: Inherited antithrombin (AT) deficiency, with prevalence in the general population ranging 0.02-0.17%, is an autosomal dominant disorder associated with a high risk of venous thromboembolism. In ...most cases, deficiency is caused by mutations in the AT-coding gene (SERPINC1). Only 24 splicing defects have been described causing AT deficiency, all affecting exon flanking regions. The aim of the current study was to characterize the mutations underlying AT deficiency in 10 venous thromboembolism Polish patients aged 42.9 (14-63) years. Whole SERPINC1 gene sequencing was done by next generation sequencing methods. Eight cases had mutations previously described. However, we identified two new intronic mutations that might affect the correct splicing of exon 6 according to in-silico predictions: c.1154-1 G>C, which strongly disturbs the acceptor sequence and c.1219-534 A>G, a deep intronic mutation that might generate a cryptic donor sequence; both might compete with the wild-type donor sequence and explain the associated moderate AT deficiency of carriers. In conclusion, we show the molecular base of AT deficiency in 10 new Polish patients, including two novel SERPINC1 gene mutations potentially affecting splicing.
Essentials Vitamin K-dependent coagulant factor deficiency (VKCFD) is a rare autosomal recessive disorder. We describe a case of inherited VKCFD due to uniparental disomy. The homozygous mutation ...caused the absence of GGCX isoform 1 and overexpression of Δ2GGCX. Hepatic and non-hepatic vitamin K-dependent proteins must be assayed to monitor VKCFD treatment.
Background Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in the γ-glutamyl carboxylase gene (GGCX) or the vitamin K epoxide reductase gene (VKORC1), with great heterogeneity in terms of both clinical presentation and response to treatment. Objective To characterize the molecular basis of VKCFD in a Spanish family. Methods and Results Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband. Uniparental disomy (UPD) of chromosome 2 caused homozygosity of a mutation (c.44-1G>A) resulting in aberrant GGCX splicing. This change contributed to absent expression of the mRNA coding for the full-length protein, and to four-fold overexpression of the smaller mRNA isoform lacking exon 2 (Δ2GGCX). Δ2GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K
supplementation; and (ii) a mild non-bleeding phenotype. Conclusions Our study identifies a new autosomal disease, VKCFD1, caused by UPD. These data suggest that the Δ2GGCX isoform may retain enzymatic activity, and strongly encourage the evaluation of both hepatic and non-hepatic vitamin K-dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.
The presence of Saccharomyces cerevisiae in grape berries and fresh musts is usually very low. However, as fermentation progresses, the population levels of this species considerably increase. In ...this study, we use the concept of fitness advantage to measure how increasing ethanol concentrations (0–25%) and temperature values (4–46 °C) in wine fermentations affects competition between S. cerevisiae and several non-Saccharomyces yeasts (Hanseniaspora uvarum, Torulaspora delbrueckii, Candida zemplinina, Pichia fermentans and Kluyveromyces marxianus). We used a mathematical approach to model the hypothetical time needed for S. cerevisiae to impose itself on a mixed population of the non-Saccharomyces species described above. This approach also took into consideration the influence of environmental factors and the initial population levels of S. cerevisiae (0.1, 1.0 and 10.0%). Our results suggest that Saccharomyces niche construction via ethanol production does not provide a clear ecological advantage (at least not until the ethanol concentration exceeds 9%), whereas a temperature rise (above 15 °C) does give S. cerevisiae a considerable advantage. The initial frequency of S. cerevisiae considerably influences the time it needs to impose itself (until it reaches a final frequency of 99% in the mixed culture), the lowest time values being found at the highest initial frequency. In light of these results, the application of low temperatures in the wine industry could favor the growth and survival of non-Saccharomyces species for a longer period of time.
► During the alcoholic wine fermentation, Saccharomyces niche construction via ethanol production does not provide a clear ecological advantage (at least not until the ethanol concentration exceeds 9%), whereas a temperature rise (above 15 °C) does give S. cerevisiae a considerable advantage. ► The initial frequency of S. cerevisiae in the grape must considerably influences the time it needs to impose itself throughout the alcoholic fermentation. ► The application of low temperatures in the wine industry could favor the growth and survival of non-Saccharomyces species for a longer period of time.
