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Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

BackgroundThe mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination.MethodsThe aim of the study was to evaluate humoral and specific T-cell response, as well as B-cell activation and survival factors, in people with MS (pwMS) under DMTs before (T0) and after two months (T1) from the third dose of vaccine, comparing the obtained findings to healthy donors (HD). All possible combinations of intracellular IFNγ, IL2 and TNFα T-cell production were evaluated, and T-cells were labelled “responding T-cells”, those cells that produced at least one of the three cytokines of interest, and “triple positive T-cells”, those cells that produced simultaneously all the three cytokines.ResultsThe cross-sectional evaluation showed no significant differences in anti-S antibody titers between pwMS and HD at both time-points. In pwMS, lower percentages of responding T-cells at T0 (CD4: p=0.0165; CD8: p=0.0022) and triple positive T-cells at both time-points compared to HD were observed (at T0, CD4: p=0.0007 and CD8: p=0.0703; at T1, CD4: p=0.0422 and CD8: p=0.0535). At T0, pwMS showed higher plasma levels of APRIL, BAFF and CD40L compared to HD (p

El presente trabajo recupera algunos hilos que atraviesan la investigación previa de los autores denominada Los orígenes del Diseño en la Universidad Nacional de La Plata, destinada a poner de relieve los hechos y personajes determinantes en la institucionalización de la disciplina dentro de esta casa de estudios. Siguiendo las trayectorias y la trama de vínculos personales entre los profesores Rodolfo Castagna, Daniel Almeida Curth y Héctor Cartier surgen nuevos datos en referencia a su relación con César Jannello y a sus aportes dentro de las instituciones educativas de arte porteñas en los años cuarenta. Hechos que, a la luz de la participación de estos mismos docentes en la creación de las carreras de Diseño de La Plata y Cuyo tres lustros después, no solo demuestran que ambos centros educativos se hallan hermanados en su origen, sino que permiten visibilizar el devenir de las Artes Aplicadas al Diseño dentro de la enseñanza artística nacional, abriendo nuevos caminos en la historia del Diseño en la Argentina.

Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too. Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (p < 0.0001), APRIL (p = 0.0223) and CD40L (p < 0.0001) levels compared to HD. Compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 (p < 0.0001 and p < 0.0001, respectively). Whereas plasma APRIL and CD40L levels were decreased at T12 (p = 0.0003 and p < 0.0001, respectively). When stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups—with (14) and without an infectious event (24)—higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). Conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk.

Abstract Background During severe immunosuppression or treatment with specific biological drugs, human polyomavirus JC (JCPyV) may establish a lytic infection in oligodendrocytes, leading to progressive multifocal leukoencephalopathy (PML). Beyond AIDS, which represents the most common predisposing condition, several biological drugs have been associated to the development of PML, such as natalizumab, fingolimod and dimethyl fumarate, which have been showed to increase the risk of PML in the multiple sclerosis (MS) population. JCPyV non-coding control region (NCCR) can be found in two different forms: a virulent neurotropic pathogenic form and a latent non-pathogenic form. The neurotropic forms contain a rearranged NCCR and are typically found in the cerebrospinal fluid, brain or blood of PML patients. Case presentation We sequenced and critically examined JCPyV NCCR from isolates detected in the cerebrospinal fluid of four newly diagnosed progressive multifocal leukoencephalopathy patients: two HIV-positive and two HIV-negative multiple sclerosis patients. More complex NCCR rearrangements were observed in the two HIV-positive patients compared to the HIV-negative multiple sclerosis patients with PML. Conclusions The comparison of HIV-positive and HIV-negative MS patients with PML, allowed us to evidence the presence of a common pattern of JCPyV NCCR rearrangement, characterized by the deletion of the D-block, which could be one of the initial rearrangements of JCPyV NCCR needed for the development of PML.

BackgroundEmerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects).MethodsOn admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups.ResultsCompared to HDs, COVID-19 subjects showed higher sCD163 (p

ObjectiveTo evaluate the effectiveness of Tocilizumab (with or without corticosteroids) in a real-life context among moderate-to-severe COVID-19 patients hospitalized at the Infectious Diseases ward of two hospitals in Lazio region, Italy, during the first wave of SARS-CoV-2 pandemic.MethodWe conducted a retrospective cohort study among moderate-to-severe COVID-19 pneumonia to assess the influence of tocilizumab (with or without corticosteroids) on: 1) primary composite outcome: risk for death/invasive mechanical ventilation/ICU-transfer at 14 days from hospital admission; 2) secondary outcome: COVID-related death only. Both outcomes were also assessed at 28 days and restricted to baseline more severe cases. We also evaluated the safety of tocilizumab.ResultsOverall, 412 patients were recruited, being affected by mild (6.8%), moderate (66.3%) or severe (26.9%) COVID-19 at baseline. The median participant' age was 63 years, 56.5% were men, the sum of comorbidities was 1.34 (±1.44), and the median time from symptom onset to hospital admission was 7 [3-10] days. Patients were subdivided in 4 treatment groups: standard of care (SoC) only (n = 172), SoC plus corticosteroid (n = 65), SoC plus tocilizumab (n = 50), SoC plus tocilizumab and corticosteroid (n = 125). Twenty-six (6.3%) patients underwent intubation, and 37 (9%) COVID-related deaths were recorded. After adjusting for several factors, multivariate analysis showed that tocilizumab (with or without corticosteroids) was associated to improved primary and secondary outcomes at 14 days, and at 28-days only when tocilizumab administered without corticosteroid. Among more severe cases the protective effect of tocilizumab (± corticosteroids) was observed at both time-points. No safety concerns were recorded.ConclusionAlthough contrasting results from randomized clinical trials to date, in our experience tocilizumab was a safe and efficacious therapeutic option for patients with moderate-to-severe COVID-19 pneumonia. Its efficacy was improved by the concomitant administration of corticosteroids in patients affected by severe-COVID-19 pneumonia at baseline.

The aim of the present study was to evaluate the possibility to extract, by supercritical fluids, nutraceuticals as polyphenolic compounds, able in the prevention and in the treatment of a series of chronic-degenerative diseases, from plant matrices like the cactus pear. Supercritical fluid technology is an innovative method to extract nutraceuticals from natural matrices. This method offers numerous advantages that include the use of moderate temperatures, solvents with good transport properties (high diffusivity and low viscosity), and cheap and nontoxic fluids. Fresh cladodes from two different wild ecotypes of Opuntia ficus-indica (L.) Mill. were extracted both with methanol and with SFE-CO2 using different samples preparations, to maximize the % yields and the selectivity of extraction of polyphenols. The biggest contents of phenolics, evaluated by Folin-Ciocalteu assay, has been observed with the sample dehydrated of O. ficus-indica cultivar that shows, as well, the best yield % (m/m) of extraction with both methanol and SFE-CO2. Better results were obtained with the samples of O. ficus-indica cult. (OFI cult.), in spite of the O. ficus-indica s.l. (OFI s.l.); the two different ecotypes of OFI showed dissimilar phytochemicals profile. We noticed that the reduction of both quantity and quality of polyphenols was drastic with the increase of pressure at 250 bar; this shows that high pressures result in a loss of bioactive principles, like polyphenols. By changing the variables of extraction processes with SFE-CO2 and by varying the preventive treatments of the natural matrices, it was possible to increase the selectivity and the purity of the products. Thus, the optimization of this useful and green technique allowed us to increase the value of the Opuntia cladodes, a by-product very diffused in Calabria, which is an extraordinary source of nutraceuticals. These extracts could be used directly as functional foods or as starting material in the pharmaceutical, nutraceutical or cosmetic companies; they are safe and without any solvents traces and it is possible to obtain it in a few hours respect to the conventional extraction that requires longer extraction time.

