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  • 1
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 6 ( 2022-03-13), p. 3084-
    Abstract: The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants (CNVs) of the ARX locus found in patients presenting wide-ranging phenotypic variations including ID, speech delay, hypotonia and psychiatric abnormalities. We also report on a further novel Xp21.3 duplication detected in a male patient with moderate ID and carrying a fully duplicated copy of the ARX locus and the ultraconserved enhancers. As consequences of this rearrangement, the patient-derived lymphoblastoid cell line shows abnormal activity of the ARX-KDM5C-SYN1 regulatory axis. Moreover, the three-dimensional (3D) structure of the Arx locus, both in mouse embryonic stem cells and cortical neurons, provides new insight for the functional consequences of ARX duplications. Finally, by comparing the clinical features of the 16 CNVs affecting the ARX locus, we conclude that—depending on the involvement of tissue-specific enhancers—the ARX duplications are ID-associated risk CNVs with variable expressivity and penetrance.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
    In: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Elsevier BV, Vol. 1645, No. 1 ( 2003-1), p. 40-48
    Type of Medium: Online Resource
    ISSN: 1570-9639
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
    detail.hit.zdb_id: 2209540-8
    SSG: 12
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  • 3
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 28, No. 24 ( 2019-12-15), p. 4089-4102
    Abstract: A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 4
    In: Genes, MDPI AG, Vol. 12, No. 7 ( 2021-07-18), p. 1088-
    Abstract: Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (KDM5C) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (ZNF711) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of ARX, KDM5C, PHF8 and ZNF711 was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527218-4
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  • 5
    Online Resource
    Online Resource
    MDPI AG ; 2022
    In:  International Journal of Environmental Research and Public Health Vol. 20, No. 1 ( 2022-12-20), p. 5-
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 20, No. 1 ( 2022-12-20), p. 5-
    Abstract: Lakes play an important role in providing various ecosystem services. However, stressors such as climate change, land use, or land-cover change threaten the ecological functions of lakes. National and international legislations address these threats and establish consistent, long-term monitoring schemes. Remote sensing techniques based on the use of Unmanned Aerial Vehicles (UAV) have recently been demonstrated to provide accurate and low-cost spatio-temporal views for the assessment of the ecological status of aquatic ecosystems and the identification of areas at risk of contamination. Few studies have been carried out so far on the employment of these tools in the monitoring of lakes. Therefore, high-resolution UAV surveys were used to analyse and evaluate natural and anthropogenic impacts on the habitat status of a volcanic lake in a protected area. Five UAV flights took place during a year-long cycle (November 2020 to November 2021) in a volcanic lake located in southern Italy. For each flight performance, an orthomosaic of georeferenced RGB images was obtained, and the different features of interest were monitored and quantified using automated processing in a GIS environment. The UAV images made it possible not only to estimate the flooded shores but also to detect the impact of human-made structures and infrastructures on the lagoon environment. It has been possible to observe how the rapid changes in lake-water level have led to the submersion of about 90.000 m2 of terrain in winter, causing the fragmentation and degradation of habitats, while the connectivity of the natural ecosystem has been threatened by the presence of the road around the lake. The proposed methodology is rather simple and easily replicable by decision makers and local administrators and can be useful for choosing the best restoration interventions.
    Type of Medium: Online Resource
    ISSN: 1660-4601
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2175195-X
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  • 6
    In: Rheumatology, Oxford University Press (OUP), Vol. 59, No. Supplement_2 ( 2020-04-01)
    Abstract: The modified Rodnan skin score (mRSS) is the current gold standard for skin assessment in systemic sclerosis (SSc) both in clinical trials and practice. Several studies have reported that skin high frequency ultrasound (HFUS) and, more recently, optical coherence tomography (OCT) are able to reflect the severity of the skin disease in SSc. Aim of the study was to compare OCT and HFUS in the assessment of skin involvement in SSc. Methods Dorsal forearm skin of consecutive diffuse cutaneous SSc (dcSSc) patients and matched-healthy controls (HC) were scanned using OCT and HFUS by investigators blinded to the clinical details using Vivosight scanner (1 assessor) and Esaote MyLab70 equipped with a 22 MHZ probe (2 assessors) respectively. Minimum Optical Density (MinOD), Maximum OD (MaxOD) and OD at 300 micron-depth (OD300) (OCT) and skin thickness (HFUS) were measured. Clinical involvement was assessed by a blinded operator using the mRSS and results were cross matched with imaging data. Statistical analysis was performed using GraphPad Prism software V.7.0. Results A total of 88 OCT images and 176 HFUS images were obtained from 22 dcSSc patients [20 Female, mean age 49 (±11) years, 12 with & lt; 5 years disease duration) and 22 HC (20 Female, mean age 50.7 (±6.7) years]. All OCT measures (MinOD, MaxOD and OD300) were significantly lower in SSc patients than in HC (p = 0.011, p & lt; 0.0001, p & lt; 0.0001 respectively). HFUS showed a lower performance in discriminating SSc skin vs HC compared to OCT (overall AUC 0.6 vs 0.72, 0.8 and 0.89 for MinOD, MaxOD and OD300 respectively). Nevertheless, mean HFUS skin thickness significantly correlated with mRSS at site of analysis (r = 0.47, p = 0.0013) and showed overall excellent interobserver reliability between assessors (ICC & gt;0.8). Importantly, MaxOD and OD300 negatively correlated with HFUS skin thickness (r=-0.32, p = 0.035; r=-0.31, p = 0.039). Conclusion OCT of the skin has been previously validated against skin biopsy in SSc. Our results validate HFUS against OCT and indicate that HFUS of the skin is a reliable measure of skin involvement. Further, here we show that HFUS and OCT outperform each other in measuring different aspects of skin involvement in SSc and they offer complementary surrogate outcome measures of disease. Disclosures D. Temiz Karadag None. G. Lettieri None. V. Picerno None. O. Gundogdu None. M. Padula None. G.A. Mennillo None. A.A. Padula None. F. Del Galdo None. S. D'Angelo None. G. Abignano None.
