C6orf10 low-frequency and rare variants in italian multiple sclerosis patients

In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value <= 5 x 10(-6)). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) <= 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs 16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 x 10(-7) and p < 1 x 10(-20)). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3' region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value ≤ 5 × 10−6). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10−7 and p < 1 × 10−20). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3′ region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS

Predictors of stigma in a sample of mental health professionals: Network and moderator analysis on gender, years of experience, personality traits, and levels of burnout

Abstract Background. Stigma is one of the most important barriers to help-seeking and to personal recovery for people suffering from mental disorders. Stigmatizing attitudes are present among mental health professionals with negative effects on the quality of health care. Methods. Network and moderator analysis were used to identify what path determines stigma, considering demographic and professional variables, personality traits, and burnout dimensions in a sample of mental health professionals (n = 318) from six Community Mental Health Services. The survey included the Attribution Questionnaire-9, the Maslach Burnout Inventory, and the Ten-Item Personality Inventory. Results. The personality trait of openness to new experiences resulted to determine lower levels of stigma. Burnout (personal accomplishment) interacted with emotional stability in predicting stigma, and specifically, for subjects with lower emotional stability lower levels of personal accomplishment were associated with higher levels of stigma. Conclusions. Some personality traits may be accompanied by better empathic and communication skills, and may have a protective role against stigma. Moreover, burnout can increase stigma, in particular in subjects with specific personality traits. Assessing personality and burnout levels could help in identifying mental health professionals at higher risk of developing stigma. Future studies should determine whether targeted interventions in mental health professionals at risk of developing stigma may be effective in stigma prevention

MONITORAMENTO TECNOLÓGICO COM BASE EM PATENTES: CATALISADORES PARA A OXIDAÇÃO DE GLICEROL

Em resposta a alguns problemas ambientais, a sociedade apresenta um novo comportamento, como a busca de fontes de energias renováveis e menos agressiva a natureza. O uso do biodiesel é uma alternativa para combater os efeitos poluentes proporcionados pelo uso de combustíveis fosseis. Com a produção de biodiesel, aumenta a quantidade de glicerol disponível para o mercado, visto que este é um coproduto do processo de obtenção de biodiesel. O glicerol possui diversas aplicações no mercado, mas com a produção de biodiesel, a tendência é que o mercado fique saturado. Visando o mapeamento de patentes relacionadas a catalisadores utilizados na reação de oxidação de glicerol, foi realizado um monitoramento tecnológico, em bancos de patentes (INPI, Derwent Innovations Index e WIPO), buscando analisar as tendências tecnológicas relativas a esta área

Relaxation of natural selection in the evolution of the giant lungfish genomes

Nonadaptive hypotheses on the evolution of eukaryotic genome size predict an expansion when the process of purifying selection becomes weak. Accordingly, species with huge genomes, such as lungfish, are expected to show a genome-wide relaxation signature of selection compared with other organisms. However, few studies have empirically tested this prediction using genomic data in a comparative framework. Here, we show that 1) the newly assembled transcriptome of the Australian lungfish, Neoceratodus forsteri, is characterized by an excess of pervasive transcription, or transcriptional leakage, possibly due to suboptimal transcriptional control, and 2) a significant relaxation signature in coding genes in lungfish species compared with other vertebrates. Based on these observations, we propose that the largest known animal genomes evolved in a nearly neutral scenario where genome expansion is less efficiently constraine

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

An integrated egenemic-transcriptomic approach to detect genes associated with atherosclerosis. The proto-oncogene BCL3 is a potential candidate.

L’aterosclerosi è una patologia degenerativa e progressiva delle arterie di grosso e medio calibro, caratterizzata da disfunzione endoteliale, accumulo di lipidi, infiltrazione di linfociti, migrazione e proliferazione di cellule muscolari lisce e deposizione di matrice extracellulare nella parete vascolare, con conseguente formazione di una placca ateromasica. Il processo aterosclerotico è alla base della patogenesi della malattia cardiovascolare nelle sue diverse manifestazioni cliniche, quali la malattia coronarica (CAD), l’infarto del miocardio (MI), l’arteriopatia ostruttiva periferica e l’ictus. L’aterosclerosi e’ responsabile delle prime tre cause di mortalità e morbilità nel mondo. L’aterosclerosi è una patologia complessa, alla quale concorrono molteplici fattori genetici ed ambientali. Lo scopo di questa tesi è stato l’identificazione di nuove componenti genetiche e molecolari della patologia aterosclerotica. Lo studio si e’ sviluppato a livello di DNA, RNA e proteina, applicando diverse metodologie e integrando dati ottenuti mediante: i) analisi di polimorfismi a singolo nucleotide (SNPs) in soggetti con e senza CAD, ii) analisi dei livelli di espressione genica in cellule muscolari lisce vascolari (VSMCs) e in placche aterosclerotiche umane, tramite microarray e Real time PCR, iii) analisi dei livelli di proteina mediante immunoistochimica di specimens di parete arteriosa carotidea. Partendo dai dati relativi a 91 SNPs analizzati in 510 pazienti con CAD e MI e in 388 soggetti di controllo senza patologia coronarica nella fase di replicazione dello studio di associazione “genome-wide” del Consorzio MiGen, sono stati selezionati 15 SNPs associati nominalmente al CAD (P<0.1). Riassunto Riassunto 2 Per studiare la potenziale associazione di questi SNPs con il processo aterosclerotico, i livelli di espressione dei 71 geni prossimali ai 15 SNPs sono stati analizzati sia in VSMCs, che rivestono un ruolo primario nel processo aterosclerotico, sia in porzioni di parete arteriosa derivanti da interventi di endoarteriectomia carotidea. A tal fine sono state condotte due consecutive ed indipendenti analisi del trascrittoma mediante microarray, la prima in culture primarie di VSMCs isolate da placche aterosclerotiche e dalla porzione prossimale virtualmente sana, la seconda in specimens di placche carotidee e delle corrispondenti porzioni “sane”. L’analisi dei profili di espressione ha permesso di identificare tre geni differenzialmente modulati, BCL3, PVRL2 e ABCA1, quest’ultimo già ampiamente studiato in relazione alla patologia aterosclerotica. Ponendo l’attenzione ai due geni adiacenti sullo stesso cromosoma (19q13) sono stati analizzati 4 SNPS intragenici, due per BCL3 e due per PVRL2 ed uno intergenico BCL3-PVRL2 in 393 soggetti di controllo e 442 pazienti con CAD senza pregresso MI. Quest’ultima coorte è stata selezionata per poter investigare in modo preferenziale l’eventuale associazione con l’aterosclerosi piuttosto che con la sua complicanza trombotica acuta. L’analisi dei genotipi ha mostrato che i portatori dell’allele G del polimorfismo BCL3 rs2965169 erano più rappresentati tra la popolazione con CAD e l’associazione con la patologia rimaneva significativa anche dopo correzione per i tradizionali fattori di rischio cardiovascolare. L’allele A del polimorfismo BCL3rs8100239 correlava con l’indice di massa corporea, l’ipertensione e il profilo lipidico. L’ analisi della distribuzione dei genotipi non ha identificato associazioni significative con la patologia coronarica o con variabili metaboliche sia per entrambi gli SNPs di PVRL2 che per la variante intergenica BCL3-PVRL2. L’analisi immunoistochimica di placche aterosclerotiche (n=10) e di porzioni adiacenti virtualmente sane (n=5) ha evidenziato espressione della proteina BCL3 solamente nella porzione aterosclerotica, associata a VSMCs e foam cells. Nella parete vascolare aterosclerotica l’espressione del mRNA per BCL3 sembra pertanto correlare con l’espressione della proteina. Complessivamente l’approccio integrato utilizzato nello sviluppo di questa tesi supporta il coinvolgimento della proteina BCL3 nel processo aterosclerotico.Atherosclerosis is the common ground of several clinical manifestations of cardiovascular diseases (CVD), including coronary artery disease (CAD), myocardial infarction (MI), peripheral artery occlusive disease and stroke. CVD is still one of the major causes of mortality and morbidity in the worldwide. Atherosclerosis is a complex multifactorial disease of the wall of medium-sized and large arteries, characterized by endothelial cell dysfunction, smooth muscle cell proliferation (VSMCs) and migration, inflammation, lipid and matrix accumulation. Susceptibility to atherosclerosis is in turn influenced by interplay of genetic and environmental factors. The aim of this thesis was to unravel new potential genetic and molecular signatures of the atherosclerosis, by using an integrated approach which joins information from i) single nucleotide gene polymorphisms (SNPs) analysis in a case-control study of subjects with or without CAD, ii) microarray-based gene expression analysis on human cultured VSMCs and on carotid artery specimens, and iii) immunohistochemical analysis in carotid artery specimens. Firstly, 15 SNPs nominally associated with CAD (P< 0.1) were selected from 91 SNPs, investigated within replication of a genome-wide association study –MiGen- (510 patients with CAD and MI and 388 subjects with normal coronary arteries CAD-free). The expression levels of 71 genes proximal to the 15 tag-SNPs were evaluated by two subsequent steps of microarray-based RNA profiling, the former in VSMC populations isolated from grossly non-atherosclerotic (NP) and atherosclerotic (DP) human carotid portions, and the latter in whole carotid specimens. BCL3 and PVRL2, located on chromosome 19, and ABCA1, extensively investigated before, were found to be differentially expressed. Focusing the attention on BCL3 and PVRL2, the only couple of contiguous genes differentially expressed in the transcriptomic analysis, a total of 5 SNPs, two within BCL3 gene, Abstract Abstract 4 two within PVRL2 gene and one BCL3-PVRL2 intergenic, were genotyped within CAD-free subjects (n=393) and CAD patients without MI history (n=442). This cohort enabled to preferentially investigate the atherosclerosis pathways, rather than its acute thrombotic complication. The carriership of the BCL3 rs2965169 G allele was more represented among CAD patients and remained independently associated with CAD after adjustment for all the traditional cardiovascular risk factors, while the BCL3 rs8100239 A allele correlated with metabolic abnormalities. No significant associations were found for either PVRL2 SNPs or BCL3-PVRL2 intergenic variant. A BCL3 positive immunostaining was detected in the intima-media of atherosclerotic specimens, but not within non-atherosclerotic ones, thus indicating a correlation between BCL3 mRNA and protein levels. This thesis, which integrates GWAS data with the downstream changes in the RNA and protein levels in human arterial wall specimens, supports a role for BCL3 in atherosclerosis