Type 1 diabetes is an autoimmune disease, in which pancreatic β cells are destroyed by autoreactive T cells in genetically predisposed individuals. Serum beta cell autoantibody specificities have represented the mainstay for classifying diabetes as autoimmune-mediated and for stratifying risk in first-degree relatives. In recent years, approaches were attempted to solve the difficult issue of detecting rare antigen-specific autoreactive T cells and their significance to etiopathogenesis such as the use of the MHC multimer technology. This tool allowed the specific detection of increased percentages of GAD65 autoreactive T cells by means of HLA A*02:01 GAD65 AA 114-122 pentamers in newly diagnosed diabetics. Here we provide evidence that GAD65 AA 114-122 pentamers can depict a GAD65 AA114-122 peptide expandable population of functionally and phenotypically skewed, preliminary characterized CD3-CD8dullCD56+ 'memory-like' NK cells in PBMC of newly diagnosed diabetics. Our data suggest that the NK cell subset could bind the HLA class I GAD65 AA 114-122 pentamer through ILT2 inhibitory receptor. CD107a expression revealed increased degranulation of CD3-CD8dullCD56+ NK cells in GAD65 AA 114-122 and FLU peptide expanded peripheral blood mononuclear cells of diabetics following GAD65 AA 114-122 peptide HLA A*02:01 presentation in respect to the unpulsed condition. CD107a expression was enriched in ILT2 positive NK cells. As opposite to basal conditions where similar percentages of CD3-CD56+ILT2+ cells were detected in diabetics and controls, CD3-CD56+CD107a+ and CD3-CD56+ILT2+CD107a+ cells were significantly increased in T1D PBMC either GAD65 AA 114-122 or FLU peptides stimulated after co-culture with GAD65 AA 114-122 pulsed APCs. As control, healthy donor NK cells showed similar degranulation against both GAD65 AA 114-122 pulsed and unpulsed APCs. The pathogenetic significance of the CD3-CD8dullCD56+ 'memory-like NK cell subset' with increased response upon secondary challenge in diabetics remains to be elucidated.

Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with paradoxical reduced T cell activation, may represent a valid therapeutic target. We aimed to develop novel wild type PTPN22 short interfering RNA duplexes (siRNA) and optimize their delivery into Jurkat T cells and PBMC by using liposomal carriers. Conformational stability, size and polydispersion of siRNA in lipoplexes was measured by CD spectroscopy and DLS. Lipoplexes internalization and toxicity evaluation was assessed by confocal microscopy and flow cytometry analysis. Their effect on Lyp expression was evaluated by means of Western Blot and confocal microscopy. Functional assays through engagement of TCR signaling were established to evaluate biological consequences of down-modulation. Both Jurkat T cells and PBMC were efficiently transfected by stable custom lipoplexes. Jurkat T cell morphology and proliferation was not affected. Lipoplexes incorporation was visualized in CD3+ but also in CD3- peripheral blood immunotypes without signs of toxicity, damage or apoptosis. Efficacy in affecting Lyp protein expression was demonstrated in both transfected Jurkat T cells and PBMC. Moreover, impairment of Lyp inhibitory activity was revealed by increase of IL-2 secretion in culture supernatants of PBMC following anti-CD3/CD28 T cell receptor-driven stimulation. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on the selective inhibition of variant PTPN22 allele using lipoplexes of siRNA antisense oligomers.

Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.

Abstract Evolution has generated a sophisticated convergence of material components, ultrastructural designs, and fabrication processes in response to similar selective pressures across a diverse array of extinct and extant species. This review explores three key convergent design strategies: struts for lightweight structures with load-bearing efficiency, sutures for increased flexibility and stress management, and helicoids for impact resistance and fracture toughness. Through this examination, the review sheds light on how evolution can inspire innovative engineering approaches and technologies through the adoption of aspects of natural design. We foresee natural evolutive processes of construction as the informative harbingers of new, advanced, ecologically aware, and energy-efficient modes of human fabrication.

Since the industrial revolution, the human world has been dominated by eco-systemically unintegrated and non-sustainable manufacturing and mass production leading to natural disasters and extinctions. However, a new perspective is now emerging: an architectural design that does not impose itself on nature but is born, inspired, and integrated with it. Over millions of years of evolution, high-performance strategies and materials have been developed in nature, providing valuable sources of inspiration. This contribution aims to provide a new vision in which the “learning from nature” approach combined with bio-based/biohybrid materials and with a coherent use of computational design and fabrication can be configured as a future direction of human design that can imitate and integrate nature through multiple dimensions. A research project is proposed: BioArch 3.8 in which bio-inspired/bio-based design and robotic fabrication are used to realize adaptive shelters for emergency contexts.

In the field of structural engineering, lightweight and resistant shell structures can be designed by efficiently integrating and optimizing form, structure and function to achieve the capability to sustain a variety of loading conditions with a reduced use of resources. Interestingly, a limitless variety of high-performance shell structures can be found in nature. Their study can lead to the acquisition of new functional solutions that can be employed to design innovative bioinspired constructions. In this framework, the present study aimed to illustrate the main results obtained in the mechanical analysis of the echinoid test in the common sea urchin Paracentrotus lividus (Lamarck, 1816) and to employ its principles to design lightweight shell structures. For this purpose, visual survey, photogrammetry, three-dimensional modelling, three-point bending tests and finite-element modelling were used to interpret the mechanical behaviour of the tessellated structure that characterize the echinoid test. The results achieved demonstrated that this structural topology, consisting of rigid plates joined by flexible sutures, allows for a significant reduction of bending moments. This strategy was generalized and applied to design both free-form and form-found shell structures for architecture exhibiting improved structural efficiency.

In biomimetic design, functional systems, principles, and processes observed in nature are used for the development of innovative technical systems. The research on functional features is often carried out without giving importance to the generative mechanism behind them: evolution. To deeply understand and evaluate the meaning of functional morphologies, integrative structures, and processes, it is imperative to not only describe, analyse, and test their behaviour, but also to understand the evolutionary history, constraints, and interactions that led to these features. The discipline of palaeontology and its approach can considerably improve the efficiency of biomimetic transfer by analogy of function; additionally, this discipline, as well as biology, can contribute to the development of new shapes, textures, structures, and functional models for productive and generative processes useful in the improvement of designs. Based on the available literature, the present review aims to exhibit the potential contribution that palaeontology can offer to biomimetic processes, integrating specific methodologies and knowledge in a typical biomimetic design approach, as well as laying the foundation for a biomimetic design inspired by extinct species and evolutionary processes: Paleomimetics. A state of the art, definition, method, and tools are provided, and fossil entities are presented as potential role models for technical transfer solutions.

Organisms and their features represent a complex system of solutions that can efficiently inspire the development of original and cutting-edge design applications: the related discipline is known as biomimetics. From the smallest to the largest, every species has developed and adapted different working principles based on their relative dimensional realm. In nature, size changes determine remarkable effects in organismal structures, functions, and evolutionary innovations. Similarly, size and scaling rules need to be considered in the biomimetic transfer of solutions to different dimensions, from nature to artefacts. The observation of principles that occur at very small scales, such as for nano- and microstructures, can often be seen and transferred to a macroscopic scale. However, this transfer is not always possible; numerous biological structures lose their functionality when applied to different scale dimensions. Hence, the evaluation of the effects and changes in scaling biological working principles to the final design dimension is crucial for the success of any biomimetic transfer process. This review intends to provide biologists and designers with an overview regarding scale-related principles in organismal design and their application to technical projects regarding mechanics, optics, electricity, and acoustics.

The diversity of cephalopod species and the differences in morphology and the habitats in which they live, illustrates the ability of this class of molluscs to adapt to all marine environments, demonstrating a wide spectrum of patterns to search, detect, select, capture, handle, and kill prey. Photo-, mechano-, and chemoreceptors provide tools for the acquisition of information about their potential preys. The use of vision to detect prey and high attack speed seem to be a predominant pattern in cephalopod species distributed in the photic zone, whereas in the deep-sea, the development of mechanoreceptor structures and the presence of long and filamentous arms are more abundant. Ambushing, luring, stalking and pursuit, speculative hunting and hunting in disguise, among others are known modes of hunting in cephalopods. Cannibalism and scavenger behavior is also known for some species and the development of current culture techniques offer evidence of their ability to feed on inert and artificial foods. Feeding requirements and prey choice change throughout development and in some species, strong ontogenetic changes in body form seem associated with changes in their diet and feeding strategies, although this is poorly understood in planktonic and larval stages. Feeding behavior is altered during senescence and particularly in brooding octopus females. Cephalopods are able to feed from a variety of food sources, from detritus to birds. Their particular requirements of lipids and copper may help to explain why marine crustaceans, rich in these components, are common prey in all cephalopod diets. The expected variation in climate change and ocean acidification and their effects on chemoreception and prey detection capacities in cephalopods are unknown and needs future research.