Slurs and Negation

We present the results of an experimental study that aims at establishing whether the offensive component of slurs exhibits nondisplaceability (Potts 2007). We found that the derogatory content survives in conditionals and questions (supporting a pragmatic approach), and diminishes in indirect reports (in line with presuppositional accounts); surprisingly, the offensiveness of slurs results almost nullified in negated sentences. In a second study, we explore the hypothesis that negated slurs were rated as not offensive because the negation was interpreted as metalinguistic

A defective ABC transporter of the MRP family, responsible for the bean lpa1 mutation, affects the regulation of the phytic acid pathway, reduces seed myo-inositol and alters ABA sensitivity

We previously identified the lpa1 (low phytic acid) 280-10 line that carries a mutation conferring a 90% reduction in phytic acid (InsP6) content. In contrast to other lpa mutants, lpa1(280-10) does not display negative pleiotropic effects. In the present paper, we have identified the mutated gene and analysed its impact on the phytic acid pathway. Here, we mapped the lpa1(280-10) mutation by bulk analysis on a segregating F2 population, an then, by comparison with the soybean genome, we identified and sequenced a candidate gene. The InsP6 pathway was analysed by gene expression and quantification of metabolites. The mutated Pvmrp1(280-10) cosegregates with the lpa1(280-10) mutation, and the expression level of several genes of the InsP6 pathway are reduced in the lpa1(280-10) mutant as well as the inositol and raffinosaccharide content. PvMrp2, a very similar paralogue of PvMrp1 was also mapped and sequenced. The lpa1 mutation in beans is likely the result of a defective Mrp1 gene (orthologous to the lpa genes AtMRP5 and ZmMRP4), while its Mrp2 paralog is not able to complement the mutant phenotype in the seed. This mutation appears to down-regulate the InsP6 pathway at the transcriptional level, as well as altering inositol-related metabolism and affecting ABA sensitivity

Effect of Conventional Versus Passive Self-Ligating Vestibular Appliances on Torque, Tip and Transverse Dental Changes in Patients Affected by Class I Malocclusion: A Retrospective Study

Objective: To evaluate the effects of passive self-ligating appliances (PSLAs) and conventional ligating appliances (CLAs) during orthodontic treatment regarding torque, tip, and transversal dental changes. Material and Methods: Dental parameters were digitally acquired from pre- and post-treatment models of each subject belonging to two groups of patients treated with PSLAs (23 patients; 11 females and 12 males with a mean age of 14.2 ± 1.6 years) and CLAs (18 patients; 10 females and 8 males with a mean age of 14.3 ± 1.9 years), respectively. All subjects had Class I or slight Class II malocclusion (≤ 2mm), permanent dentition and no previous orthodontic treatment. After normality of data was assumed, a paired sample t-test rejected any side differences at T0 and, therefore, the data were grouped by tooth group. Statistical analyses were performed using a linear mixed-effect framework, assuming the appliance, time, and interactions as fixed effects and the tooth type as random effects. Finally, post-hoc effect analysis was used to contrast modeled marginal effects (p<0.05). Results: For both appliances, there is a general increase of both torque and transverse values at T1, especially for PSLAs. Tip shows a general reduction in the lateral sectors for both appliances is registered. The only significant statistical difference referred to appliances’ efficacy is located to mandibular intermolar width. Conclusion: Both appliances have an expansive potential for both torque and transverse dental changes. No evident differences are detectable between appliances except for the rate of the mandibular intermolar width increase

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Background: Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype. Methods: To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value. Results: Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Background: Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype. Methods: To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value. Results: Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Background: Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype. Methods: To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value. Results: Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells

Cytogenetics of Premature Ovarian Failure: An Investigation on 269 Affected Women

The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause

Language in autism: domains, profiles and co-occurring conditions

This article reviews the current knowledge state on pragmatic and structural language abilities in autism and their potential relation to extralinguistic abilities and autistic traits. The focus is on questions regarding autism language profles with varying degrees of (selective) impairment and with respect to potential comorbidity of autism and language impairment: Is language impairment in autism the co-occurrence of two distinct conditions (comorbidity), a consequence of autism itself (no comorbidity), or one possible combination from a series of neurodevelopmental properties (dimensional approach)? As for language profles in autism, three main groups are identifed, namely, (i) verbal autistic individuals without structural language impairment, (ii) verbal autistic individuals with structural language impairment, and (iii) minimally verbal autistic individuals. However, this tripartite distinction hides enormous linguistic heterogeneity. Regarding the nature of language impairment in autism, there is currently no model of how language difculties may interact with autism characteristics and with various extralinguistic cognitive abilities. Building such a model requires carefully designed explorations that address specifc aspects of language and extralinguistic cognition. This should lead to a fundamental increase in our understanding of language impairment in autism, thereby paving the way for a substantial contribution to the question of how to best characterize neurodevelopmental disorders