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FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments
No full textHomologous recombination (Hr) deficiency upon breast cancer Gene 2 (brcA2) loss arises from defects in the formation of rAD51 nucleoprotein filaments. We demonstrate that loss of the anti-recombinase Fidgetin Like 1 (FIGNL1) retains rAD51 loading at DNA double-stranded breaks (DSbs) in brcA2-deficient cells, leading to genome stability, Hr proficiency, and viability of brcA2-deficient mouse embryonic stem cells. Mechanistically, we demonstrate that strand invasion and subsequent Hr defects upon brcA2 loss primarily arise from the unrestricted removal of rAD51 from DSb sites by FIGNL1, rather than from defective rAD51 loading. Furthermore, we identify that the MMS22L-tONSL complex interacts with FIGNL1 and is critical for Hr in brcA2/FIGNL1 double-deficient cells. these findings identify a pathway for tightly regulating rAD51 activity to promote efficient Hr, offering insights into mechanisms of chemoresistance in brcA2-deficient tumors.</p
When seeing through students’ eyes clouds the view:Rethinking perspective-taking in teacher-focused interventions
No full textIt is widely believed that teachers’ perspective-taking can improve students’ social-emotional learning (SEL) and their own social-emotional competencies by fostering a deeper understanding of students’ thoughts, feelings, or viewpoints. It is therefore not surprising that perspective-taking is usually one of the key components in teacher-focused interventions designed to improve various SEL outcomes. Drawing together insights from empirical and theoretical work, this paper focuses on how perspective-taking is embedded in teacher-focused interventions designed to support SEL, and identifies three boundary conditions that may inadvertently limit its effectiveness. These include teachers’ reliance on egocentric and stereotypical defaults when trying to take a student's perspective, a predominant focus on the perspective taker's mind when considering intervention outcomes, and potential declines in teachers’ perspective-taking accuracy due to increased confidence. By identifying these boundary conditions, this paper aims to advance a more nuanced understanding of perspective-taking as a mechanism of change and to inform the development of interventions that more effectively foster SEL outcomes. Impact statement: This paper reviews how perspective-taking is embedded in teacher-focused interventions designed to support social-emotional learning (SEL), and identifies three conditions that may limit its effectiveness. Drawing together insights from empirical and theoretical work, it offers a more nuanced account of perspective-taking as a mechanism of change. The insights provided may help educators and intervention designers anticipate challenges and strengthen strategies that reliably support SEL outcomes in the classroom.</p
The distinctive psychopathology of NMDAR-antibody encephalitis compared with primary psychoses:an international, multicentre, retrospective phenotypic analysis
No full textBACKGROUND: N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is a life-threatening neuropsychiatric disorder requiring prompt immunotherapy. The earliest features are mental-state changes, often mistaken for primary psychosis. Improved clinical differentiation could assist rational diagnostic investigation and expedite immunotherapy. Inspired by patients' and relatives' lived experience, we aimed to explore the psychiatric phenotype of NMDAR-antibody encephalitis and the features common to and distinct from real-world episodes of psychosis. METHODS: In this international, multicentre, retrospective phenotypic analysis we collected data on episodes of NMDAR-antibody encephalitis from specialised neurology services in Europe (UK, Germany, and Sweden) and the USA. For comparison, we collected similar data from de-identified accepted referrals to a UK early intervention in psychosis service, including consecutively presenting cases (unselected psychosis) and a group defined by having been assessed and admitted to hospital under the Mental Health Act (selected psychosis). Additionally, we included episodes of postpartum psychosis from a mother and baby unit in the Netherlands. In our mental-state inventory we included core features from ICD-11, the Bush-Francis catatonia score, and the Neuropsychiatric Inventory encompassing anxiety, depression, mania, schizophrenia, catatonia, and also more granular transdiagnostic behavioural features including those common to neuropsychiatric and neurobehavioural syndromes, such as delirium and dementia. Ethnicity data were not available. We compared and visualised the neuropsychiatric phenotype of these cohorts. FINDINGS: We collected data from 100 episodes of NMDAR-antibody encephalitis from 96 patients between 2010 and 2022 (median age 22 years, female:male ratio 3·80), 135 episodes of psychosis from 135 patients between 2018 and 2019 (median age 27 years, female:male ratio 0·75), and ten episodes of postpartum psychosis from ten patients between 2005 and 2012 (median age 30 years, all female sex). Psychopathology in NMDAR-antibody encephalitis was abundant (92 [92%] of 100 episodes) and ultra-rapid in onset (median 1 day [95% CI 1-1; IQR 1-7]) versus unselected primary psychoses (median 180 days [120-210; 91-365]; p<0·0001). 21 (36%) of 58 mental-state features, including catatonic and visual hallucinations, were over-represented in NMDAR-antibody encephalitis and 12 (21%) were under-represented, including features typical of affective (eg, elated mood, flight of ideas, grandiose delusions) and non-affective psychoses (eg, thought broadcasting, thought withdrawal, paranoid delusions; false discovery rate threshold <0·05). Typically, in NMDAR-antibody encephalitis, the complexity sequentially evolved from mood to psychotic to catatonic predominance within 2 weeks.INTERPRETATION: NMDAR-antibody encephalitis has a rapid-onset, complex, and dynamic neuropsychiatric phenotype, sufficiently distinctive to drive a clinical approach to differentiation. </p
Peri-conceptional maternal vulnerability risk score and embryonic growth:the Rotterdam Periconception Cohort
No full textResearch question: What is the association of peri-conceptional maternal vulnerability, assessed through a weighted multi-domain risk score with embryonic growth? Design: 638 pregnancies were included from the Rotterdam Periconception Cohort. Data on nine vulnerability factors (encompassing lifestyle, mental health and environmental factors) were obtained through self-administered questionnaires. The Periconceptional Vulnerability Risk Score (PVRS) was calculated using weighted estimates of associations between vulnerability factors and ‘Big 3’ pregnancy outcomes (congenital anomalies, preterm birth and small for gestational age). Embryonic growth was assessed by repeated first-trimester 3D transvaginal ultrasound measurements of crown-rump length and embyronic volume, analyzed with VR-software. Results: For the total study population, the PVRS ranged from –0.071 to 0.320 (median 0.131). Higher PVRS values were significantly associated with reduced embryonic growth trajectories (CRL: β = –0.58 mm, 95% CI –0.94 to –0.23, P = 0.001; embryonic volume: β = –0.31 cm³, 95% CI –0.49 to –0.13, P = 0.001). Subgroup analyses revealed significant negative associations in naturally conceived pregnancies (CRL: β = –0.82 mm, 95% CI –1.48 to –0.16, P = 0.015; embryonic volume: β = –0.39 cm³, 95% CI –0.71 to –0.08, P = 0.015) and in overweight women (CRL: β = –0.91 mm, 95% CI –1.55 to –0.27, P = 0.006; embryonic volume: β = –0.51 cm³, 95% CI –0.82 to –0.21, P = 0.001).Conclusions: The PVRS provides a weighted measure of maternal vulnerability, significantly associated with reduced embryonic growth, particularly in naturally conceived pregnancies and overweight women. Although no causality can be inferred from this study, the observed associations suggest that a broad peri-conceptional vulnerability assessment could help to identify potentially modifiable risk factors.</p
Assessing metal mixture effects on neuropsychological development:A trade-off between complexity and interpretability
No full textSeveral studies have explored the joint effect of mixtures of metals on health outcomes by using sophisticated statistical techniques such as Bayesian Kernel Machine Regression (BKMR). Although these appealing tools can detect complex relationships between metals, their interpretation is not straightforward. Indeed, BKMR is frequently used jointly with other methods, and final conclusions are simplified in terms of increase/decrease of the risk function at fixed values for individual metals. In this paper, we explore the feasibility and interpretability of such techniques to assess the effect of metal mixture exposures on neuropsychological development in early childhood. This is a cross-sectional study. Initially, we use Principal Components Analysis (PCA) to detect main latent neurodevelopment domains. The scores derived by the BKMR exposure-response function were computed and compared with those provided by traditional linear regression models (LRM). Pearson's correlation coefficients of the estimations obtained by BKMR and LRM accounting for pairwise interactions between metals (lead, molybdenum, and selenium) were 0.95, 0.95 and 0.92, for the three identified latent domains: executive functions, motor functions and visual and verbal functions, respectively. The observed differences between both estimations mainly occurred in participants having low concentrations of lead and low and high values of selenium, which suggest linearity in the associations and not high order interactions between metals. We concluded that, in this case, employing linear regression to model the impact of mixtures on targeted outcomes led to similar results than more complex statistical techniques allowing a better understanding of both individual and interaction effects between metals.</p
The animal-machine:New ideas on animals in early modern philosophy and science
No full textThis dissertation examines seventeenth-century conceptions of animals through comparative analysis of five mechanist philosophers: Descartes, Gassendi, Hobbes, Spinoza, and Leibniz. Given their shared commitment to mechanistic explanations of natural phenomena and collective rejection of Scholastic substantial forms, one would expect these thinkers to reach similar conclusions about animal nature, particularly endorsing the Cartesian "bête-machine" doctrine that animals are automata devoid of sensation and consciousness.Through systematic examination of each philosopher's experimental work, epistemology, scientific principles, and views on human-animal distinctions, the thesis demonstrates that this expected uniformity did not materialize. Rather than mechanism itself determining these philosophers' positions on animals, their collective opposition to Cartesian doctrine served as the organizing principle. Gassendi, Hobbes, Spinoza, and Leibniz, despite sharing mechanistic frameworks, maintained that animals possess genuine sensory experience, perception, and varying degrees of sentience.The analysis reveals that specific Cartesian commitments generated the restrictive view that denied animal experience. Leibniz's retention of substantial forms, uniquely among these mechanists, enabled a particularly rich account of animal life within his mechanistic framework. The dissertation demonstrates that divergent philosophical systems, rather than shared scientific methodology, determined positions on animal minds. This finding contributes to early modern intellectual history and illuminates how theoretical commitments beyond empirical observation shape conclusions about non-human experience.<br/
Frequency and survival of delayed breast cancer diagnosis in women participating at screening mammography in the Netherlands:a population-based study
