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Abstract MP0250 is a designed ankyrin repeat protein that specifically inhibits both vascular endothelial growth factor A (VEGF‐A) and hepatocyte growth factor (HGF), aiming at potentiating cancer therapy by disrupting the tumour microenvironment. Encouraging results from a phase 1 trial of MP0250 in patients with solid tumours prompted further investigation in multiple myeloma (MM) as both MP0250 targets are reported to be drivers of MM pathogenesis. In this open‐label, single‐arm phase 1b/2 study (NCT03136653) in patients with proteasome inhibitor‐ and/or immunomodulatory drug‐relapsed or refractory MM, MP0250 was administered every 3 weeks with standard bortezomib/dexamethasone regimen. Thirty‐three patients received at least one dose of MP0250. The most frequent treatment‐related adverse events were arterial hypertension (58.1%), thrombocytopenia (32.3%), proteinuria (29.0%) and peripheral oedema (19.4%). Of the 28 patients evaluable for response (median age: 60 [range 44–75]), nine achieved at least partial response, corresponding to an overall response rate of 32.1% (95% confidence interval [CI]: 17.9%, 50.7%), with a median duration of response of 8 months (95% CI 5–NR). An additional three patients achieved minimal response and nine stable diseases as the best overall response. Overall median progression‐free survival was 4.2 months (95% CI 1.9–7.1). These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.

Abstract Background Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. Methods Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. Results mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. Limitations The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. Conclusions The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

Abstract The dysregulation of miRNAs in lung cancer has been extensively documented, with specific miRNAs acting as both tumor suppressors and oncogenes, depending on their target genes. Recent research has unveiled the regulatory roles of miRNAs in key metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, fatty acid metabolism, and autophagy, which collectively contribute to the aberrant energy metabolism characteristic of cancer cells. Furthermore, miRNAs are increasingly recognized as critical modulators of the tumor microenvironment, impacting immune response and angiogenesis. This review embarks on a comprehensive journey into the world of miRNAs, unraveling their multifaceted roles, and more notably, their emerging significance in the context of cancer, with a particular focus on lung cancer. As we navigate this extensive terrain, we will explore the fascinating realm of miRNA-mediated metabolic rewiring, a phenomenon that plays a pivotal role in the progression of lung cancer and holds promise in the development of novel therapeutic strategies.

ABSTRACT: The microbiota of a cheese play a critical role in influencing its sensory and physicochemical properties. In this study, traditional Apulian Caciocavallo cheeses coming from 4 different dairies in the same area and produced following standardized procedures were examined, as well as the different bulk milks and natural whey starter (NWS) cultures used. Moreover, considering the cheese wheels as the blocks of Caciocavallo cheeses as whole, these were characterized at different layers (i.e., core, under-rind, and rind) of the block using a multi-omics approach. In addition to physical-chemical characterization, culturomics, quantitative PCR, metagenomics, and metabolomics analysis were carried out after salting and throughout the ripening time (2 mo) to investigate major shifts in the succession of the microbiota and flavor development. Culture-dependent and 16S rRNA metataxonomics results clearly clustered samples based on microbiota biodiversity related to the production dairy plant as a result of the use of different NWS or the intrinsic conditions of each production site. At the beginning of the ripening, cheeses were dominated by Lactobacillus, and in 2 dairies (Art and SdC), Streptococcus genera were associated with the NWS. The analysis allowed us to show that although the diversity of identified genera did not change significantly between the rind, under-rind, and core fractions of the same samples, there was an evolution in the relative abundance and absolute quantification, modifying and differentiating profiles during ripening. The real-time PCR, also known as quantitative or qPCR, mainly differentiated the temporal adaptation of those species originating from bulk milks and those provided by NWS. The primary starters detected in NWS and cheeses contributed to the high relative concentration of 1-butanol, 2-butanol, 2-heptanol, 2-butanone, acetoin, delta-dodecalactone, hexanoic acid ethyl ester, octanoic acid ethyl ester, and volatile free fatty acids during ripening, whereas cheeses displaying low abundances of Streptococcus and Lactococcus (dairy Del) had a lower total concentration of acetoin compared with Art and SdC. However, the subdominant strains and nonstarter lactic acid bacteria present in cheeses are responsible for the production of secondary metabolites belonging to the chemical classes of ketones, alcohols, and organic acids, reaffirming the importance and relevance of autochthonous strains of each dairy plant although only considering a delimited production area.

