Learning difficulties : a portuguese perspective of a universal issue

In this article we present findings of a study that was conducted with the purpose of deepening the knowledge about the field of learning difficulties in Portugal. Therefore, within these findings we will discuss across several cultural boundaries, themes related with the existence of learning difficulties as a construct, the terminology, the political, social and scientific influences on the field, and the models of identification and of ongoing school support for students. While addressing the above-mentioned themes we will draw attention to the different, yet converging, international understandings of learning difficulties

Tuning the excited state of water-soluble IrIII-based DNA intercalators that are isostructural with [RuII(NN)2(dppz)] light-switch complexes

The synthesis of two new IrIII complexes which are effectively isostructural with well-established [Ru(NN)2-(dppz)]2+ systems is reported (dppz = dipyridophenazine; NN = 2,2′-bipyridyl, or 1,10-phenanthroline). One of these IrIII complexes is tricationic and has a conventional N6 coordination sphere. The second dicationic complex has a N5C coordination sphere, incorporating a cyclometalated analogue of the dppz ligand. Both complexes show good water solubility. Experimental and computational studies show that the photoexcited states of the two complexes are very different from each other and also differ from their RuII analogues. Both of the complexes bind to duplex DNA with affinities that are two orders of magnitude higher than previously reported Ir(dppz)-based systems and are comparable with RuII(dppz) analogues

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation

European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,  ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I (“ready for clinical use”) classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II (“investigational”) classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted. MTG4Molecular tumour pathology - and tumour genetic

Advances in multidisciplinary therapy for meningiomas

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-Institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas