Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia : a case report

Background Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. Case presentation Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. Conclusions We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.Peer reviewe

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine

Antipsychotic use in pregnancy and risk of attention/ deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study

Background Antipsychotics are increasingly used among women of childbearing age and during pregnancy. Objective To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. Findings Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. Discussion Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. Clinical implications Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.publishedVersio

Estrogen receptor alpha gene polymorphism and endometrial cancer risk – a case-control study

Background: Estrogen is an established endometrial carcinogen. One of the most important mediators of estrogenic action is the estrogen receptor alpha. We have investigated whether polymorphic variation in the estrogen receptor alpha gene (ESR1) is associated with endometrial cancer risk. Methods: In 702 cases with invasive endometrial cancer and 1563 controls, we genotyped five markers in ESR1 and used logistic regression models to estimate odds ratios (OR) and 95 percent confidence intervals (CI). Results: We found an association between rs2234670, rs2234693, as well as rs9340799, markers in strong linkage disequilibrium (LD), and endometrial cancer risk. The association with rs9340799 was the strongest, OR 0.75 (CI 0.60–0.93) for heterozygous and OR 0.53 (CI 0.37–0.77) for homozygous rare compared to those homozygous for the most common allele. Haplotype models did not fit better to the data than single marker models. Conclusion: We found that intronic variation in ESR1 was associated with endometrial cancer risk

Enacting the Prevent Duty in Early Childhood Education Settings

This chapter examines the implementation of the Prevent Duty in early childhood education (ECE) provision in England. Findings from a small-scale empirical study suggest that ECE practitioners simultaneously performed, resisted and embodied the requirements of the Prevent Duty in practice. ECE practitioners were performative in their response to the requirement to promote fundamental British values (FBVs) as they evidenced compliance within an environment of regulation. However, ECE practitioners simultaneously operated a pedagogy rich in values education in which children were positioned as constructors of values. The layering of counter-terrorism within safeguarding policy led to a repositioning of practices of surveillance of children and families, which resonates with some critical readings of counter-terrorism policy in ECE

A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Immunoglobulin G (IgG) formed during pregnancy against human platelet antigens (HPAs) of the fetus mediates fetal or neonatal alloimmune thrombocytopenia (FNAIT). Because antibody titer or isotype does not strictly correlate with disease severity, we investigated by mass spectrometry variations in the glycosylation at Asn297 in the IgG Fc because the composition of this glycan can be highly variable, affecting binding to phagocyte IgG-Fc receptors (FcγR). We found markedly decreased levels of core fucosylation of anti-HPA-1a-specific IgG1 from FNAIT patients (n = 48), but not in total serum IgG1. Antibodies with a low amount of fucose displayed higher binding affinity to FcγRIIIa and FcγRIIIb, but not to FcγRIIa, compared with antibodies with a high amount of Fc fucose. Consequently, these antibodies with a low amount of Fc fucose showed enhanced phagocytosis of platelets using FcγRIIIb(+) polymorphonuclear cells or FcγRIIIa(+) monocytes as effector cells, but not with FcγRIIIa(-) monocytes. In addition, the degree of anti-HPA-1a fucosylation correlated positively with the neonatal platelet counts in FNAIT, and negatively to the clinical disease severity. In contrast to the FNAIT patients, no changes in core fucosylation were observed for anti-HLA antibodies in refractory thrombocytopenia (post platelet transfusion), indicating that the level of fucosylation may be antigen dependent and/or related to the immune milieu defined by pregnancy.Sanquin/PPOC-09- 025 Landsteiner Foundation for Blood Transfusion/0721 info:eu-repo/grantAgreement/EC/FP7/27853

What factors contribute to positive early childhood health and development in Australian Aboriginal children? Protocol for a population-based cohort study using linked administrative data (The Seeding Success Study)

