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Dissecting the genetic heterogeneity of familial dementias
Full text linkLa demenza è una sindrome clinica caratterizzata da declino cognitivo le cui principali manifestazioni comprendono la perdita di memoria, deficit del linguaggio, deterioramento delle capacità di pianificazione e di giudizio, cambiamenti di comportamento e, non di rado, compromissione delle funzioni motorie ed infine dell'autonomia. Oggigiorno, si stima che circa 36 milioni di persone in tutto il mondo siano affette da demenza, stime che, secondo le ultime predizioni, è destinata a crescere fino a 115 milioni nel 2050. Considerando non solo la prevalenza bensì anche l'impatto sociale ed economico che questa malattia comporta, negli ultimi anni la ricerca scientifica sta investendo molte risorse in studi finalizzati all'identificazione delle cause e dei meccanismi patologici che sottendono a questa malattia. Lo scopo ultimo è quello di riuscire ad identificare dei trattamenti terapeutici efficaci che vadano a sostituire le cure palliative, le uniche disponibili oggi per questa malattia.
Esistono diverse forme di demenza e, tra esse, la Malattia di Alzheimer (MA) è la più frequente, seguita dalla Demenza Vascolare (DV) e dalla Degenerazione Frontotemporale Lobare (FTLD), la quale, rappresenta il sottotipo più comune dopo la MA negli individui al di sotto dei 65 anni. Tutti e tre questi disordini possono presentare una componente genetica e, malgrado i notevoli investimenti e progressi degli ultimi anni per chiarirne le basi molecolari, la conoscenza dei meccanismi patologici che li determinano è ancora limitata.
Tre forme di demenza, che possono avere una componente genetica, sono state incluse in questo studio: la Malattia di Alzheimer, la Degenerazione Frontotemporale Lobare e l'Arteriopatia Cerebrale Autosomica Dominante con Infarti Sottocorticali e Leucoencefalopatia (CADASIL), quest'ultima rappresentante un sottotipo di DV. I principali obiettivi di questo studio hanno compreso l'analisi mutazionale dei geni associati a queste malattie con il duplice intento di definirne le frequenze mutazionali in una casistica italiana e di valutare l'esistenza di eventuali correlazioni genotipo-fenotipo. Lo scopo finale era quello di definire degli algoritmi diagnostici utili ai medici specialisti nella selezione dei pazienti da sottoporre ad indagine genetica.
Sono state allestite due coorti: una comprendente pazienti con diagnosi di MA, FTLD o disordini correlati, e l'altra, pazienti con CADASIL. L'analisi mutazionale è stata eseguita mediante due principali approcci: la Cromatografia Liquida Denaturante (DHPLC) ed il sequenziamento diretto. Sono stati analizzati i seguenti geni: proteina Precursore dell'Amiloide (APP), Presenilina1 (PSEN1) e Presenilina2 (PSEN2) per la Malattia di Alzheimer; Progranulina (PGRN), Proteina Tau Associata ai Microtubuli (MAPT), Proteina Contenente Valosina (VCP), Proteina di Modificazione della Cromatina 2B (CHMP2B), Proteina Legante TAR DNA (TARDBP) per la Degenerazione Frontotemporale Lobare ed il gene NOTCH3 per il CADASIL. L'analisi mutazionale dei geni associati a MA e FTLD ha portato all'identificazione di 8 mutazioni: 3 nuove variazioni, PSEN1 p.Ile437Asn, PSEN2 p.Thr18Met e PGRN p.His400ThrfsX12 e, cinque sostituzioni già descritte, PSEN2 p.Arg71Trp e p.Met174Val, PGRN p.Phe86SerfsX170 e p.Thr272SerfsX10 e MAPT c.IVS10+16C>T. I risultati delle analisi molecolari e delle simulazioni al computer depongono a favore di una natura patogenetica per le variazioni dei geni Presenilina, malgrado il ruolo di alcune di esse sia dibattuto in letteratura. Le sostituzioni identificate nei geni PGRN e MAPT sono mutazioni il cui meccanismo patologico è già stato descritto.
Il fenotipo clinico riscontrato nei pazienti con le mutazioni identificate non era univoco e, specialmente le mutazioni nella PGRN erano associate ad una notevole variabilità delle manifestazioni cliniche, anche all'interno di una stessa famiglia. Inoltre, l'identificazione di una famiglia con diagnosi di FTD-MND in linkage al cromosoma 9 sottolinea ulteriormente l'eterogeneità genetica delle FTLD.
L'analisi mutazionale del gene NOTCH3 ha portato all'identificazione di 21 diverse mutazioni, incluse 7 nuove variazioni, distribuite non uniformemente lungo il gene. Si è osservata una clusterizzazione delle mutazioni in aree geografiche diverse: la maggior parte identificate in pazienti provenienti dal nord-est Italia, alcune nel nord-ovest ed altre nell'Italia centrale. Nell'ipotesi che questa regionalizzazione rispecchiasse un effetto fondatore, si sono studiati gli aplotipi associati a queste mutazioni: i risultati, sebbene compatibili, non hanno permesso di confermare l'effetto fondatore in quanto la maggior parte di queste variazioni cadeva nell'aplotipo più frequente.