Purpose: Arts-integration is a promising approach to building students' abilities to create and critique arguments with data, also known as informal inferential reasoning (IIR). However, differences in disciplinary practices and routines, as well as school organization and culture, can pose barriers to subject integration. The purpose of this study is to describe synergies and tensions between data science and the arts, and how these can create or constrain opportunities for learners to engage in IIR. Design/methodology/approach: The authors co-designed and implemented four arts-integrated data literacy units with 10 teachers of arts and mathematics in middle school classrooms from four different schools in the USA. The data include student-generated artwork and their written rationales, and interviews with teachers and students. Through maximum variation sampling, the authors identified examples from the data to illustrate disciplinary synergies and tensions that appeared to support different IIR processes among students. Findings: Aspects of artistic representation, including embodiment, narrative and visual image; and aspects of the culture of arts, including an emphasis on personal experience, the acknowledgement of subjectivity and considerations for the audience's perspective, created synergies and tensions that both offered and hindered opportunities for IIR (i.e. going beyond data, using data as evidence and expressing uncertainty). Originality/value: This study answers calls for humanistic approaches to data literacy education. It contributes an interdisciplinary perspective on data literacy that complements other context-oriented perspectives on data science. This study also offers recommendations for how designers and educators can capitalize on synergies and mitigate tensions between domains to promote successful IIR in arts-integrated data literacy education.

The Anglo-Arabian horse breed (AA) is the result of crossing between Thoroughbred and Arabian horses renowned for versatility in show-jumping and racing. Southwest France and Sardinia in Italy are considered the historical nucleus of European AA breeding. Since little is known on genetic variability in the AA breed, especially those bred in the Sardinia region, this study investigates: i) inbreeding levels via pedigree and SNP genotyping; ii) runs of homozygosity (ROH) and selection signatures; iii) effective population size; and iv) distinctiveness of AA compared to Arabian and Thoroughbred horses. The ROH revealed an excessive amount of homozygosity, with a high kurtosis value observed in several chromosomes and an average inbreeding based on ROH of 21.1%. This latter value is higher compared to what was found based on pedigree data, highlighting the importance of complete pedigree records when estimating inbreeding based on genealogical data. The genomic inbreeding in AA horses was higher compared to other Italian horse breeds but lower than what was found in pure Thoroughbred and Arabian horses. This result suggests that the selection process for AA horses, may have prioritised racing ability over breed preservation which is the main goal in most local Italian breeds. The reduction in effective population size found in the latest 20 generations corroborates the potential presence of genetic diversity reduction due to selection in the AA breed. Remarkably, a large ROH island was identified on ECA17, which overlapped with two QTLs associated with racing performance.

Abstract Background Goats were domesticated in the Fertile Crescent about 10,000 years before present (YBP) and subsequently spread across Eurasia and Africa. This dispersal is expected to generate a gradient of declining genetic diversity with increasing distance from the areas of early livestock management. Previous studies have reported the existence of such genetic cline in European goat populations, but they were based on a limited number of microsatellite markers. Here, we have analyzed data generated by the AdaptMap project and other studies. More specifically, we have used the geographic coordinates and estimates of the observed (Ho) and expected (He) heterozygosities of 1077 European, 1187 African and 617 Asian goats belonging to 38, 43 and 22 different breeds, respectively, to find out whether genetic diversity and distance to Ganj Dareh, a Neolithic settlement in western Iran for which evidence of an early management of domestic goats has been obtained, are significantly correlated. Results Principal component and ADMIXTURE analyses revealed an incomplete regional differentiation of European breeds, but two genetic clusters representing Northern Europe and the British-Irish Isles were remarkably differentiated from the remaining European populations. In African breeds, we observed five main clusters: (1) North Africa, (2) West Africa, (3) East Africa, (4) South Africa, and (5) Madagascar. Regarding Asian breeds, three well differentiated West Asian, South Asian and East Asian groups were observed. For European and Asian goats, no strong evidence of significant correlations between Ho and He and distance to Ganj Dareh was found. In contrast, in African breeds we detected a significant gradient of diversity, which decreased with distance to Ganj Dareh. Conclusions The detection of a genetic cline associated with distance to the Ganj Dareh in African but not in European or Asian goat breeds might reflect differences in the post-domestication dispersal process and subsequent migratory movements associated with the management of caprine populations from these three continents.

