Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model

Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient’s life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2^-/meth cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2^-/meth cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2^-/meth cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.     

Basophil Activation Test with Different Polyethylene Glycols in Patients with Suspected PEG Hypersensitivity Reactions

Allergic reactions to COVID-19 vaccine components are rare but should be considered. Polyethylene glycol (PEG) is responsible for anaphylaxis in mRNA vaccines. Skin tests have been used in the allergological work-up programs for COVID-19 vaccine evaluation. However, the reproducibility of the skin prick test is time-dependent and the reactivity declines over time. Therefore, we combined the administration of the skin tests with the basophil activation test (BAT) using PEG2000, PEG4000 and DMG-PEG2000, where the BAT was considered positive when the percentage of activated basophils was higher than 6%, 5% and 6.5%, for PEG 4000, PEG2000 and DMG-PEG2000, respectively. To this end, among the subjects that underwent allergy counseling at the Allergy Unit of our Institution during the 2020/2021 vaccination campaign, 13 patients had a suggested medical history of PEG/drug hypersensitivity and were enrolled together with 10 healthy donors. Among the enrolled patients 2 out of 13 tested patients were positive to the skin test. The BAT was negative in terms of the percentages of activated basophils in all analyzed samples, but the stimulation index (SI) was higher than 2.5 in 4 out of 13 patients. These data evidenced that, when the SI is higher than 2.5, even in the absence of positivity to BAT, the BAT to PEG may be a useful tool to be coupled to skin tests to evidence even low-grade reactions.     

Polyglycerol Adipate-Grafted Polycaprolactone Nanoparticles as Carriers for the Antimicrobial Compound Usnic Acid

Nanoparticle (NP) drug delivery systems are known to potentially enhance the efficacy of therapeutic agents. As for antimicrobial drugs, therapeutic solutions against drug-resistant microbes are urgently needed due to the worldwide antimicrobial resistance issue. Usnic acid is a widely investigated antimicrobial agent suffering from poor water solubility. In this study, polymer nanoparticles based on polyglycerol adipate (PGA) grafted with polycaprolactone (PCL) were developed as carriers for usnic acid. We demonstrated the potential of the developed systems in ensuring prolonged bactericidal activity against a model bacterial species, Staphylococcus epidermidis. The macromolecular architecture changes produced by PCL grafted from PGA significantly influenced the drug release profile and mechanism. Specifically, by varying the length of PCL arms linked to the PGA backbone, it was possible to tune the drug release from a burst anomalous drug release (high PCL chain length) to a slow diffusion-controlled release (low PCL chain length). The developed nanosystems showed a prolonged antimicrobial activity (up to at least 7 days) which could be used in preventing/treating infections occurring at different body sites, including medical device-related infection and mucosal/skin surface, where Gram-positive bacteria are commonly involved.     

Influence of high temperature thermal treatment on grain stability and mechanical properties of medium strength aluminium alloy friction stir welds

A heat treatment of 2 h at 535 °C was applied to 6082T6 friction stir welds. One of the effects of post-welding heat treatment on microstructure was abnormal grain growth. The presence, in the same nugget, of zones with different grain size, is the key factor to understand why, after exposure at 535 °C for 2 h, abnormal grain growth is locally observed. The ductility substantially increased and tensile strengths remained comparable to those of as-friction stir welded samples. Particle evolution influenced microhardness values and determined deformation to fracture, even if abnormal grain growth appeared in the nuggets.     

Effects of partial ventriculectomy on left ventricular mechanical properties, shape, and geometry in patients with dilated cardiomyopathy

This study evaluated the 6-month clinical response to sustained-release tetracycline fibers used alone or with scaling and root planing in 25 adult periodontal maintenance patients. All subjects had at least one pocket > or = 4.0 mm that bled on probing and required therapy. Thirty-six teeth were treated with tetracycline fibers for 7 to 12 days; twelve of the 36 teeth also received scaling and root planing. The selection of teeth for scaling and root planing was based on the condition of the teeth. Therapeutic results were evaluated by changes in probing depth and frequency of bleeding on probing. Use of tetracycline fibers and fibers with scaling produced 1.8- and 1.7-mm reductions in probing depth, respectively, 1 month after treatment; reductions declined to 1.3 and 0.8 mm at 3 months, but rebounded to 1.5 and 1.3 mm at 6 months. The percentage of teeth exhibiting bleeding on probing decreased from 100% at baseline to 68% and 50% in the fiber and fiber plus scaling groups, respectively, at 6 months. None of the differences was statistically significant. Tetracycline fibers clearly decreased clinical signs of periodontal inflammation. Addition of scaling and root planing at the time of fiber placement further decreased, although not significantly, the degree of inflammation.     

Clinical findings and hemodynamic changes associated with severe occlusive carotid artery disease

