Tooth agenesis and orofacial clefting: genetic brothers in arms?

L’Agenesia Dentaria e le Schisi Oro-facciali costituiscono comuni anomalie dello sviluppo e la loro co-occorrenza è osservata spesso in pazienti ed in modelli animali. Lo scopo della presente revisione sistematica è quello di indagare a fondo la letteratura corrente (PubMed, EMBASE) per identificare i geni e loci genomici che contribuiscono alla co-occorrenza di Agenesia Dentaria e di Schisi Oro-facciali sindromiche e non-sindromiche, al fine di conoscere i meccanismi molecolari sottostanti al duplice coinvolgimento nello sviluppo dei denti e primordi facciali. Complessivamente sono stati analizzate 84 pubblicazioni comprendenti descrizioni fenotipiche e genotipiche riconducibili a 9 loci genomici e 26 geni candidati alla base della co-occorrenza dei due difetti congeniti: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFβ3, TGFβR1, TGFβR2, FGF8, FGFR1, KISS1R, WNT3, Wnt5a, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, e PVRL1. I percorsi molecolari, le funzioni cellulari, di espressione tessuto-specifica e di associazione con la patologia sono stati esaminati utilizzando database accessibili al pubblico (EntrezGene, UniProt, OMIM). I termini Gene Ontology dei processi biologici mediati da geni candidati sono stati usati per creare raggruppamenti utilizzando il GOTermMapper (Lewis-Sigler Institute, Princeton University), speculando su sei super-cluster: (a) sviluppo anatomico, (b) la divisione cellulare, crescita e motilità, (c) il metabolismo cellulare e catabolismo, (d) trasporto cellulare, (e) organizzazione struttura cellulare e (f) organo / processi specifici del sistema. Questa recensione ha lo scopo di aumentare la conoscenza sui meccanismi alla base della co-occorrenza di Agenesia Dentaria e di Schisi Oro-facciali, al fine di aprire la strada per migliorare la diagnosi molecolare mirata (prenatale) e, infine, per riflettere sullo sviluppo futuro di strategie terapeutiche o preventive per queste condizioni invalidanti.Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFβ3, TGFβR1, TGFβR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future

FE parametric study of RWS/WUF-B moment connections with elliptically-based beam web openings under monotonic and cyclic loading

This paper provides numerical results investigating the behaviour of steel web-perforated beams with different shaped single openings located close to beam-to-column connections under monotonic and cyclic loading. In particular, the beams considered feature circular and patented elliptically-based perforations. Non-standard elliptically-based perforations have been proposed previously and are optimally designed to maximise resistance against Vierendeel moments and web-post buckling under static loads at the ultimate limit state. Comprehensive parametric nonlinear finite element analyses using the commercial FE package ANSYS were conducted. Initially, a FE model of the beam-to-column WUF-B moment connection was developed and calibrated against pertinent experimental results found in the literature. Next, parametric analyses were undertaken to assess the RWS/WUF-B connection regarding strength (moment), deformation (rotation) and column web shear panel zone deformation for different shapes of beam web perforations, hole sizes, and their locations. The study concludes that larger web openings are capable of moving the plastic hinge away from the column face and the CJP weld. Also, interstory drifts can be controlled with the wise use of the beam web opening size, shape, and distance from the face of the column, as suggested in the paper. Following, a step-by-step design process for RWS/WUF-B connection is presented

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

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Safety and Outcome of Revascularization Treatment in Patients With Acute Ischemic Stroke and COVID-19: The Global COVID-19 Stroke Registry.

COVID-19 related inflammation, endothelial dysfunction and coagulopathy may increase the bleeding risk and lower efficacy of revascularization treatments in patients with acute ischemic stroke. We aimed to evaluate the safety and outcomes of revascularization treatments in patients with acute ischemic stroke and COVID-19. Retrospective multicenter cohort study of consecutive patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021, tested for SARS-CoV-2 infection. With a doubly-robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT). Of a total of 15128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19. 5848 (38.7%) patients received IVT-only, and 9280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted odds ratio [OR] 1.53; 95% CI 1.16-2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20-2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23-1.99), 24-hour (OR 2.47; 95% CI 1.58-3.86) and 3-month mortality (OR 1.88; 95% CI 1.52-2.33).COVID-19 patients also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26-1.60). Patients with acute ischemic stroke and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 treated patients. Current available data does not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in COVID-19 patients, or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring and establishing prognosis