Abstract We study substructures of the Weyl group of conformal transformations of the metric of (pseudo)Riemannian manifolds. These substructures are identified by differential constraints on the conformal factors of the transformations which are chosen such that their composition is associative. Mathematically, apart from rare exceptions, they are partial associative groupoids, not groups, so they do not have an algebra of infinitesimal transformations, but this limitation can be partially circumvented using some of their properties cleverly. We classify and discuss the substructures with two-derivatives differential constraints, the most famous of which being known as the harmonic or restricted Weyl group in the physics literature, but we also show the existence of a lightcone constraint which realizes a proper subgroup of the Weyl group. We then show the physical implications that come from invariance under the two most important substructures, concentrating on classical properties of the energy-momentum tensor and a generalization of the quantum trace anomaly. We also elaborate further on the harmonic substructure, which can be interpreted as partial gauge fixing of full Weyl invariance using BRST methods. Finally, we discuss how to construct differential constraints of arbitrary higher-derivative order and present, as examples, generalizations involving scalar constraints with four and six derivatives.

Abstract Immune cell-derived extracellular vesicles (EV) affect tumor progression and hold promise for therapeutic applications. Eosinophils are major effectors in Th2-related pathologies recently implied in cancer. Here, we evaluated the anti-tumor activities of eosinophil-derived EV following activation with the alarmin IL-33. We demonstrate that IL-33-activated mouse and human eosinophils produce higher quantities of EV with respect to eosinophils stimulated with IL-5. Following incorporation of EV from IL-33-activated eosinophils (Eo33-EV), but not EV from IL-5-treated eosinophils (Eo5-EV), mouse and human tumor cells increased the expression of cyclin-dependent kinase inhibitor (CDKI)-related genes resulting in cell cycle arrest in G0/G1, reduced proliferation and inhibited tumor spheroid formation. Moreover, tumor cells incorporating Eo33-EV acquired an epithelial-like phenotype characterized by E-Cadherin up-regulation, N-Cadherin downregulation, reduced cell elongation and migratory extent in vitro, and impaired capacity to metastasize to lungs when injected in syngeneic mice. RNA sequencing revealed distinct mRNA signatures in Eo33-EV and Eo5-EV with increased presence of tumor suppressor genes and enrichment in pathways related to epithelial phenotypes and negative regulation of cellular processes in Eo33-EV compared to Eo5-EV. Our studies underscore novel IL-33-stimulated anticancer activities of eosinophils through EV-mediated reprogramming of tumor cells opening perspectives on the use of eosinophil-derived EV in cancer therapy.

Abstract Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E2GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and E2GFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy.

IntroductionPrevalence of oral, metabolic, circulatory, and nutritional diseases has tended to increase globally. As these diseases have common contributing factors, such as unhealthy diets, evaluating their epidemiological trends and the relation between them is relevant. In Colombia, the Ministry of Health records the frequency of consultation for these diseases through the Integrated Social Protection Information System. It facilitates the evaluation of their epidemiological behavior at the population level.AimTo analyze and correlate the burden of oral diseases (caries and periodontitis) with respect to nutritional, circulatory and metabolic pathologies, as well as their relationships with socioeconomic indices in Colombian regions from 2016 to 2023.MethodsThis study analyzes retrospective data collected between 2016 and 2023 by the National Health Registry in Colombia (SISPRO) according to the ICD-10. Sociodemographic data and the number of disease consultations were extracted. The number of consultations for oral diseases was correlated with systemic pathologies, socioeconomic indices through the Spearman test. Associations were explored via multiple linear regressions. A Principal Component Analyses (PCA) was conducted to identify patterns between socioeconomic, oral and systemic disease variables, as well as to reduce the complexity of the analysis by creating clusters that capture the greatest possible variability in the data.ResultsThe average number of consultations per biennium was 24.550.435 being the highest number for 2018–2019. The highest percentage of consultations was related to extensive caries, followed by chronic gingivitis. Moreover, consultations for oral diseases were found to correlate with systemic pathologies. All socioeconomic indices were associated with caries and/or periodontal diseases. This study is the first in Colombia that uses national data on diagnoses assigned to medical and dental consultations. PCA revealed a clustering pattern of pathologies suggesting that they are highly associated one to each other.ConclusionCorrelations between consultations for oral and systemic diseases stratified by life cycle and socioeconomic indices highlight the importance of conducting epidemiological and public health characterizations and their associations. Identifying these factors is imperative in the prevention and management of both diseases.