I risultati di questo studio, complessivamente sono stati utili per definire degli algoritmi diagnostici che potrebbero aiutare i clinici ad identificare i pazienti, suggestivi di una base molecolare, da sottoporre ad analisi genetica.Dementia is a clinical syndrome associated with progressive deterioration of intellectual functions including loss of memory, difficulties with language, simple calculations, planning and judgment, and motor skills with eventually loss of autonomy. Currently there are an estimated 36 million people worldwide with dementia and this figure is set to increase to more than 115 million people by 2050. Given the prevalence of dementia and the associated significant financial and human costs, in recent years there has been a huge burst of studies aimed to identify the causes of this disorder and its underlain pathological mechanisms, in order to define therapeutic treatments to replace the nowadays available palliative cares.
Among different subtypes of dementia, Alzheimer's Disease (AD) is the most frequent form, followed by Vascular Dementia and Frontotemporal Lobar Degeneration (FTLD) which represents the second most common form in people younger than 65 years. All three of these diseases may have a genetic component and, despite considerable progress and efforts made in recent years to clarify their molecular basis, little is known about the pathological mechanisms determining these diseases.
Three forms of dementia, which may have a genetic component, were included in this study: Alzheimer's Disease, Frontotemporal Lobar Degeneration and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leuokoencephalopathy (CADASIL) which is a subtype of vascular dementia. The main objectives of this study included mutational analysis of the genes associated with these diseases with the dual purpose of defining their mutational frequencies in an Italian series and to evaluate the presence of possible genotype-phenotype correlations. The secondary purpose is to be able to draw diagnostic algorithms useful to clinicians in selecting which patients submit to genetic testing.
Two clinical cohorts were set up; one consisting in patients with diagnosis of AD, FTLD or related disorders, and the other made up of patients with CADASIL. The mutational analysis was performed by two main techniques: Denaturing High Performance Liquid Chromatography and direct sequencing. The analyzed genes encompassed: Amyloid Precursor Protein (APP), Presenilin1 (PSEN1) and Presenilin2 (PSEN2) for Alzheimer's Disease; Progranulin (PGRN), Microtubule Associated Protein Tau (MAPT), Valosin Containing Protein (VCP), Charged Multivesicular Body Protein 2B (CHMP2B), TAR DNA Binding Protein (TARDBP) for Frontotemporal Lobar Degeneration and NOTCH3 for CADASIL.
The mutational analysis of AD- and FTLD-associated genes led to the identification of 8 mutations: three novel variations, PSEN1 p.Ile437Asn, PSEN2 p.Thr18Met and PGRN p.His400ThrfsX12 and five already described substitutions, PSEN2 p.Arg71Trp and p.Met174Val, PGRN p.Phe86SerfsX170 and p.Thr272SerfsX10 and MAPT c.IVS10+16C>T.
The molecular data and in silico analyses performed in this study argue in favour of pathogenetic nature for Presenilins variations even though the role of some of them is debated in literature. The substitution identified in PGRN and MAPT are mutations whose pathogenic mechanism has already been described.
The clinical phenotype associated to identified mutations was not unique and, especially mutations in the PGRN gene showed a marked variability in clinical presentations, even within the same family. Furthermore, the identification of a FTD-MND family linked to a locus on chromosome 9 further emphasizes the genetic heterogeneity of FTLD.
The mutational screening of NOTCH3 gene led to the identification of 21 different mutations, including 7 novel variations, distributed unevenly along the gene. A geographical clustering was observed with mutations identified only in patients living in North-East Italy, a few in North-West and other in Central Italy. Haplotype analysis was performed to assess a possible founder effected underlying this regionalization but, although consistent, it was not confirmed as the majority of mutations was associated with the most common haplotype.
The results of this study together were useful to define diagnostic algorithms that could help clinicians to identify patients suggestive of a molecular basis of disease to address to genetic testing
Co-Occurrence of the C9ORF72 Expansion and a Novel GRN Mutation in a Family with Alternative Expression of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
No full textThe C9ORF72 repeat expansion is the major cause of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. In the reported pedigree, the 47-year old proband, presenting a four-year history of frontotemporal dementia, carried the C9ORF72 expansion plus a novel GRN p.Cys246X mutation. The father and a paternal uncle, harboring the C9ORF72 expansion only, had died by pure ALS with onset at 63 and 76 years, respectively. The case report and a review of the literature emphasize that phenotypical variations of the FTLD-ALS spectrum could be due to digenic inheritance
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Nutritional traits of dorsal and ventral fillets from farmed European sea bass, gilthead sea bream and rainbow trout.