OBJECTIVE: The purpose of the study was to evaluate the ophthalmologic findings and to analyze the retrobulbar hemodynamics of patients with severe (greater than 70% stenosis) occlusive carotid artery disease (OCAD) by means of color Doppler imaging (CDI). DESIGN: A case-controlled study. PARTICIPANTS: Fifty-six consecutive patients with severe OCAD and an age- and sex-matched control group consisting of 56 healthy patients without OCAD were studied. INTERVENTION: All 112 patients underwent a complete ophthalmologic examination. Color Doppler imaging of both orbits was performed by one masked investigator. MAIN OUTCOME MEASURES: Peak systolic velocity, end diastolic velocity, and the resistive index of the ophthalmic, central retinal, and temporal short posterior ciliary arteries were measured. The authors compared the hemodynamic parameters measured in patients with severe OCAD with those obtained in the control group. The hemodynamic parameters of patients with asymmetric OCAD (stenosis > 70% in one internal carotid artery and stenosis < 50% in the contralateral artery) were also compared. In an attempt to determine risk factors associated with the ocular ischemic syndrome (OIS), the authors compared patients with severe OCAD and OIS with patients with severe OCAD without OIS. RESULTS: Peak systolic and end diastolic velocities in the ophthalmic, central retinal, and temporal short posterior ciliary arteries were significantly lower in patients with severe OCAD (P < 0.01). The mean resistive indices in the central retinal and temporal short posterior ciliary arteries were higher in the group with severe OCAD (P < 0.01). Similar results were obtained in the analysis of 25 patients with asymmetric carotid stenosis. Younger age (P = 0.012), severe bilateral OCAD (P = 0.01), high-grade carotid stenosis (P = 0.013), and reversed ophthalmic artery flow (P = 0.038) were significant risk factors for OIS. CONCLUSIONS: Patients with severe OCAD show hemodynamic changes that suggest reduced retrobulbar blood flow. Patients with severe bilateral OCAD, high-grade carotid stenosis, and reversed ophthalmic artery flow may have a greater risk of developing OIS.     

Effect of fat source differing in fatty acid profile on metabolic parameters, fertilization, and embryo quality in high-producing dairy cows

The objectives were to evaluate the effects of source of fatty acids (FA) on embryo quality of dairy cows. A total of 154 Holstein cows were assigned randomly to 1 of 2 sources of FA supplemented at 2% of the dietary dry matter as calcium salts of either palm oil (PO) or linoleic and trans-octadecenoic acids (LTFA) from 25 d prepartum to 80 d in milk (DIM). Cows were presynchronized beginning at 30 ± 3 DIM and then subjected to the Ovsynch protocol beginning on d 39 ± 3 postpartum. Timed artificial insemination was performed 12 h after the final GnRH of the Ovsynch protocol with semen from a single sire of proven fertility. The uteri of cows were nonsurgically flushed at 5 d after artificial insemination for collection of embryos-oocytes. Ovaries were examined by ultrasonography throughout the synchronization protocol. Blood was sampled and plasma was analyzed for concentrations of metabolites and hormones. The body condition score and yields of milk and milk components were measured throughout the first 90 DIM. Treatment did not affect concentrations of nonesterified FA, β-hydroxybutyrate, glucose, and progesterone in plasma. Body condition was similar between treatments. Milk production was similar between treatments, but concentrations of fat in milk and yields of fat and 3.5% fat-corrected milk decreased in cows fed LTFA, whereas concentration of true protein increased. Source of dietary FA did not influence ovulatory responses, diameter of the ovulatory follicle, and diameter of the corpus luteum during synchronization. Embryo-oocyte recovery relative to the number of corpora lutea did not differ between treatments. Fertilization tended to increase in cows fed LTFA compared with cows fed PO. Feeding LTFA improved the proportion of excellent-, good-, and fair-quality embryos, and embryos from cows fed LTFA had a greater number of blastomeres than embryos from cows fed PO. Feeding a more unsaturated source of FA improved fertilization and embryo development in lactating dairy cows, despite similar indicators of metabolic status.     

Modeling Hot Tearing during Solidification of Steels: Assessment and Improvement of Macroscopic Criteria through the Analysis of Two Experimental Tests

Hot tearing is an unacceptable defect found in products and parts obtained by solidification processes such as ingot and continuous casting. It consists of the development of cracks during solidification, in regions that are not completely solidified, more precisely, in areas of mushy zones with a high fraction of solid (typically 0.9 and beyond), when the material undergoes deformations associated with tensile stress. In this study, two hot tearing tests have been studied in order to evaluate the predictive capability of several macroscopic criteria published in the literature. The first test is a new test specifically designed for constrained shrinkage by the present authors, while the second test is an ingot bending test developed in the 1980s. For both tests, a thermal-mechanical analysis is performed, in order to provide the key variables for the different selected criteria. A comparison with experimental results allows us to make a critical assessment of those criteria regarding their ability to predict crack occurrence. The criterion initially proposed by Won et al.[7] has been found to be the best suited for the prediction of solidification cracking. Because this criterion is essentially based on the “brittle temperature range,” (BTR) critical considerations regarding nonequilibrium solidification have led to suggest an extension of this criterion. This new macroscopic criterion improves the prediction capacity.     

MARS-2: A “current sensitive” liquid argon calorimeter

The performances of a liquid argon calorimeter with wide gaps (2.8 cm) operating in current sensitive mode have been studied with 6.6–36 GeV electron and 40 GeV pion beams at the IHEP accelerator.The good uniformity in charge collection efficiency obtained with this unusual mode has led to a reduction of sampling fluctuations to values of $\text{σ}{}_{\mathrm{<mtext>S</mtext>}}\text{E}\text{=}\text{0.04}\text{√E}$.Spatial and angular resolutions have been measured as well. The equivalent noise energy was 82 MeV rms for the whole detector.     

SERVICES,SEMANTICS, AND STANDARDS: ELEMENTS OF A LEARNING GRID INFRASTRUCTURE

There has been considerable political pressure and much hope invested in the use of communication and information technologies to provide wider access to education, while improving quality and reducing costs. Unfortunately, many of the responses to the challenge of these aspirations have consisted of simple Web technology-driven products, which have failed to progress effective learning. In this paper we outline the characteristics and pedagogical goals of a learning paradigm that is used to drive the technical requirements, rather than being constrained by what is easily achieved in XHTML. We identify and explain the key roles played by services, semantics, and standards in meeting pedagogical goals of novel learning situations, and illustrate with some scenarios that build bridges between traditional learning contexts and future possibilities. Crucially, we explain why we have adopted Grid technologies in the European Learning Grid Infrastructure (ELeGI) research program.