IntroductionVaccination practice is a well-known individual protective measure for biological risk in healthcare. During the COVID-19 pandemic vaccine hesitancy has grown among healthcare workers (HCWs). The study aims to investigate how vaccine hesitancy influences the psychological burden experienced by healthcare workers.MethodsThis study aimed to explore attitudes of HCWs in acceptance or refusal of vaccinations related to the risk of psychological impairment (PI) and describe the associated occupational factors, during the seasonal flu/COVID-19 vaccination campaign of 2022–2023. 302 HCWs were enrolled in the study. A questionnaire was self-administered, including two scales on the risk of psychological impairment (Psychological Injury Risk Indicator, PIRI) and vaccine hesitancy (Adult Vaccine Hesitancy Scale, AVHS).ResultsPIRI scores revealed that 29.8% of participants were at risk of PI. Differences in sex, age, occupational seniority, professional category, and night shifts were found between HCWs at risk of PI and those not at risk. Females registered a four-fold higher risk than males (85.6% vs. 14.4%, χ2 = 4.450, p

Summary: Autism spectrum disorder (ASD) affects social interaction and communication. Emerging evidence links ASD to gut microbiome alterations, suggesting that microbial composition may play a role in the disorder. This study employs explainable artificial intelligence (XAI) to examine the contributions of individual microbial species to ASD. By using local explanation embeddings and unsupervised clustering, the research identifies distinct ASD subgroups, underscoring the disorder’s heterogeneity. Specific microbial biomarkers associated with ASD are revealed, and the best classifiers achieved an AU-ROC of 0.965 ± 0.005 and an AU-PRC of 0.967 ± 0.008. The findings support the notion that gut microbiome composition varies significantly among individuals with ASD. This work’s broader significance lies in its potential to inform personalized interventions, enhancing precision in ASD management and classification. These insights highlight the importance of individualized microbiome profiles for developing tailored therapeutic strategies for ASD.

Abstract We study multifield extensions of Reggeon Field Theory (also equivalent to Directed Percolation model) at criticality in the perturbative ϵ-expansion below the upper critical dimension D c = 4 at one loop, for the special case when all fields have the same scale (anomalous) dimensions. Analyzing all the fixed points of the renormalization group flow for N = 2 flavors and some for N = 3, we find scale invariant solutions which are characterized by specific emergent global symmetries of the interacting potential. We also study two infinite families as a function of N having ℤ N and S N+1 symmetries.

Autosomal polymorphisms (STRs) or Y-Chromosome polymorphisms (Y-STRs) are usually used for the study and deconvolution of mixed DNA profiles in forensic genetics, accompanying data interpretation with biostatistical evaluations (e.g., RMP, RMNE, LR). Sometimes, however, some mixed DNA profiles are so complex that autosomal and Y markers are not sufficient for correct discrimination and identification. In this work is reported a robbery case in which the analysis of the polymorphic markers of the X Chromosome (X-STRs) was applied to the mixed profiles obtained from the traces. This falls outside the classic use of the X-STRs. Indeed, the aim of the authors is to encourage the usage of X-STRs not only in parental relationships, but also in pure forensic cases for interpreting complex mixed DNA profiles, since their application in case resolution could be more decisive than autosomal STRs and Y-STRs.