Intermixed Product and Service Boundaries: Exploring Servitization in Sheet Metal Industry

In the sheet metal industry, single machines or more complex production systems are integrated with a software needed to control them. While it is clear both for the company and the client that the machine is a product offered with the related services, the software deserves more attention. In the company where our team has been involved in an action research program, the software is conceived as a product with its related services, but this concept has not been properly transmitted to clients, who don't recognize it and pretend software services for free. In this industry, machinery is linked to its software and both are enhanced by the related services, so the final product-service bundle should be made by four components. In order to better clarify this concept and illustrate the solutions our research team has identified to promote a complete PSS offer, the four-leg chair metaphor is proposed. The proper value of the whole PSS offer can be transmitted by an effective communication process, supporting sales people with instruments such as predefined packets for software services. Organisational changes should be adopted such as job enlargement for software technicians and cross-training with salespeople. By the former, software technicians, who are frontline employees in direct contact with customers during the training phase, can be transformed into internal entrepreneurs by proper incentives. Since they lack marketing education and sometimes trust of salespeople, cross-training is proposed as an effective way to keep in touch software technicians with salespeople with mutual learning

Individuals with Down Syndrome: Editorial

Down syndrome (DS) is the most common syndromic cause of intellectual disability, so it has long been of interest to researchers [...]

Mental rotation ability and everyday-life spatial activities in individuals with Down syndrome

Although certain visuospatial abilities, such as mental rotation, are crucially important in everyday activities, they have been little explored in individuals with Down syndrome (DS). This study investigates: i) mental rotation ability in individuals with DS; and ii) its relation to cognitive abilities and to everyday spatial activities. Forty-eight individuals with DS and 48 typically-developing (TD) children, matched on measures of vocabulary and fluid intelligence, were compared on their performance in a rotation task that involved detecting which of two figures would fit into a hole if rotated (five angles of rotation were considered: 0\ub0, 45\ub0, 90\ub0, 135\ub0, 180\ub0). Participants were also assessed on their visuospatial and verbal cognitive abilities, and on their parents and/or educators reports regarding their everyday spatial activities. Results showed that: (i) individuals with DS were less accurate in mental rotation than TD children, with larger differences between the groups for smaller angles of rotation; individuals with DS could not mentally rotate through 180\ub0, while TD children could; (ii) mental rotation ability was related to fluid intelligence and to spatial activities (though other cognitive abilities are also involved in the latter) to a similar degree in the DS group and the matched TD children. These results are discussed with regard to the atypical development domain and spatial cognition models