Australian Aboriginal children are more likely than non-Aboriginal children to have developmental vulnerability at school entry that tracks through to poorer literacy and numeracy outcomes and multiple social and health disadvantages in later life. Empirical evidence identifying the key drivers of positive early childhood development in Aboriginal children, and supportive features of local communities and early childhood service provision, are lacking.The study population will be identified via linkage of Australian Early Development Census data to perinatal and birth registration data sets. It will include an almost complete population of children who started their first year of full-time school in New South Wales (NSW), Australia, in 2009 and 2012. Early childhood health and development trajectories for these children will be constructed via linkage to a range of administrative data sets relating to birth outcomes, congenital conditions, hospital admissions, emergency department presentations, receipt of ambulatory mental healthcare services, use of general practitioner services, contact with child protection and out-of-home care services, receipt of income assistance and fact of death. Using multilevel modelling techniques, we will quantify the contributions of individual-level and area-level factors to variation in early childhood development outcomes in Aboriginal and non-Aboriginal children. Additionally, we will evaluate the impact of two government programmes that aim to address early childhood disadvantage, the NSW Aboriginal Maternal and Infant Health Service and the Brighter Futures Program. These evaluations will use propensity score matching methods and multilevel modelling.Ethical approval has been obtained for this study. Dissemination mechanisms include engagement of stakeholders (including representatives from Aboriginal community controlled organisations, policy agencies, service providers) through a reference group, and writing of summary reports for policy and community audiences in parallel with scientific papers.Kathleen Falster, Louisa Jorm, Sandra Eades, John Lynch, Emily Banks, Marni Brownell, Rhonda Craven, Kristjana Einarsdóttir, Deborah Randall, on behalf of the Seeding Success Investigator

The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2

RMRP was the first non-coding nuclear RNA gene implicated in a disease. Its mutations cause cartilage-hair hypoplasia (CHH), an autosomal recessive skeletal dysplasia with growth failure, immunodeficiency, and a high risk for malignancies. This study aimed to gain further insight into the role of RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) in cellular physiology and disease pathogenesis. We combined transcriptome analysis with single-cell analysis using fibroblasts from CHH patients and healthy controls. To directly assess cell cycle progression, we followed CHH fibroblasts by pulse-labeling and time-lapse microscopy. Transcriptome analysis identified 35 significantly upregulated and 130 downregulated genes in CHH fibroblasts. The downregulated genes were significantly connected to the cell cycle. Multiple other pathways, involving regulation of apoptosis, bone and cartilage formation, and lymphocyte function, were also affected, as well as PI3K-Akt signaling. Cell-cycle studies indicated that the CHH cells were delayed specifically in the passage from G2 phase to mitosis. Our findings expand the mechanistic understanding of CHH, indicate possible pathways for therapeutic intervention and add to the limited understanding of the functions of RMRP.Peer reviewe

Thyroid hormone receptor expression during metamorphosis of Atlantic halibut (Hippoglossus hippoglossus)

Flatfish such as the Atlantic halibut (Hippoglossus hippoglossus) undergo a dramatic metamorphosis that transforms the pelagic, symmetric larva into a benthic, cranially asymmetric juvenile. In common with amphibian metamorphosis, flatfish metamorphosis is under endocrine control with thyroid hormones being particularly important. In this report we confirm that tri-iodothyronine (T3) levels peak at metamorphic climax during halibut metamorphosis. Moreover we have isolated cDNA clones of TR and TR genes and confirmed the presence in halibut of two TR isoforms (representing the products of distinct genes) and two TR isoforms (generated from a single gene by alternative splicing). Real time PCR was used to assess expression of these genes during metamorphosis. TR shows the most dramatic expression profile, with a peak occurring during metamorphic climax.This work has been carried out within the project “Arrested development: The Molecular and Endocrine Basis of Flatfish Metamorphosis” (Q5RS-2002-01192) with financial support from the Commission of the European Communities. However, it does not necessarily reflect the Commission’s views and in no way anticipates its future policy in this area. We thank Heiddis Smáradóttir (Fiskeldi Eyjafjarðar, IS-600 Akureyri, Iceland) for collecting and providing the Atlantic halibut samples, and Karin Pittman and Øystein Sæle (both from the Department of Biology, University of Bergen, Norway) for analysing samples to determine developmental stage. We are also grateful to Marco Campinho for preparing the RNA used in the study