whole transcriptomes byRNA sequencing, and cell motility. We observed that the exposure to low doses of gefitinib more frequently induced a partial EMT associated with an induced migratory ability, and an enhanced transcription of cancer stem cell markers, particularly in the HCC827 gefitinib-resistant cells. Finally, the HCC827 gefitinib-resistant cells showed increased secretion of the EMT inducer transforming growth factor (TGF)-β1, whose inhibition was able to partially restore gefitinib sensitivity. These data provide evidence that different levels of exposure to EGFR-TKIs in tumor masses might promote different mechanisms of acquired resistance.

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.

Irritable bowel syndrome (IBS) involves low-grade mucosal inflammation. Among the various approaches capable of managing the symptoms, physical activity is still under investigation. Despite its benefits, it promotes oxidative stress and inflammation. Mitochondria impacts gut disorders by releasing damage-associated molecular patterns, such as cell-free mtDNA (cf-mtDNA), which support inflammation. This study evaluated the effects of a 12-week walking program on the cf-mtDNA and DNase in 26 IBS and 17 non-IBS subjects. Pro- and anti-inflammatory cytokines were evaluated by ELISA. Digital droplet PCR was used to quantify cf-mtDNA; DNase activity was assessed using a single radial enzyme diffusion assay. PCR-RFLP was used to genotype DNASE1 rs1053874 SNP. Significantly lower IL-10 levels were found in IBS than in non-IBS individuals. Exercise reduced cf-mtDNA in non-IBS subjects but not in IBS patients. DNase activity did not correlate with the cf-mtDNA levels in IBS patients post-exercise, indicating imbalanced cf-mtDNA clearance. Different rs1053874 SNP frequencies were not found between groups. The study confirms the positive effects of regular moderate-intensity physical activity in healthy subjects and its role in cf-mtDNA release and clearance. Walking alone might not sufficiently reduce subclinical inflammation in IBS, based on imbalanced pro- and anti-inflammatory molecules. Prolonged programs are necessary to investigate their effects on inflammatory markers in IBS.

Natural compounds like flavonoids preserve intestinal mucosal integrity through their antioxidant, anti-inflammatory, and antimicrobial properties. Additionally, some flavonoids show prebiotic abilities, promoting the growth and activity of beneficial gut bacteria. This study investigates the protective impact of Lens culinaris extract (LE), which is abundant in flavonoids, on intestinal mucosal integrity during LPS-induced inflammation. Using Caco-2 cells as a model for the intestinal barrier, the study found that LE did not affect cell viability but played a cytoprotective role in the presence of LPS. LE improved transepithelial electrical resistance (TEER) and tight junction (TJ) protein levels, which are crucial for barrier integrity. It also countered the upregulation of pro-inflammatory genes TRPA1 and TRPV1 induced by LPS and reduced pro-inflammatory markers like TNF-α, NF-κB, IL-1β, and IL-8. Moreover, LE reversed the LPS-induced upregulation of AQP8 and TLR-4 expression. These findings emphasize the potential of natural compounds like LE to regulate the intestinal barrier and reduce inflammation’s harmful effects on intestinal cells. More research is required to understand their mechanisms and explore therapeutic applications, especially for gastrointestinal inflammatory conditions.

A healthy intestinal permeability facilitates the selective transport of nutrients, metabolites, water, and bacterial products, involving cellular, neural, hormonal, and immune factors. An altered intestinal permeability indicates pathologic phenotypes and is associated with the exacerbation of obesity and related comorbidities. To investigate the impact of altered permeability in obese patients undergoing a calorie-restrictive dietary regimen (VLCKD), we collected urinary and fecal samples from obese patients with both normal and altered permeability (determined based on the lactulose/mannitol ratio) before and after treatment. The analysis of volatile organic compounds (VOCs) aids in understanding the metabolites produced by the intestinal microbiota in this unique ecological niche. Furthermore, we examined clinical and anthropometric variables from the cohort and compared them to significant VOC panels. Consequently, we identified specific markers in the metabolomics data that differentiated between normal and altered profiles before and after the diet. These markers indicated how the variable contribution specifically accounted for interleukins and lipopolysaccharides (LPS). The targeted metabolomics experiment detected no differences in measured short-chain fatty acids (SCFA). In summary, our study evaluated metabolomic markers capable of distinguishing low-grade inflammation conditions, exacerbated in more advanced stages of obesity with altered intestinal permeability.