Abstract Environmental concerns have pushed toward electrified technologies for off‐road vehicle actuations that can lower greenhouse gas emissions and reduce energy consumption. Replacing a central diesel engine with a dedicated electric machine (EM) as a prime mover for the hydraulic supply offers several opportunities for so‐called ePumps (aka electric‐driven pumps) to maximize energy efficiency and limit the usage of electric materials. This paper discusses the impact of different choices for the ePumps architecture (i.e., fixed vs. variable displacement pump; variable speed vs. fixed speed electrical machine), and on their main design parameters in terms of size and efficiency. Although the procedure followed in the study could be extended to different types of electric and hydraulic units, the paper particularly considers ePumps based on permanent magnet synchronous machines combined with axial piston machines. The importance of properly considering the ePump drive cycle and its cooling requirements is taken into account while addressing energy efficiency, mass, and overall compactness of the solution. The results show that an ePump based on a variable displacement pump, when compared to fixed displacement ePumps, reduces the electrical machine size both in volume and mass up to 40%, when the high‐pressure demand is not combined with high flow rate demand, thus decreasing the cost of the EM. In all drive cycles, the variable speed EM–fixed displacement pump architecture has a higher efficiency, ranging from 1% to 5%, compared to the case of fixed speed EM–variable displacement pump. Finally, the paper compares the advantages and shortcomings of each ePump architecture presented, based on representative drive cycles.

Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed to prevent or treat various intestinal and extraintestinal diseases. However, full-scale clinical trials examining hookworm therapy are limited by the inability to scale-up the production of hookworm larvae to infect sufficient numbers of patients. With the aim of overcoming this challenge, this study infected four healthy individuals with hookworm larvae that had been reanimated from cryopreserved eggs to examine their viability and immunogenicity. We demonstrate that reanimated cryopreserved hookworm larvae establish a viable hookworm infection and elicit a similar immune response to larvae cultured from fresh stool. Furthermore, a refined understanding of the therapeutic mechanisms of hookworm is imperative to determine which diseases to target with hookworm therapy. To investigate potential therapeutic mechanisms, this study assessed changes in the immune cells, microbiome, and plasma metabolome in the four healthy individuals infected with cryopreserved hookworm larvae and another nine individuals infected with larvae cultured from freshly obtained stool. We identified potential immunoregulatory mechanisms by which hookworm may provide a beneficial effect on its host, including increased expression of CTLA-4 on regulatory T cells (Tregs) and upregulation of tryptophan metabolism. Furthermore, we found that a participant’s baseline microbiome predicted the severity of symptoms and intestinal inflammation experienced during a controlled hookworm infection. In summary, our findings demonstrate the feasibility of full-scale clinical trials examining hookworm therapy by minimizing the reliance on human donors and optimizing the culturing process, thereby enabling viable hookworm larvae to be mass-produced and enabling on-demand inoculation of patients. Furthermore, this study provides insights into the complex interactions between helminths and their host, which could inform the development of novel therapeutic strategies.

ABSTRACTIL-37 is a member of the IL-1 superfamily exerting anti-inflammatory functions in a number of diseases. Extracellular IL-37 triggers the inhibitory receptor IL-1R8 that is known to regulate different NK cell pathways and functional activities including their anti-tumor effect. However, the effect of IL-37 on human NK cell functions is still to be unveiled. This study aimed to investigate the functional effect of IL-37 in human NK cells activated with IL-15. We found that IL-37 enhanced both NK cell cytotoxic activity against different tumor cell lines and cytokines production. These effects were associated with increased phosphorylation of ERK and NF-Kb. The improved NK cell activity was also strictly related to a time-dependent GSK3β-mediated degradation of IL-1R8. The enhanced activation profile of IL-37 treated NK cells possibly due to IL-1R8 degradation was confirmed by the results with IL-1R8-silenced NK cells. Lastly, in line with these data, through the analysis of the TNM plot database of a large group of patients, IL-37 mRNA expression was found to be significantly lower in colon and skin cancers than in normal tissues. Colon adenocarcinoma and neuroblastoma patients with higher IL-37 mRNA levels had significantly higher overall survival, suggesting that the presence of IL-37 might be considered an independent positive prognostic factor for this tumor. Our results provide novel information on the mechanisms regulating IL-1R8 function in human NK cells, highlighting the IL-37-IL-1R8 axis as a potential new target to improve the anti-tumor immune response.

Informed by Bronfenbrenner's ecological model of development, this mixed-methods study's aims are to: (1) describe rural Latino/a adolescents' (N = 62) narratives and lived social experiences in the context of rurality, and (2) examine their personal networks to better understand their social interactions (subset of 30 adolescents). Rural Latino/a adolescents move in limited social circles and experience geographic, cultural, and social isolation due to immigration status problems, socioeconomic issues, racial discrimination, and family dynamics. This limitation is reflected by personal networks that tend to be homogenous in terms of ethnicity, age, and sociodemographic characteristics. School, although characterized by weak social ties often disconnected from community and family contacts, emerged as the dominant context of sociability where adolescents build their social identity outside the circle of dense family ties. Findings suggest a critical need for interventions to reduce isolation and enhance social connectedness between family, school, and rural community in this population.