No full textQuality differences due to fillet region have been quite extensively researched in farmed Atlantic salmon, but much less so in other important farmed species, namely European sea bass, gilthead sea bream and rainbow trout. The paucity of information on this issue is most likely due to the relatively small fillet size of these latter species, yet it deserves attention as a potential problem in sampling techniques in view of nutritional, storage and sensory analyses. Therefore this preliminary study was conducted to determine if and to what extent compositional differences exist between dorsal and ventral fillets from farmed European sea bass (Dicentrarchus labrax, ESB in the following), gilthead sea bream (Sparus aurata, GSB) and rainbow trout (Oncorhynchus mykiss, RT).
Five specimens for each species were randomly selected from stocks of fish intensively reared in Italian commercial farms producing for the Italian market and ready for sale. Fish were weighed, eviscerated and filleted, each fillet being weighed with skin, then cut along the insertion line of the ribs to obtained a dorsal and a ventral fillet. After skinning, the two dorsal fillets obtained from each fish were joined, their sum being named “dorsal portion” (DP), and weighed. The same was made with the two ventral fillets, thus giving a “ventral portion” (VP). Both DP and VP obtained from each fish were analysed in duplicate for proximate and fatty acid composition, expressed as g/100 g flesh.
Despite wide differences in body weight (mean  standard error: ESB = 226  20 g; GSB = 273  18 g; RT = 519  35 g), the three species did not differ as to the yield of DP (range: 22.11-22.80%) or VP (range: 16.08-18.20%), both calculated on body weight. ESB proximate composition proved to be the most affected by fillet location, followed by GSB, and then RT. Lipid content (g/100 g flesh) was by far the most variable trait (4.45 vs 8.58 vs 4.00 in DP, and 12.99 ab vs 14.43 a vs 6.62 b in VP, for ESB, GSB and RT, respectively, the ratio DP:VP being 1:2.92, 1:1.68 and 1:1.66 in that order). Species effect within location was examined to compare ESB, GSB and RT flesh lipid for both their content of health-related polyunsaturated fatty acids (PUFA) and their susceptibility to oxidation, evaluated through the Peroxidisability Index (PI). DP of GSB was significantly (and predictably, given its higher lipid content) richer in n-3 PUFA than ESB and RT (1.83 a vs 1.05 b vs 1.12 b, resp., as g/100 g flesh); GSB superiority was maintained, though only marginally, in VP (2.82 vs 2.68 vs 1.80, in the same order). The ratio between eicosapentaenoic (EPA, C20:5 n-3) and docosahexaenoic (DHA, C22:6 n-3) acids was higher in ESB than GSB and RT, both in DP (0.49 a vs 0.44 a vs 0.33 b, resp.) and in VP (0.59 a vs 0.49 b vs 0.34 c, resp.). Within each species n-6/n-3 was lower, i.e. more favourable, in DP than in VP, RT oil emerging as the most healthful in that respect. The higher n-3 PUFA (most notably DHA) percentage in RT oil was also responsible for its higher PI, both in DP (192 ab vs 170 b vs 227 a, for ESB, GSB and RT, resp.) and in VP (163 b vs 155 b vs 220 a, in the same order).
On the grounds of the present results, though obtained on few specimens for each species, there seems to be ample reason to further investigate the effect of location on fillet compositional traits
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
No full textCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis
Malattia di Charco-Marie-Tooth. Guida alla diagnosi molecolare.
No full textLa malattia di Charcot-Marie-Tooth (CMT) è la patologia genetica più frequente del sistema nervoso periferico. La diagnosi molecolare è essenziale per il counselling genetico, per la diagnosi differenziale con neuropatie acquisite fenotipicamente convergenti, nonché un prerequisito per terapie sperimentali mirate ai meccanismi patogenetici. Gli ultimi anni hanno registrato il moltiplicarsi dei fenotipi CMT e dei geni associati. Gli autori passano in rassegna le recenti acquisizioni della genetica ed illustrano i possibili percorsi clinici che orientino i tests molecolari
Growth response and body composition of sharpsnout sea bream (Diplodus puntazzo) fed a high energy diet with different protein levels.
Full text linkA study was undertaken to determine the effect of a high energy diet with two different protein levels on growth, feed efficiency and whole body composition of sharpsnout sea bream (Diplodus puntazzo). Two isoenergetic diets (24.1-24.7 MJ Kg-1 dry weight) with two different protein levels (46.7 and 52.5 % dry weight) were fed to satiety to duplicate groups of 300 fish (initial body weight 27.7 ± 0.2 g) for 94 days. At the end of the experiment, the fish fed 52.5 % protein showed a statistically higher (P < 0.05) daily intake rate (DIR) of feed. Feed conversion rate (FCR) was similar among groups. Whole body composition was similar among treatments while the high enrgy level of the diets significantly modified lipid and moisture content in comparison with fish at the beginning of the experiment. Protein efficiency ratio (PER), gross protein efficiency (GPE) of fish fed 46.7 % protein diet were statistically higher than those for the other diet. It may be concluded that the diet with a lower protein level has given better protein utilization and a protein sparing effect but tended to result in reduced weight gain and feed intake, when compared with diet containing higher protein levels
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