We investigate a tractable Singular Value Decomposition (SVD) method used in thermography for the characterization of thermal parameters. The inverse problem to solve is based on the model of ...transient heat transfer. The most significant advantage is the transformation of the dynamic identification problem into a steady identification equation. The time dependence is accounted for by the SVD in a performing way. We lay down a mathematical foundation well fitted to this approach, which relies on the spectral expansion of Mercer kernels. This enables us to shed more light on most of its important features. Given its potentialities, the analysis we propose here might help users understanding the way the SVD algorithm, or the TSVD, its truncated version, operate in the thermal parameters estimation and why it is relevant and attractive. When useful, the study is complemented by some analytical and numerical illustrations realized within matlab's code.
BackgroundFetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy; although additional factors might be involved, as development and severity are not directly related ...to alcohol intake. The abnormal glycosylation caused by alcohol might play a role in FAS according to the clinical similarities shared with congenital disorders of glycosylation (CDG). Thus, mutations underlying CDG, affecting genes involved in glycosylation, could also be involved in FAS.MethodsA panel of 74 genes involved in N-glycosylation was sequenced in 25 FAS patients and 20 controls with prenatal alcohol exposure. Transferrin glycoforms were evaluated by HPLC.ResultsRare (minor allele frequency<0.009) missense/splice site variants were more frequent in FAS than controls (84% vs. 50%; P=0.034, odds ratio: 5.25, 95% confidence interval: 1.3-20.9). Remarkably, three patients, but no controls, carried variants with functional effects identified in CDG patients. Moreover, the patient with the most severe clinical phenotype was the only one carrying two variants with functional effects. Family studies support that the combination of a genetic defect and alcohol consumption during pregnancy might have a role in FAS development.ConclusionsOur study supports that the rare variants of genes involved in N-glycosylation could play a role in the development and severity of FAS under prenatal alcohol exposure.
In recent years, there has been an increasing interest in identifying and characterizing the yeast populations associated with diverse types of table olive elaborations because of the many desirable ...technological properties of these microorganisms. In this work, a total of 199 yeast isolates were directly obtained from industrial green table olive fermentations and genetically identified by means of a RFLP analysis of the 5.8S-ITS region and sequencing of the D1/D2 domains of the 26S rDNA gene.
Candida diddensiae,
Saccharomyces cerevisiae and
Pichia membranifaciens were the most abundant yeast species isolated from directly brined Aloreña olives, while for Gordal and Manzanilla cultivars they were
Candida tropicalis,
Pichia galeiformis and
Wickerhamomyces anomalus. In the case of Gordal and Manzanilla green olives processed according to the Spanish style, the predominant yeasts were
Debaryomyces etchellsii,
C. tropicalis,
P. galeiformis and
Kluyveromyces lactis. Biochemical activities of technological interest were then qualitatively determined for isolates belonging to all yeast species. This preliminary screening identified two isolates of
W. anomalus with interesting properties, such as a strong β-glucosidase and esterase activity, and a moderate catalase and lipolytic activity, which were also confirmed by quantitative assays. The results obtained in this survey show the potential use that some yeast species could have as starters, alone or in combination with lactic acid bacteria, during olive processing.
► Molecular methods were used to identify the yeast biodiversity related to Spanish style olives. ►
C. thaimueangensis and
C. sorbosivorans were related for the first time to olive fermentations. ► The work identified two isolates of
W. anomalus suitable to be used as starters.
Comparisons of different treatments or production processes are the goals of a significant fraction of applied research. Unsurprisingly, two-sample problems play a main role in statistics through ...natural questions such as "Is the the new treatment significantly better than the old?" However, this is only partially answered by some of the usual statistical tools for this task. More importantly, often practitioners are not aware of the real meaning behind these statistical procedures. We analyze these troubles from the point of view of the order between distributions, the stochastic order, showing evidence of the limitations of the usual approaches, paying special attention to the classical comparison of means under the normal model. We discuss the unfeasibility of statistically proving stochastic dominance, but show that it is possible, instead, to gather statistical evidence to conclude that slightly relaxed versions of stochastic dominance hold.
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