This research aims at studying the intrinsic vulnerability of groundwater to diffuse environmental pollutants in the Muravera coastal agricultural area of Sardinia, Italy. The area faces contamination risks arising from agricultural practices, especially the use of fertilizers, pesticides, and various chemicals that can seep into the groundwater. The study examined the interplay among hydrological elements, including soil characteristics, groundwater depth, climate conditions, land use, and aquifer properties. To do that, the outcomes of FLOWS 1D physically-based agrohydrological model were analyzed in parallel with those of the overlay-and-index model SINTACS, in a sort of reciprocal benchmarking. By using FLOWS, water movement and solute transport in the unsaturated zone were simulated by, respectively, solving the Richard Equation (RE) and the Advection-Dispersion equation (ADE). As such, this model allowed to account for the role of soil hydraulic and hydro-dispersive properties variability in determining the travel times of a conservative solute through the soil profile to the groundwater. For FLOWS simulations, a complete dataset was used as input, including soil horizons, soil physical and hydraulic properties of 36 soil profiles, average annual depth to groundwater table at each soil profile (ranging from 1 to 50 meters), and climatic temporal series data on rainfall and evapotranspiration. Detailed analyses of travel times for the movement of 25, 50, 75, and 100% of the solute mass to reach groundwater were conducted, revealing that the depth to groundwater predominantly influences vulnerability. This result was coherent with SINTACS vulnerability map due to the large impact of the depth to groundwater on SINTACS analysis.

ABSTRACT Gluten possesses unique properties that render it only partially digestible. Consequently, it exerts detrimental effects on a part of the worldwide population who are afflicted with celiac disease (1%) or related disorders (5%), particularly due to the potential for cross-contamination even when adhering to a gluten-free diet (GFD). Finding solutions to break down gluten during digestion has a high nutritional and social impact. Here, a randomized double-blind placebo-controlled in vivo challenge investigated the gluten-degrading activity of a novel probiotic preparation comprising lactobacilli and their cytoplasmic extracts, Bacillus sp., and bacterial protease. In our clinical trial, we collected feces from 70 healthy volunteers at specific time intervals. Probiotic/placebo administration lasted 32 days, followed by 10 days of wash-out. After preliminary GFD to eliminate residual gluten from feces, increasing amounts of gluten (50 mg–10 g) were administered, each one for 4 consecutive days. Compared to placebo, the feces of volunteers fed with probiotics showed much lower amounts of residual gluten, mainly with increased intakes. Probiotics also regulate the intestinal microbial communities, improving the abundance of genera pivotal to maintaining homeostasis. Quantitative PCR confirmed that all probiotics persisted during the intervention, some also during wash-out. Probiotics promoted a fecal metabolome with potential immunomodulating activity, mainly related to derivatives of branched-chain amino acids and short-chain fatty acids.IMPORTANCEThe untapped potential of gluten-degrading bacteria and their application in addressing the recognized limitations of gluten-related disorder management and the ongoing risk of cross-contamination even when people follow a gluten-free diet (GFD) emphasizes the significance of the work. Because gluten, a common protein found in many cereals, must be strictly avoided to stop autoimmune reactions and related health problems, celiac disease and gluten sensitivity present difficult hurdles. However, because of the hidden presence of gluten in many food products and the constant danger of cross-contamination during food preparation and processing, total avoidance is frequently challenging. Our study presents a novel probiotic preparation suitable for people suffering from gluten-related disorders during GFD and for healthy individuals because it enhances gluten digestion and promotes gut microbiota functionality.

Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by biallelic mutations in the VPS13B gene. It is characterized by multiple clinical features, including acquired microcephaly, developmental delay, intellectual disability, neutropenia, and retinal degeneration. VPS13B is part of the bridge-like lipid transport (BLTP) protein family, which in mammals also includes VPS13A, -C, and -D. The proteins of this family are peripheral membrane proteins with different sub-cellular localization, but all share similar structural features and have been proposed to act as lipid transport proteins at organellar membrane contact sites. VPS13B is localized at the Golgi apparatus and is essential for the maintenance of organelle architecture. Here we present a review of the experimental data on the function of the protein at the cellular level, discussing the potential link with disease phenotype and review the studies on animal models recapitulating features of the human disease.

Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4–1BB (MP0310) with FAP-dependent 4–1BB agonistic activity. The α-FAPx4–1BB DARPin simultaneously binds to FAP and 4–1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4–1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4–1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4–1BB overexpression allowed the engagement of α-FAPx4–1BB that acted as a bridge between FAP+FBs and 4–1BB+NK cells. Therefore, α-FAPx4–1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4–1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs’ immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4–1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.

Abstract Accurate determination of the prevalence of erosive tooth wear (ETW) and associated risk factors in adolescents can inform clinical management guidelines. The aim of this analytical cross-sectional study was to estimate the prevalence, severity, and risk factors of ETW in adolescents aged 12–15 years in the municipality of Usaquén in Bogotá, Colombia. Two calibrated examiners clinically assessed ETW using Basic Erosive Wear Examination (BEWE) Index (range: 0–3). All tooth surfaces (excluding proximal) were scored to allow estimation of the Highest (0–3) and Total BEWE (sum of Highest BEWE score per sextant: 0–18) scores per patient. Sociodemographic characteristics, ETW risk factors, and caries severity (ICDAS-epi-merged) were evaluated, and their association with the presence of ETW (indicated by a Highest BEWE score of 2–3) was examined using preliminary analyses and logistic regression models. The study sample included 454 adolescents (mean age: 13.5±1.1 years; female: 61.7%), and the prevalence of ETW was 71.6%. The majority of participants exhibited a Highest BEWE score of 3 (58.0%) and a Total BEWE score ≤8 (84.3%). The preliminary analysis showed an association between the presence of ETW and age, caries, and brushing teeth before eating (p-value < 0.05). Risk factors for ETW included always brushing teeth before eating [adjusted Prevalence Ratio (PRa) 1.31, p-value=0.014], presence of extensive carious lesions (PRa 1.23, p-value = 0.024), male gender (PRa 1.14, p-value = 0.028), and age > 14 years (PRa 1.17, p-value = 0.009). Although ETW was highly prevalent, most Colombian adolescents exhibited low Total BEWE scores. ETW was associated with frequent fruit intake, age, toothbrushing habits, caries lesions, and sex.

Abstract Antimicrobial resistance (AMR) is nowadays a global health concern as bacterial pathogens are increasingly developing resistance to antibiotics. Monoclonal antibodies (mAbs) represent a powerful tool for addressing AMR thanks to their high specificity for pathogenic bacteria which allows sparing the microbiota, kill bacteria through complement deposition, enhance phagocytosis or inhibit bacterial adhesion to epithelial cells. Here we describe a visual opsono-phagocytosis assay which relies on confocal microscopy to measure the impact of mAbs on phagocytosis of the bacterium Neisseria gonorrhoeae by macrophages. With respect to traditional CFU-based assays, generated images can be automatically analysed by convolutional neural networks. Our results demonstrate that confocal microscopy and deep learning-based analysis allow screening for phagocytosis-promoting mAbs against N. gonorrhoeae, even when mAbs are not purified and are expressed at low concentration. Ultimately, the flexibility of the staining protocol and of the deep-learning approach make the assay suitable for other bacterial species and cell lines where mAb activity needs to be investigated.

The support of geospatial data and technologies for the United Nations Sustainable Development Goals (SDG) framework is critical for assessing and monitoring key indicators, revealing the planet’s trajectory towards sustainability. The availability of global open geospatial datasets, especially high-resolution land cover datasets, provides significant opportunities for computing and comparing indicators across different regions and scales. However, barriers to their proficient use remain due to a lack of data awareness, management and processing capacities using geographic information systems software. To address this, the ”Capacity Building for GIS-based SDG Indicator Analysis with Global High-resolution Land Cover Datasets” project created open training material on discovering, accessing, and manipulating global geospatial datasets for computing SDG indicators. The material focuses on water and terrestrial ecosystems, urban environments, and climate, by leveraging world-class global geospatial datasets and using the Free and Open Source Software QGIS. The training material is released under a Creative Commons Attribution 4.0 License, ensuring broad accessibility and facilitating continuous improvement.

Abstract Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.