Mathematical Modeling of Uniaxial Mechanical Properties of Collagen Gel Scaffolds for Vascular Tissue Engineering

Article ID 859416Small diameter tissue - engineered arteries improve their mechanical and functional properties when they are mechanically stimulated. Applying a suitable stress and-or strain with or without a cycle to the scaffolds and cells during the culturing process resides in our ability to generate a suitable mechanical model. Collagen gel is one of the most used scaffolds in vascular tissue engineering, mainly because it is the principal constituent of the extracellular matrix for vascular cells in human. The mechanical modeling of such a material is not a trivial task, mainly for its viscoelastic nature. Computational and experimental methods for developing a suitable model for collagen gels are of primary importance for the field. In this research, we focused on mechanical properties of collagen gels under unconfined compression. First, mechanical viscoelastic models are discussed and framed in the control systemtheory. Second,models are fitted using system identification. Several models are evaluated and two nonlinear models are proposed:Mooney - Rivlin inspired and Hammerstein models. Theresults suggest that Mooney - Rivlin andHammerstein models succeed in describing the mechanical behavior of collagen gels for cyclic tests on scaffolds (with best fitting parameters 58.3 per cent and .75.8 per cent, resp.). When Akaike criterion is used, the best is the Mooney - Rivlin inspired model

Mathematical modeling of uniaxial mechanical properties of collagen gel scaffolds for vascular tissue engineering

Small diameter tissue-engineered arteries improve their mechanical and functional properties when they are mechanically stimulated. Applying a suitable stress and/or strain with or without a cycle to the scaffolds and cells during the culturing process resides in our ability to generate a suitable mechanical model. Collagen gel is one of the most used scaffolds in vascular tissue engineering, mainly because it is the principal constituent of the extracellular matrix for vascular cells in human. The mechanical modeling of such a material is not a trivial task, mainly for its viscoelastic nature. Computational and experimental methods for developing a suitable model for collagen gels are of primary importance for the field. In this research, we focused on mechanical properties of collagen gels under unconfined compression. First, mechanical viscoelastic models are discussed and framed in the control system theory. Second, models are fitted using system identification. Several models are evaluated and two nonlinear models are proposed: Mooney-Rivlin inspired and Hammerstein models. The results suggest that Mooney-Rivlin and Hammerstein models succeed in describing the mechanical behavior of collagen gels for cyclic tests on scaffolds (with best fitting parameters 58.3% and 75.8%, resp.). When Akaike criterion is used, the best is the Mooney-Rivlin inspired model.Facultad de Ciencias ExactasInstituto de Física de Líquidos y Sistemas Biológico

Técnicas de ultrasonido : Una herramienta potencial para la ingeniería de tejidos

El objetivo de este trabajo es desarrollar dos montajes experimentales para la evaluación de las propiedades acústicas de hidrogeles de colágeno y para estudiar su correlación con las propiedades mecánicas. El primero permite estimar la velocidad del sonido, atenuación e impedancia acústica de las muestras manejando la temperatura. En el segundo, la configuración anterior se combina con un ensayo mecánico de compresión, lo que permite interrogar al mismo tiempo, tanto propiedades acústicas como mecánicas de la muestra. Se observan las propiedades acústicas y mecánicas de los geles de colágeno preparados de acuerdo a diferentes condiciones experimentales: pH y la concentración de colágeno. La variación de estos parámetros permite modificar las condiciones mecánicas de la matriz.Facultad de Ingenierí

Formazione di giovani leader di sanità pubblica: un’esperienza sperimentale dell’Accademia Lombarda di Sanità Pubblica

Introduzione L’Accademia Lombarda di Sanità Pubblica (ALSP), Associazione no-profit fondata nel 2017, ha come obiettivo quello di promuovere il progresso in Sanità Pubblica (SP) attraverso il coinvolgimento di studiosi impegnati a vario titolo nei molteplici ambiti della SP come quello dell’igiene, dell’epidemiologia, della prevenzione, dell’ambiente, della direzione sanitarie, dell’edilizia sanitaria, del management, del diritto e dell’economia sanitaria. A tale scopo l’Accademia ha promosso, all’inizio del 2019, l’iniziativa Academy of Young Leader in Public Health (AYLPH). Si tratta di un percorso didattico-scientifico di un anno rivolto a 10 giovani con background formativo differente, fortemente motivati a sviluppare competenze di leadership in SP e già avviati a carriere professionali e di ricerca. Metodi Questo percorso formativo per i 10 giovani, selezionati con bando competitivo aperto ai soci, basa il suo metodo didattico-formativo su incontri con riconosciuti leader nazionali e internazionali di SP; visite a istituzioni; collaborazione a progetti di ricerca; training specifico sulla scrittura di lavori scientifici; opportunità di partecipare a convegni nazionali internazionali e a corsi brevi ad hoc. Risultati A metà programma, le attività condotte sono state: esperienza di team building in località montana; incontro con alcune importanti figure impegnate, a vari livelli, nella sanità pubblica come l’ex Ministro della salute Beatrice Lorenzin, l’Editor-in-chief della rivista European Journal of Public Health Peter Allebeck, il Presidente EUPHA Natasha Azzopardi-Muscat oltre ai past-Presidenti EUPHA Walter Ricciardi e Martin Mc Kee. Ha fatto seguito un corso intensivo sulle revisioni sistematiche che ha visto l’attivazione di 6 gruppi di ricerca coinvolti in altrettanti progetti di revisione sistematica della letteratura. Ulteriori attività sono state: la partecipazione all’Assemblea Generale dell’Organizzazione Mondiale della Sanità, la partecipazione al Deans’ and Directos’ Retreat dell’ASPHER e al Congresso Americano di Sanità Pubblica (APHA). Sono in programma anche un corso di Public speaking, presso l’Università di Pisa ed alcuni incontri ad hoc. Conclusioni Nel contesto attuale, in cui la salute delle persone è minata da un senso di sfiducia nei confronti delle Istituzioni, dalla mancata equità nell’accesso alle cure e da stili di vita scorretti, la SP ha necessità di formare nuovi leaders in grado di promuovere valori e guidare al cambiamento individuale, organizzativo e politico. La AYLPH rappresenta un’occasione formativa di alto livello per giovani professionisti interessati a conoscere e attuare strategie di leadership in SP

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor