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)

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

Synergies, Strengths and Challenges: Findings on Community Capability from a Systematic Health Systems Research Literature Review

Background: Community capability is the combined influence of a community’s social systems and collective resources that can address community problems and broaden community opportunities. We frame it as consisting of three domains that together support community empowerment: what communities have; how communities act; and for whom communities act. We sought to further understand these domains through a secondary analysis of a previous systematic review on community participation in health systems interventions in low and middle income countries (LMICs). Methods: We searched for journal articles published between 2000 and 2012 related to the concepts of “community”, “capability/participation”, “health systems research” and “LMIC.” We identified 64 with rich accounts of community participation involving service delivery and governance in health systems research for thematic analysis following the three domains framing community capability. Results: When considering what communities have, articles reported external linkages as the most frequently gained resource, especially when partnerships resulted in more community power over the intervention. In contrast, financial assets were the least mentioned, despite their importance for sustainability. With how communities act, articles discussed challenges of ensuring inclusive participation and detailed strategies to improve inclusiveness. Very little was reported about strengthening community cohesiveness and collective efficacy despite their importance in community initiatives. When reviewing for whom communities act, the importance of strong local leadership was mentioned frequently, while conflict resolution strategies and skills were rarely discussed. Synergies were found across these elements of community capability, with tangible success in one area leading to positive changes in another. Access to information and opportunities to develop skills were crucial to community participation, critical thinking, problem solving and ownership. Although there are many quantitative scales measuring community capability, health systems research engaged with community participation has rarely made use of these tools or the concepts informing them. Overall, the amount of information related to elements of community capability reported by these articles was low and often of poor quality. Conclusions: Strengthening community capability is critical to ensuring that community participation leads to genuine empowerment. Our simpler framework to define community capability may help researchers better recognize, support and assess it