No full textBackground: Although breast cancer screening programmes aim to enable early breast cancer detection, diagnostic delays still occur among participants. Limited information is available on the frequency and survival of women with a delay in breast cancer diagnosis within the screening population. We determined the frequency of various types of delay in breast cancer diagnosis at screening mammography and specified the tumour characteristics, surgical therapy and survival rates of women with these delayed diagnoses, as well as variations in their proportions over time. Methods: We included 901,133 screening examinations obtained in the southern Netherlands between 1999 and 2019. Screening mammograms of women with interval cancers (ICs) and breast cancers detected at subsequent screening were reviewed to determine whether the cancer had been missed. Findings: Of the 7129 women with breast cancers, 5419 (76.0%) were diagnosed without delay after recall and 1101 (15.4%) had a true IC (i.e., not detectable at the previous screen). In total, 1601 women experienced a delay in breast cancer diagnosis, comprising the following three study groups: (i) recalled women with a delay in diagnostic work-up (n = 264), (ii) recalled women with screen-detected cancers (SDCs) at subsequent screening and without a delay in diagnostic work-up, that had been missed at the previous screening round (n = 992), and (iii) women with ICs missed at the latest screening round (n = 345). Overall, 26.6% of cancers were associated with a delay (1601/6028), primarily due to SDCs missed at the previous screen (62.0%, 992/1601), followed by missed ICs (21.5%, 345/1601) and misdiagnosis after recall (16.5%, 264/1601). Compared to SDCs missed at the previous screen and misdiagnosis after recall, missed ICs demonstrated the poorest tumour characteristics, highest mastectomy rate (42.6% vs 20.1% and 19.3%, p < 0.0001) and poorest overall survival (5-year rate 86.9% vs 93.8% and 93.8%, p = 0.0017). Temporal trends in tumour characteristics were mainly observed in SDCs missed at the previous screen. Interpretation: Delayed breast cancer diagnosis at screening mammography or after recall remains a serious point of concern. Most delays are related to SDCs missed at a previous screen, whereas missed ICs show the worst survival. </p
A robust method for primary cerebellar culture and genetic manipulation of Purkinje cells from postnatal mice
No full textBackground:Primary cerebellar cultures are a powerful system for studying genes and pathways involved in development and disease. However, maintaining the survival of Purkinje cells in vitro remains challenging. These neurons represent a small fraction of the cerebellar population and are highly sensitive to culture conditions, making genetic manipulation difficult. Existing protocols often use more than one culture medium, vary in the developmental stage of the cerebellar tissue used, and may require supplementary support cell cultures. New method:We describe a robust method for dissociated cerebellar cultures that supports Purkinje cell development and enables efficient genetic manipulation using two techniques. Results:Our protocol supports the development of Purkinje cells from embryonic day 18 and postnatal day 1 mouse cerebellar tissue, with P1-derived neurons more closely resembling their in vivo counterparts. Genetic manipulation was achieved via cell-specific adeno-associated viral transduction and non-cell-specific antisense oligonucleotide transfection. Functional neuronal activity was confirmed using calcium imaging with Fluo-4 AM.Comparison with existing methods:Our approach unifies key aspects of existing protocols. It uses a single-medium composition, eliminating the need for separate seeding and maintenance media. Culturing each cerebellum individually preserves the intrinsic number of supporting cells, eliminating the need for parallel cultures. Using postnatal tissue also reduces animal usage. Additionally, gene expression can be successfully modulated using antisense oligonucleotides. Conclusions:This protocol provides an efficient framework for the culture, development, and genetic manipulation of Purkinje cells, facilitating their application in molecular, cellular, and functional studies of cerebellar development and disease models.</p
Genetics of Thyroid Function:Relevance for Biology and Disease Management
No full textContext: Genetic factors are a major contributor to variation in thyroid function. Recent studies have partly identified the responsible common genetic variants and studied their application in unraveling thyroid (patho)physiology as well as their potential clinical use. Evidence Acquisition: This review summarizes the current state of knowledge regarding the genetic architecture of thyroid function as well as its applications to improve (patho)physiological understanding and clinical management of thyroid (dys)function. Evidence Synthesis: Genome-wide association studies (GWAS) have been successful in detecting numerous genetic variants affecting variation in thyrotropin (TSH), free thyroxine, and triiodothyronine concentrations. Subsequent emerging high-throughput in silico and in vitro strategies are of particular value in unraveling functionality of these novel genes and its genetic variants. Translational methods such as mendelian randomization (MR) and polygenic scores (PGSs) can provide important insights into causal associations or susceptibility to disease. Moreover, PGSs show potential in adjusting personalized TSH reference ranges by distinguishing between individual hypothalamicpituitary-thyroid–axis set-point effects and (subclinical) thyroid dysfunction. Conclusion: Functional characterization of the associated genes and variants in GWAS is warranted as the majority are located in genes with a yet unknown role in thyroid hormone physiology. Integration of multi-omics data and optimalization of translational applications such as MR and PGS show potential to further unravel the underlying molecular mechanisms and pave the way for incorporation of genetics in personalized management of thyroid diseases.</p