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

Mutations in MAPT give rise to aneuploidy in animal models of tauopathy

Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration

Biological heterogeneity of putative bladder cancer stem-like cell populations from human bladder transitional cell carcinoma samples.

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells, the cancer stem-like cells (CSCs) or tumor initiating cells. We report on the isolation and biological characterization of putative bladder CSC populations from primary TCCs. Isolated cells were induced to proliferate in stem cell culture conditions (serum-free medium containing mitogenic growth factors). The proliferating cells formed spheroids (urospheres) and their abilities for extensive proliferation and self-renewal were assayed. Their positivity for several stem cell markers (CD133, Oct-3/4, nestin, and cytokeratins) was also assessed by immunofluorescence tests and they could have the potential to differentiate in the presence of serum. In stem cell culture conditions they gradually showed loss of proliferation, adherence to the substrate, and morphological changes, which might reflect their progressive acquisition of differentiative capacity and loss of self-renewal ability. To evaluate if effective cell selection occurred after isolation, conventional cytogenetic studies on fresh chromosome spreads immediately after isolation and after culture were carried out. In addition, a molecular cytogenetic study by UroVysion assay was carried out on paraffin-embedded tissue sections and on fresh and after culture nuclei preparations. The data collected indicated important karyotype changes and a positive selection for hypo- or near-diploid cells, losing the complexity present in fresh tumors

Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes

Defects in the endoplasmic reticulum (ER) membrane shaping and interaction with other organelles seem to be a crucial mechanism underlying Hereditary Spastic Paraplegia (HSP) neurodegeneration. REEP1, a transmembrane protein belonging to TB2/HVA22 family, is implicated in SPG31, an autosomal dominant form of HSP, and its interaction with Atlastin/SPG3A and Spastin/SPG4, the other two major HSP linked proteins, has been demonstrated to play a crucial role in modifying ER architecture. In addition, the Drosophila ortholog of REEP1, named ReepA, has been found to regulate the response to ER neuronal stress. Herein we investigated the role of ReepA in ER morphology and stress response. ReepA is upregulated under stress conditions and aging. Our data show that ReepA triggers a selective activation of Ire1 and Atf6 branches of Unfolded Protein Response (UPR) and modifies ER morphology. Drosophila lacking ReepA showed Atf6 and Ire1 activation, expansion of ER sheet-like structures, locomotor dysfunction and shortened lifespan. Furthermore, we found that naringenin, a flavonoid that possesses strong antioxidant and neuroprotective activity, can rescue the cellular phenotypes, the lifespan and locomotor disability associated with ReepA loss of function. Our data highlight the importance of ER homeostasis in nervous system functionality and HSP neurodegenerative mechanisms, opening new opportunities for HSP treatment

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

Insights into the Complexation Mechanism of a Promising Lipophilic PyTri Ligand for Actinide Partitioning from Spent Nuclear Fuel

The challenging issue of spent nuclear fuel (SNF) management is being tackled by developing advanced technologies that point to reduce environmental footprint, long-term radiotoxicity, volumes and residual heat of the final waste, and to increase the proliferation resistance. The advanced recycling strategy provides several promising processes for a safer reprocessing of SNF. Advanced hydrometallurgical processes can extract minor actinides directly from Plutonium and Uranium Reduction Extraction raffinate by using selective hydrophilic and lipophilic ligands. This research is focused on a recently developed N-heterocyclic selective lipophilic ligand for actinides separation to be exploited in advanced Selective ActiNide EXtraction (SANEX)- like processes: 2,6-bis(1-(2-ethylhexyl)-1H-1,2,3-triazol-4-yl)pyridine (PyTri-Ethyl-Hexyl-PTEH). The formation and stability of metal−ligand complexes have been investigated by different techniques. Preliminary studies carried out by electrospray ionization mass spectrometry (ESI−MS) analysis enabled to qualitatively explore the PTEH complexes with La(III) and Eu(III) ions as representatives of lanthanides. Time-resolved laser fluorescence spectroscopy (TRLFS) experiments have been carried out to determine the ligand stability constants with Cm(III) and Eu(III) and to better investigate the ligand complexes involved in the extraction process. The contribution of a 1:3 M/L complex, barely identified by ESI−MS analyses, was confirmed as the dominant species by TRLFS experiments. To shed light on ligand selectivity toward actinides over lanthanides, NMR investigations have been performed on PTEH complexes with Lu(III) and Am(III) ions, thereby showing significant differences in chemical shifts of the coordinating nitrogen atoms providing proof of a different bond nature between actinides and lanthanides. These scientific achievements encourage consideration of this PyTri ligand for a potential large-scale implementation

Case report: A novel FARS2 deletion and a missense variant in a child with complicated, rapidly progressive spastic paraplegia

Defects in FARS2 are associated with either epileptic phenotypes or a spastic paraplegia subtype known as SPG77. Here, we describe an 8-year-old patient with severe and complicated spastic paraplegia, carrying a missense variant (p.Pro361Leu) and a novel intragenic deletion in FARS2. Of note, the disease is unexpectedly progressing rapidly and in a biphasic way differently from the previously reported cases. Our study provides the first detailed molecular characterization of a FARS2 deletion and its underlying molecular mechanism, and demonstrates the need for combining different tools to improve the diagnostic rate

KIF5A and ALS2 Variants in a Family With Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis

This paper describes the clinical evolution and the novel genetic findings in a KIF5A mutated family previously reported as affected by spastic paraparesis only. The additional evidence we report here, a homozygous ALS2 mutation detected in the proband, and the clinical evolution observed in the affected members of the family, are in line with the evidence of an overlap between Hereditary Spastic Paraplegias and Amyotrophic Lateral Sclerosis associated with variants in these genes. The proband, a 14-years-old boy, started manifesting a pure form of HSP at age 14 months. The disease rapidly progressed to a juvenile form of ALS. This boy carries a heterozygous missense variant in KIF5A p.(Glu755Lys), inherited from the father, and a homozygous missense variant in the alsin protein encoded by the ALS2 gene p.(Pro192Leu). The father shows a family history of ALS. In the last few years, he has been developing signs and symptoms of both upper and lower motor neuron degeneration, with mild bulbar motor involvement and emotional lability. The patients described in this family, confirm the continuum and partial overlap of the two clinical entities, HSP and ALS, historically viewed as distinct entities. The genetic findings in this family further substantiate the genetic bases underlying the overlap, broadening the clinical spectrum associated with KIF5A mutations

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