Adaptive immune response to BNT162b2 mRNA vaccine in immunocompromised adolescent patients

Protective immunity against COVID-19 is orchestrated by an intricate network of innate and adaptive anti-viral immune responses. Several vaccines have been rapidly developed to combat the destructive effects of COVID-19, which initiate an immunological cascade that results in the generation of neutralizing antibodies and effector T cells towards the SARS-CoV-2 spike protein. Developing optimal vaccine-induced anti-SARS- CoV-2 protective immunity depends on a fully competent immune response. Some evidence was gathered on the effects of vaccination outcomes in immunocompromised adult individuals. Nonetheless, protective immunity elicited by the Pfizer Biontech BNT162b2 vaccine in immunocompromised adolescents received less attention and was mainly focused on the antibody response and their neutralization potential. The overall immune response, including T-cell activities, was largely understudied. In this study, we characterized the immune response of vaccinated immunocompromised adolescents. We found that immunocompromised adolescents, which may fail to elicit a humoral response and develop antibodies, may still develop cellular T-cell immunity towards SARS-CoV-2 infections. Furthermore, most immunocompromised adolescents due to genetic disorders or drugs (Kidney and liver transplantation) still develop either humoral, cellular or both arms of immunity towards SARS-CoV-2 infections. We also demonstrate that most patients could mount a cellular or humoral response even after six months post 2nd vaccination. The findings that adolescents immunocompromised patients respond to some extent to vaccination are promising. Finally, they question the necessity for additional vaccination boosting regimens for this population who are not at high risk for severe disease, without further testing of their post-vaccination immune status

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder

[Background]: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called ‘neurocardiofaciodigital’ syndrome. [Objective and methods]: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. [Results]: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. [Conclusion]: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.HH is funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). SE is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder

BACKGROUND: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called 'neurocardiofaciodigital' syndrome. OBJECTIVE AND METHODS: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. RESULTS: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. CONCLUSION: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome

Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies

Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality, and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

The Role of Teacher Education in Introducing Action Research into the Education System: A Case Study of an Education College

The study presents a case of a teacher education college which took upon itself the role of providing teachers with an opportunity to study their work as part of their professional development studies in three different frameworks. The objective of the study was to examine the role of the college as promoting research carried out by practicing teachers regarding their own work, from the teachers’ point of view. In all three frameworks the teachers had to conduct a study of their own work, following which they were asked to write a reflective text regarding the research process. These texts were analyzed using the grounded theory approach, resulting in three major categories. In-depth examination of the categories led to insights related to the responsibility academia can and should take upon itself in assisting teachers in developing their abilities to combine practice and theory and evolve from knowledge consumers to knowledge creators

The role of cognitive flexibility in moderating the effect of school-related stress exposure

Abstract Educators are exposed to various stressful events as part of their ongoing work, including violence, sexual assaults, suicidal behavior, and loss or illness of students or their family members. Previous studies revealed an increased risk of developing PTSD symptoms in healthcare and supportive professionals exposed to repeated stress as part of their work. Cognitive flexibility might be a protective factor against the negative effect of such stress. The current study aimed to examine the interactive effects of school-related stress exposure and cognitive flexibility on the tendency to develop Post Traumatic Stress Disorder (PTSD) symptoms and the coping abilities of educators. One hundred and fifty educators (86.5% female; M age = 43.08, M teaching_experience = 12.90) volunteered to participate in this study. They completed questionnaires measuring levels of stress exposure, cognitive flexibility, coping ability, and PTSD symptoms. Analyses revealed that cognitive flexibility moderated the relationship between school-related stress exposure and both PTSD symptoms severity and maladaptive coping. Specifically, whereas educators with low cognitive flexibility exhibited positive associations between continuous stress exposure and both levels of PTSD symptoms and maladaptive coping, no such association was found among educators with high cognitive flexibility. The results highlight the importance of cognitive flexibility as a protective factor against the harmful effects of possible stress exposure in school environments. Awareness of the crucial role of cognitive flexibility as a protective factor for educators can be a breakthrough in improving educators' well-being and adaptive functioning

iClassifier, a digital research tool for corpus-based classifier networks in complex writing systems

This article presents the method applied by the iClassifier (©Goldwasser/Harel/Nikolaev) digital research tool for the study of the linguistic phenomenon of classifiers. The tool was created in 2019 with the objective of curating corpus-based and data-driven documentation of classifier systems. The record of classifiers comprises millions of tokens worth of “big data” analysis. By tagging classifiers in various corpora, a topography of categories emerges, visualized as complex, multilayered networks. This article offers an overview of how classifier-based networks are created and how network analysis methods can be applied to analyze knowledge organization. We present the data structure and annotation scheme of the iClassifier research tool, demonstrating how one can plot classifier networks and generate reports of lemma and classifier repertoires in each corpus. The iClassifier tool provides quantitative reports, including classifier frequency, variation and co-occurrence statistics. Each data subset, such as a certain part of speech, timespan, geographical location, or textual genre, can be queried and visualized. The tool is meant to allow browsing between a macro-overview of all categories in a corpus and zooming in into micro-analysis of the individual categories and lemmas that built up a corpus. Each classifier is seen as a category head, and the categories are drawn in their multilayered and multidimensional relationships. The potency of this tool is in documenting the phenomenon in large corpora of texts and expanding our knowledge about the rules and functions of classifier systems, leading us to a more reined mind-mapping of ancient cultures. Currently, very little systematic analysis has been done on this ancient record of emic information

Computational Paradigm to Elucidate the Effects of Arts-Based Approaches and Interventions: Individual and Collective Emerging Behaviors in Artwork Construction

<div><p>Art therapy, as well as other arts-based therapies and interventions, is used to reduce pain, stress, depression, breathlessness and other symptoms in a wide variety of serious and chronic diseases, such as cancer, Alzheimer and schizophrenia. Arts-based approaches are also known to contribute to one’s well-being and quality of life. However, much research is required, since the mechanisms by which these non-pharmacological treatments exert their therapeutic and psychosocial effects are not adequately understood. A typical clinical setting utilizing the arts consists of the creation work itself, such as the artwork, as well as the therapist and the patient, all of which constitute a rich and dynamic environment of occurrences. The underlying complex, simultaneous and interwoven processes of this setting are often considered intractable to human observers, and as a consequence are usually interpreted subjectively and described verbally, which affect their subsequent analyses and understanding. We introduce a computational research method for elucidating and analyzing emergent expressive and social behaviors, aiming to understand how arts-based approaches operate. Our methodology, which centers on the visual language of Statecharts and tools for its execution, enables rigorous qualitative and quantitative tracking, analysis and documentation of the underlying creation and interaction processes. Also, it enables one to carry out exploratory, hypotheses-generating and knowledge discovery investigations, which are empirical-based. Furthermore, we illustrate our method’s use in a proof-of-principle study, applying it to a real-world artwork investigation with human participants. We explore individual and collective emergent behaviors impacted by diverse drawing tasks, yielding significant gender and age hypotheses, which may account for variation factors in response to art use. We also discuss how to gear our research method to systematic and mechanistic investigations, as we wish to provide a broad empirical evidence for the uptake of arts-based approaches, also aiming to ameliorate their use in clinical settings.</p></div

An example of parameters/metrics comparison of an individual's artworks construction processes.

<p>The processes compared are of the creation of a positive feeling image and that of a negative feeling.</p