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474143-X
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  • 7
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-02-18)
    Abstract: Anti-Dense Fine Speckled 70 (DFS70) antibodies are a common finding in clinical laboratory referrals. High prevalence of DFS70 autoantibodies in healthy population and usual negative association with Antinuclear Antibody (ANA)-associated autoimmune rheumatic diseases (AARD) were reported. The aim of this study was to evaluate the prevalence of DFS70 autoantibodies and their association with other autoantibodies in the context of a routine ANA referral cohort. Consecutive sera submitted for ANA screening were analyzed for anti-DFS70 antibodies by indirect immunofluorescence (IIF) (n = 3175, 1030 men and 2145 women) then confirmed by immunoblotting. Anti-DFS70 positive samples were also assayed for a large spectrum of other circulating autoantibodies. The prevalence of anti-DFS70 antibodies was 1.7% in the whole population and 4.6% in the ANA-positive samples. Comparison between DFS70 IIF and immunoblotting showed an excellent correlation between the two methods. The prevalence of anti-DFS70 positive was significantly higher in females (2.1%, 45/2145) than in males (1.0%, 10/1030). Of note, no concomitant autoantibodies were found in the DFS70-positive male group compared with DFS70-positive females group that showed other serum autoantibodies in the 51% of cases. Anti-DFS70 reactivity in male population may represent an useful biomarker predicting the absence of other autoantibodies. On the contrary, the serological profile of DFS70-positive females required further investigations in order to define the presence of concomitant disease-marker autoantibodies.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 8
    In: Rheumatology, Oxford University Press (OUP), Vol. 59, No. Supplement_2 ( 2020-04-01)
    Abstract: The Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study has shown that 82% of patients with Raynaud’s phenomenon, specific ANA positivity and scleroderma pattern at nailfold video capillaroscopy will fulfill classification criteria within 5 years. This is suggesting that there is a sub-clinical window of opportunity to diagnose systemic sclerosis (SSc) before clinical manifestations occur. In this scenario, a non-invasive tool to diagnose SSc in clinically unaffected skin might improve the early detection of disease in at risk-patients. Optical coherence tomography (OCT) of the skin has been shown to be a sensitive and accurate biomarker of skin fibrosis in SSc. Here we aimed to assess the ability of skin OCT to detect SSc in clinically unaffected skin from a multicentre cohort. Methods Dorsal forearm skin of SSc patients and matched-healthy controls (HC) was evaluated using VivoSight scanner (Michelson Diagnostics). Mean A-scans (mean OCT signal plotted against depth-in-tissue) were derived as previously described. Minimum Optical Density (MinOD), Maximum OD (MaxOD) and OD at 300 micron-depth (OD300) were calculated. Clinical involvement was assessed by an operator blinded to OCT findings using the mRSS. Receiver-operating characteristic (ROC) curve analysis was carried out for MinOD, MaxOD, and OD300 to evaluate their ability to discriminate between SSc and HC. Statistical analysis was performed using GraphPad Prism software V.7.0. Results One hundred seventy four OCT images were collected from 87 subjects [43 SSc (39 Female, mean age 49.7±9.1 years) and 44 gender/age-matched healthy controls (HC) (36 Female, mean age 50.2±8.3 years)] in two different SSc centres. All patients fulfilled classification criteria for SSc. OCT measures demonstrated discriminative ability in SSc skin detection with any clinical skin involvement (0-3 at site of analysis) with an AUC of 0.73 (MinOD, 95%CI 0.64-0.81), 0.77 (MaxOD, 95%CI 0.7-0.85) and 0.82 (OD300, 95%CI 0.76-0.89); p & lt; 0.0001 for all as previously indicated. Most importantly, all three measures showed comparable performance in detecting scleroderma also in clinically unaffected skin (mRss=0 at site of analysis), with an AUC of 0.7 (95%CI 0.6-0.81, p = 0.001), 0.72 (95%CI 0.61-0.83, p = 0.0003) and 0.72 (95%CI 0.61-0.83, p = 0.0003) for MinOD, MaxOD and OD300 respectively. Conclusion Virtual biopsy by OCT recognises clinically unaffected skin of SSc patients from the HC skin. This is consistent with gene array data showing that scleroderma specific signatures are consistent in affected and clinically unaffected skin. These results inform future studies on at risk patients with clinically unaffected skin which may define a role for OCT in detecting subclinical SSc. Disclosures G. Abignano None. D. Temiz Karadag None. O. Gundogdu None. G. Lettieri None. M. Padula None. A.A. Padula None. P. Emery None. S. D'Angelo None. F. Del Galdo None.
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474143-X
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  • 9
    In: Internal and Emergency Medicine, Springer Science and Business Media LLC, Vol. 14, No. 5 ( 2019-8), p. 713-718
    Type of Medium: Online Resource
    ISSN: 1828-0447 , 1970-9366
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2378342-4
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  • 10
    In: Journal of Autoimmunity, Elsevier BV, Vol. 108 ( 2020-03), p. 102397-
    Type of Medium: Online Resource
    ISSN: 0896-8411
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1468989-3
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