Adolescent idiopathic scoliosis (AIS) is a lateral, rotated curvature of the spine. It is a 3-dimensional deformity that arises in otherwise healthy children at or around puberty. AIS is the most common form of scoliosis in the pediatric population. The etiology is multifactorial, including genetic and environmental factors. The incidence is roughly equal between males and females, while there is a higher risk of progression in females. Guidelines for AIS treatment identify three levels of treatment: observation, physiotherapy scoliosis-specific exercises, and braces. In this paper, we carried out a review of the scientific literature about the indication and success rates of the braces provided for free by the National Health Service in Italy (SSN). Despite a general consensus on the efficacy of rigid bracing treatment and its use in AIS, an important heterogeneity about the treatment is present in the scientific literature, demonstrating a high degree of variability. The overall success rate of the braces provided by the SSN is high, suggesting an important therapeutic role in the treatment of AIS. Robust guidelines are needed to ensure uniform and effective treatments.

Overweight and obesity have been suggested as significant factors in irritable bowel syndrome (IBS) development. However, the relationship between overweight/obesity and IBS is unclear. It is known that a modified intestinal barrier, especially the permeability of the small intestine (s-IP), can play a significant role in the pathogenesis of both obesity and IBS. Moreover, dietary interventions are essential for treating both pathologies. We evaluated the gastrointestinal (GI) symptoms and the urinary and circulating markers of GI barrier function and integrity, the markers of intestinal dysbiosis and bacterial translocation, in 40 IBS patients with predominant diarrhea (IBS-D) (32 females and 8 males; mean age = 43.5 ± 1.4 years), categorized using their Body Mass Index levels as normal (NW) and overweight (OW). Evaluations were performed before and after 12 weeks of a Low FODMAP Diet (LFD). At the baseline, OW patients showed a significantly higher s-IP than NW. After an LFD, a significant improvement of s-IP in OW patients occurred, along with a significant decrease in markers of epithelial integrity and bacterial translocation. Our findings highlight the close relationship between overweight and the intestinal barrier and support their involvement in IBS-D pathophysiology. Furthermore, the positive role of an LFD in managing overweight IBS-D was highlighted.

The aim of this study is to evaluate the effectiveness of electrosuit therapy in the clinical treatment of children with Cerebral Palsy, focusing on the effect of the therapy on spasticity and trunk control. Moreover, the compliance of caregivers with respect to the use of the tool was investigated. During the period ranging from 2019 to 2022, a total of 26 children (18 M and 8 F), clinically stable and affected by CP and attending the Neurorehabilitation Unit of the “Padre Pio Foundation and Rehabilitation Centers”, were enrolled in this study. A subset of 12 patients bought or rented the device; thus, they received the administration of the EMS-based therapy for one month, whereas the others received only one-hour training to evaluate the feasibility (by the caregivers) and short-term effects. The Gross Motor Function Classification System was utilized to evaluate gross motor functions and to classify the study sample, while the MAS and the LSS were employed to assess the outcomes of the EMS-based therapy. Moreover, between 80% and 90% of the study sample were satisfied with the safety, ease of use, comfort, adjustment, and after-sales service. Following a single session of electrical stimulation with EMS, patients exhibited a statistically significant enhancement in trunk control. For those who continued this study, the subscale of the QUEST with the best score was adaptability (0.74 ± 0.85), followed by competence (0.67 ± 0.70) and self-esteem (0.59 ± 0.60). This study investigates the impact of the employment of the EMS on CP children’s ability to maintain trunk control. Specifically, after undergoing a single EMS session, LSS showed a discernible improvement in children’s trunk control. In addition, the QUEST and the PIADS questionnaires demonstrated a good acceptability and satisfaction of the garment by the patients and the caregivers.

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.

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.

Colorectal cancer (CRC) is one of the leading causes of mortality for cancer in industrialized countries. The link between diet and CRC is well-known, and presumably CRC is the type of cancer which is most influenced by dietary habits. In Western countries, an inadequate dietary intake of fibers is endemic, and this could be a driving factor in the increase of CRC incidence. Indeed, several epidemiologic studies have elucidated an inverse relationship between daily fiber intake and risk of CRC. Long-term prognosis in CRC survivors is also dependent on dietary fibers. Several pathogenetic mechanisms may be hypothesized. Fibers may interfere with the metabolism of bile acids, which may promote colon carcinogenesis. Further, fibers are often contained in vegetables which, in turn, contain large amounts of antioxidant agents like resveratrol, polyphenols, or phytoestrogens. Moreover, fibers can be digested by commensal flora, thus producing compounds such as butyrate, which exerts an antiproliferative effect. Finally, fibers may modulate gut microbiota, whose composition has shown to be associated with CRC onset. In this regard, dietary interventions based on high-fiber-containing diets are ongoing to prevent CRC development, especially in patients with high potential for this type of tumor. Despite the fact that outcomes are preliminary, encouraging results have been observed.

Several recent studies deepened the strong connection between gut microbiota and obesity. The effectiveness of the very-low-calorie ketogenic diet (VLCKD) has been measured in terms of positive impact on the host homeostasis, but little is known of the modification exerted on the intestinal metabolome. To inspect this complex relationship, we analyzed both fecal and urinary metabolome in terms of volatile organic compounds (VOCs) by the GC-MS method in 25 obese patients that were under VLCKD for eight weeks. Partial least square discriminant analysis evidenced specific urinary and fecal metabolites whose profile can be considered a signature of a partial restore toward the host eubiosis. Specifically, among various keystone VOCs, the decreased concentration of four statistically significant fecal esters (i.e., propanoic acid pentyl ester, butanoic acid hexyl ester, butanoic acid pentyl ester, and pentanoic acid butyl ester) supports the positive effect of VLCKD treatment. Our pilot study results suggest a potential positive effect of VLCKD intervention affecting fecal and urinary volatilome profiles from obese patients. Meta-omics techniques including the study of genes and transcripts will help in developing new interventions useful in preventing or treating obesity and its associated health problems.

Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing. In this review, we describe the correlation status between channelopathies and FGIDs. Different findings are available. Among others, mutations in the ABCC7/CFTR gene have been described as a cause of constipation and diarrhea. Mutations of the SCN5A gene are instead associated with irritable bowel syndrome. In contrast, mutations of the TRPV1 and TRPA genes of the transient receptor potential (TRP) superfamily manifest hypersensitivity and visceral pain in sensory nerves. Recently, mice and humans affected by Cantu syndrome (CS), which is associated with the mutations of the KCNJ8 and ABCC9 genes encoding for the Kir6.1 and SUR2 subunits, showed dysfunction of contractility throughout the intestine and death in the mice after the weaning on solid food. The discovery of a correlation between channelopathies and FIGD opens new avenues for discovering new direct drug targets for specific channelopathies, leading to significant implications for diagnosing and treating functional GI diseases.

Electrical stimulation through surface electrodes is a non-invasive therapeutic technique used to improve voluntary motor control and reduce pain and spasticity in patients with central nervous system injuries. The Exopulse Mollii Suit (EMS) is a non-invasive full-body suit with integrated electrodes designed for self-administered electrical stimulation to reduce spasticity and promote flexibility. The EMS has been evaluated in several clinical trials with positive findings, indicating its potential in rehabilitation. This review investigates the effectiveness of the EMS for rehabilitation and its acceptability by patients. The literature was collected through several databases following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Positive effects of the garment on improving motor functions and reducing spasticity have been shown to be related to the duration of the administration period and to the dosage of the treatment, which, in turn, depend on the individual’s condition and the treatment goals. Moreover, patients reported wellbeing during stimulation and a muscle-relaxing effect on the affected limb. Although additional research is required to determine the efficacy of this device, the reviewed literature highlights the EMS potential to improve the motor capabilities of neurological patients in clinical practice.

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.

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.

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.