Genetic variability of the functional domains of chromodomains helicase DNA-binding (CHD) proteins

In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life. Here, we analysed the evolution of CHD proteins by performing a comparative study of the functional domains of CHD proteins between orthologous and paralogous protein sequences. Our findings show that the highest degree of inter-species conservation was observed at Group II (CHD3, CHD4, and CHD5) and that most of the pathological variations documented in humans involve amino acid residues that are conserved not only between species but also between paralogs. The parallel analysis of both orthologous and paralogous proteins, in cases where gene duplications have occurred, provided extra information showing patterns of flexibility as well as interchangeability between amino acid positions. This added complexity needs to be considered when the impact of novel mutations is assessed in terms of evolutionary conservation.This research was funded by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funding through FCT—Fundação para a Ciência e a Tec-nologia, within the framework of the Project POCI-01–0145-FEDER-007274 to i3S and by FCT research project POCI-01–0145-FEDER-29723. ARC holds a FCT PhD Fellowship (SFRH/BD/141702/2018)

Autoimmune alternating hyper- and hypo-thyroidism: a rare condition in pediatrics

Alternating between hyper- and hypo-thyroidism may be explained by the simultaneous presence of both types of TSH receptor autoantibodies (TRAbs) - thyroid stimulating autoantibodies (TSAbs) and TSH blocking autoantibodies (TBAbs). It is a very rare condition, particulary in the pediatric age. The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time. Many mechanisms may be involved in fluctuating thyroid function: hormonal supplementation, antithyroid drugs and levels of TSAbs and TBAbs. Frequent dose adjustments are needed in order to achieve euthyroidism. A definitive therapy may be necessary to avoid switches in thyroid function and frequent need of therapeutic changes. We describe an immune-mediated case of oscillating thyroid function in a 13-year-old adolescent. After a short period of levothyroxine treatment, the patient switched to a hyperthyroid state that was only controlled by adding an antithyroid drug. LEARNING POINTS: Autoimmune alternating hypo- and hyper-thyroidism is a highly uncommon condition in the pediatric age.It may be due to the simultaneous presence of both TSAbs and TBAbs, whose activity may be estimated in vitro through bioassays.The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time.The management of this condition is challenging, and three therapeutic options could be considered: I-131 ablation, thyroidectomy or pharmacological treatment (single or double therapy).Therapeutic decisions should be taken according to clinical manifestations and thyroid function tests, independent of the bioassays results.A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment. A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment.info:eu-repo/semantics/publishedVersio

Essential genetic findings in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of distinct types (chromosomal rearrangements, copy number variants, small indels, and nucleotide substitutions) with distinct frequencies in the population (common, rare, de novo). Such a network of interacting players creates difficulties in establishing rigorous genotype-phenotype correlations. Furthermore, individual lifestyles may also contribute to the severity of the symptoms fueling a large spectrum of gene-environment interactions that have a key role on the relationships between genotypes and phenotypes.Herein, a review of the genetic discoveries related to NDDs is presented with the aim to provide useful general information for the medical community.This work was financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia, in the framework of the project POCI-01-0145-FEDER-007274 to i3S and UID/ BIM/04501/2013 and UID/BIM/04501/2019 to iBiMED, as well as by national funds (OE), through FCT, in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19 to RMS, and by FCT research project POCI-01-0145-FEDER-29723. ARC and CS hold FCT PhD fellowships (SFRH/BD/141702/2018-ARC and SFRH/BD/137925/2018-CS). Funders had no role in the design, collection, analysis, interpretation of the data, and writing of the manuscript

Nearly K\"ahler heterotic compactifications with fermion condensates

We revisit AdS_4 heterotic compactifications on nearly K\"ahler manifolds in the presence of H-flux and certain fermion condensates. Unlike previous studies, we do not assume the vanishing of the supersymmetry variations. Instead we determine the full equations of motion originating from the ten-dimensional action, and subsequently we provide explicit solutions to them on nearly K\"ahler manifolds at first order in alpha'. The Bianchi identity is also taken into account in order to guarantee the absence of all anomalies. In the presence of H-flux, which is identified with the torsion of the internal space, as well as of fermion condensates in the gaugino and dilatino sectors, new solutions are determined. These solutions provide a full classification of consistent backgrounds of heterotic supergravity under our assumptions. All the new solutions are non-supersymmetric, while previously known supersymmetric ones are recovered too. Our results indicate that fully consistent (supersymmetric or not) heterotic vacua on nearly K\"ahler manifolds are scarce, even on AdS_4, and they can be completely classified.Comment: 1+17 pages, 1 figure; v2: remark and two references added, published versio

Moduli Stabilisation in Heterotic Models with Standard Embedding

In this note we analyse the issue of moduli stabilisation in 4d models obtained from heterotic string compactifications on manifolds with SU(3) structure with standard embedding. In order to deal with tractable models we first integrate out the massive fields. We argue that one can not only integrate out the moduli fields, but along the way one has to truncate also the corresponding matter fields. We show that the effective models obtained in this way do not have satisfactory solutions. We also look for stabilised vacua which take into account the presence of the matter fields. We argue that this also fails due to a no-go theorem for Minkowski vacua in the moduli sector which we prove in the end. The main ingredient for this no-go theorem is the constraint on the fluxes which comes from the Bianchi identity.Comment: 20 pages, LaTeX; references adde

Agency and intentionality-dependent experiences of moral emotions

Moral emotions are thought to influence moral behaviour by providing a driving force to do good and to avoid doing bad. In this study we examined moral emotions; specifically, guilt, shame, annoyance and feeling “bad” from two different perspectives in a moral scenario; the agent and the victim whilst manipulating the intentionality of the harm; intentional and unintentional. Two hundred participants completed a moral emotions task, which utilised cartoons to depict everyday moral scenarios. As expected, we found that self-blaming emotions such as shame and guilt were much more frequent when taking on the perspective of the agent whilst annoyance was more frequent from the victim perspective. Feeling bad, however, was not agency-specific. Notably, when the harm was intentional, we observed significantly greater shame ratings from the perspective of the agent compared to when the harm was unintentional. In addition, we also found clear gender differences and further observed correlations between moral emotions and personality variables such as psychoticism and neuroticism

Fake supersymmetry versus Hamilton-Jacobi

We explain when the first-order Hamilton-Jacobi equations for black holes (and domain walls) in (gauged) supergravity, reduce to the usual first-order equations derived from a fake superpotential. This turns out to be equivalent to the vanishing of a newly found constant of motion and we illustrate this with various examples. We show that fake supersymmetry is a necessary condition for having physically sensible extremal black hole solutions. We furthermore observe that small black holes become scaling solutions near the horizon. When combined with fake supersymmetry, this leads to a precise extension of the attractor mechanism to small black holes: The attractor solution is such that the scalars move on specific curves, determined by the black hole charges, that are purely geodesic, although there is a non-zero potential.Comment: 20 pages, v2: Typos corrected, references adde

DWSB in heterotic flux compactifications

We address the construction of non-supersymmetric vacua in heterotic compactifications with intrinsic torsion and background fluxes. In particular, we implement the approach of domain-wall supersymmetry breaking (DWSB) previously developed in the context of type II flux compactifications. This approach is based on considering backgrounds where probe NS5-branes wrapping internal three-cycles and showing up as four-dimensional domain-walls do not develop a BPS bound, while all the other BPS bounds characterizing the N=1 supersymmetric compactifications are preserved at tree-level. Via a scalar potential analysis we provide the conditions for these backgrounds to solve the ten-dimensional equations of motion including order \alpha' corrections. We also consider backgrounds where some of the NS5-domain-walls develop a BPS bound, show their relation to no-scale SUSY-breaking vacua and construct explicit examples via elliptic fibrations. Finally, we consider backgrounds with a non-trivial gaugino condensate and discuss their relation to supersymmetric and non-supersymmetric vacua in the present context.Comment: 56 pages, 1 figur