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s Bowel inflammation, impaired intestinal epithelial barrier (IEB), and gut dysbiosis could represent early events in Parkinson’s disease (PD). This study examined, in a descriptive manner, the correlation among enteric α-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T α-synuclein Tg mice were sacrificed at 3, 6, and 9 months of age to evaluate concomitance of enteric inflammation, IEB impairments, and enteric bacterial metabolite alterations during the early phases of α-synucleinopathy. The molecular mechanisms underlying the interplay between α-synuclein, activation of immune/inflammatory responses and IEB alterations were investigated with in vitro experiments in cell cultures. Tg mice displayed an increase in colonic levels of IL-1β, TNF, caspase-1 activity and enteric glia activation since 3 months of age. Colonic TLR-2 and zonulin-1 expression were altered in Tg mice as compared with controls. Lipopolysaccharide levels were increased in Tg animals at 3 months, while fecal butyrate and propionate levels were decreased. Co-treatment with lipopolysaccharide and α-synuclein promoted IL-1β release in the supernatant of THP-1 cells. When applied to Caco-2 cells, the THP-1-derived supernatant decreased zonulin-1 and occludin expression. Such an effect was abrogated when THP-1 cells were incubated with YVAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric α-synuclein accumulation contributes to compromise IEB through the direct activation of canonical caspase-1-dependent inflammasome signaling. These changes could contribute both to bowel symptoms as well as central pathology.

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

Background Understanding and predicting the behavior of additively manufactured (AM) parts in real-case scenarios is essential for optimizing the design process. Little literature presents a throughout investigation on the influence of the stress state on the anisotropic response of AM materials, and there has not been a great effort to validate the applicability of conventional material models for AM components. Objective This work aims to assess the effect of building orientation and the stress state on the mechanical response of as-built laser powder bed fusion (L-PBF) AlSi10Mg and to propose, based on the experimental results, a material model able to represent its mechanical response thoroughly. Methods Several mechanical characterization tests, including uniaxial tensile and compressive tests, tensile tests on round-notched bars, and shear tests, were carried out for each investigated building direction (0°, 45°, 90°). The Cazacu-Barlat yield surface was selected to describe the mechanical behavior of the material. Material parameters were identified by inverse calibration and verified using finite element simulation of performed experimental tests. Results The results showed a more consistent effect of the building direction on ductility and maximum stress value, while the effect on yield stress was less significant. Under multiaxial stress states, the anisotropic behavior became less noticeable yet present. No anisotropic behavior was observed under shear conditions. In tension and compression, a slight asymmetry in response was noted. Computational results were found in agreement with the experimental data. Conclusion The influence of both stress state and of the building direction has been systematically investigated by performing several characterization tests on different sample geometries. In combination with mechanical testing, a material model has been proposed and validated to show the applicability of conventional modeling techniques to AM material.

This study presents an original mapping of hydrological karst features of the Matese massif (southern Italy), whose relevance is given by large basal springs supplying millions of people and the hydroelectric exploitation of the major endorheic areas. We mapped dolines and endorheic areas from 1- and 5-meter Digital Elevation Models (DEM) using Geographic Information System (GIS) tools and techniques. Instead, ponors, caves, and karst springs were mapped mainly based on cartographic and literature analyses. We identified 321 endorheic areas occupying 31% of the massif area and 489 dolines, distinguished in (i) solution (N = 433) and collapse dolines (N = 56), the latter located in the discharge zones of the massif and connected to ascendant flows of CO 2 - and H 2 S-rich groundwater. The map shows the hydrological features of a karst massif from a more detailed and new perspective, and it can be helpful in water management, groundwater resource protection, environmental safeguarding, and ecological development.

Abstract Purpose Flexible flatfoot (FFF) is a widespread condition in juvenile patients. If symptomatic, FFF can require surgical treatment. The calcaneo-stop procedure has shown excellent clinical and radiographic outcomes and low rates of complications. The aim of the present study was to assess the sport practice of young athletes affected by FFF having undergone the calcaneo-stop procedure. Methods Between 2008 and 2016, 68 sport practitioners were bilaterally treated by the calcaneo-stop procedure, for a total of 136 FFF cases. Clinical evaluation, including the American Orthopedic Foot and Ankle Score (AOFAS), the Yoo et al score and The Foot & Ankle Disability Index (FADI) and FADI Sport scores were assessed. Radiographic evaluation was based on measurement of talar declination, Costa-Bertani's angle and calcaneal pitch. Results Mean follow-up was 57.6 months (sd 16.8). The AOFAS score mean increased from 79.3 (sd 5.7) to 97.3 (sd 4.5) three years after surgery. The Yoo score improved from 3.1 (sd 1.0) preoperatively to 11.7 (sd 0.6) three years after surgery. The FADI Sport subscale mean improved from 74.1 (sd 10.4) preoperatively to 95.9 (sd 4.9) three years after surgery. Costa-Bertani's angle decreased from 156.1° (sd 4.2°) to 135.8° (sd 7.3°) at three years postoperatively; mean talar declination angle decreased from 44.2° (sd 6.3°) to 30.6° (sd 3.2°) at three years postoperatively and mean calcaneal pitch increased from 12.6° (sd 2.3°) to 16.3° (sd 1.3°) at three years postoperatively. Conclusion Adolescent patients who underwent the calcaneo-stop procedure reported satisfactory outcomes in terms of clinical and radiological evaluations. Moreover, our results showed an improvement of sport activity levels, with patients recovering sports activity within three months of surgery and without limitation in the execution of preferred activities. Level of Evidence IV

The increasing interest in Additive Manufacturing (AM) technologies is mainly driven by their high design flexibility and on-demand production. As these processes expand, there is a critical need to explore the material properties of resulting products under diverse loading conditions. This work investigates the impact response of the as-built aluminum alloy AlSi10Mg, additively manufactured employing a laser powder bed fusion (L-PBF) process. Taylor-cylinder impact tests have been performed with a light gas gun at different impact velocities to probe material deformation and damage behavior under high-rate loadings and complex stress paths. Three building orientations were systematically investigated– horizontal, vertical, and at 45°. At lower striking velocities (between 180 and 200 m/s), observable mushrooming deformation occurred with no apparent damage. The shape of the impact faces and deformed profiles were recorded to assess deformation differences across the tested printing directions. In the intermediate range of velocities (240–260 m/s), shear cracking emerged as the principal damage mechanism, resulting in the formation of 45°/135° oriented cracks on the samples’ lateral surface. Increasing the impact velocity promoted these cracks’ growth, ultimately leading to the samples’ fragmentation. The vertically printed sample exhibited a slightly lower onset fragmentation velocity than the other two building directions.

Governance theories consider policy steering as modes sustained in hierarchies, markets, and networks. If governance depoliticizes public management structures, then populism and technocratic forms’ emergence in politics is a threat to public governance. This article analyzes governance styles, showing how a reconciliation between the dimensions of policy and politics is necessary to think about policy steering’s complexity and its ensuing paths. We develop a typology of governance styles to address policy and political dynamics. This typology shows how different governance styles combine pluralist, populist, and technocratic elements, along with hierarchies, markets, and networks. We illustrate our typology with different policies conceived in distinct political regimes in Brazil. We argue that governance theories must incorporate a perspective of political conflict, path dependence, and contingency. This perspective on political conflict is essential for understanding governance reforms and how they shape public management practices.

The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c-Myc . Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4 , Sox2 and Klf4 , or four genes, OSK plus c-Myc . Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming.

In numerical simulation of self-pierce riveting process (SRP) material separation criteria plays a critical role. In most of published works, material failure is simulated using numerical techniques, such as erosion criteria, that are calibrated on available experimental results. The lack of material based criteria strongly limits the use of numerical simulation as effective investigative tool for manufacturing process parameters assessment. In this work, damage mechanics is used to determine failure conditions in SRP considering dissimilar material sheets. In particular, the extended Bonora Damage Model (XBDM), which account for both void growth and void sheeting, was used. Damage model parameters for metal sheets have been determined independently and successively used in the simulation of SRP process. Results were compared with available experimental data.

Forming limit diagrams (FLD's) are used to evaluate the workability of metal sheets. These diagrams provide the failure locus at which plastic instability occurs and localized necking develops (commonly designated as the forming limit curve - FLC), and the failure loci at the onset of fracture by tension or by in-plane shear. In this work, the possibility to predict the FLD's using damage mechanics is presented. Following the approach proposed by Lemaitre [1], the fracture forming limit (FFL) for ductile metals is theoretically derived using the extended Bonora damage model (XBDM). The XBDM is used in numerical simulation with FEM of formability tests (Nakazima and Marciniak) to demonstrate the possibility to account correctly for necking development before fracture. The proposed model prediction was validated with available experimental data for high purity copper.