Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the ...possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3β in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.
Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of ...cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.
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•Coupling NGN2 expression and SMAD/WNT inhibition yields human patterned induced neurons (hpiNs)•Single-cell analysis indicates excitatory, neuronal identity, with variable maturity•A CAMK2A::GFP reporter gene isolates more differentiated neurons from progenitors•CAMK2A+ hpiNs display AMPAR- and NMDAR-mediated synaptic transmission
Nehme et al. combine two strong neuralizing factors (transcription factor programming and small molecule patterning) to generate human excitatory neurons from stem cells. They further undertake single-cell and reporter gene approaches to select highly differentiated neurons with increased functionality, augmenting their utility in the modeling of nervous system disorders.
The ageing work force is heterogeneous, following distinct development in work ability. This study aims to identify trajectories of long-term sickness absence (SA) in later careers and to examine ...potentially modifiable factors associated with the development of SA.
Data comprised of municipal employees of the city of Helsinki aged 50-60 years during 2004-2018 (N = 4729, 80% women). The developmental trajectories of long-term (> 10 working days) SA were examined with Group-based trajectory modelling (GBTM) using SA records of the Social Insurance Institution of Finland during 2004-2018. All-cause and diagnosis-specific (mental disorder- and musculoskeletal disease-related) SA days were analysed. The association of social and health-related factors with trajectory membership was examined using multinomial logistic regression (odds ratios and 95% confidence intervals).
A model with three trajectories was selected for both all-cause and diagnosis-specific SA. Regarding all-cause long-term SA trajectories, 42% had no long-term SA, 46% had low levels of SA, and 12% had a high rate of SA during follow-up. Lower occupational class, reporting smoking, overweight or obesity, moderate or low leisure-time physical activity, and sleep problems were associated with a higher likelihood of belonging to the trajectory with a high rate of SA in both all-cause and diagnosis-specific models.
Most ageing employees have no or little long-term SA. Modifiable factors associated with trajectories with more SA could be targeted when designing and timing interventions in occupational healthcare.
Prior analyses of class differences in health trajectories among employees have often omitted women and transitions to retirement. We examined social class trajectories in physical functioning among ...Finnish female employees from midlife to retirement age, and whether transitions to retirement modified these trajectories.
Data were derived from mail surveys at Phases 1-3 (2000-2012) among employees of the City of Helsinki, Finland, aged 40-60 at baseline (n = 8960, 80% women, response rates 69-83%). We included respondents to any of the Phases 1-3 aged 40-72 (n = 6976). We distinguished higher and lower social classes, and employment statuses, i.e. employed, mandatorily retired and disability-retired. Short Form 36 physical component summary was used to measure physical functioning. Mixed-effect growth curve models were used to assess the association of social class and employment status with functioning over age.
For employed women, physical functioning deteriorated faster in the lower than in the higher class, with class trajectories widening in ages 40-65. After mandatory retirement, functioning deteriorated in both classes, whereas after disability retirement, functioning improved. Across employment statuses, functioning converged at older ages, and the disability-retired caught up with the better functioning of the employed and mandatorily retired. Employment status modified the trajectories, as among the continuously employed and mandatorily retired women functioning deteriorated, but among the disability-retired, trajectories improved and reached a similar level with employed and mandatorily retired women. Social class inequalities remained in all employment status groups.
Overall, our results suggest evidence for the cumulative disadvantage model, with accumulating work exposures among lower classes potentially contributing to their trajectories of ill health.
2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological ...symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation.
COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.
Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. ...Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large >1 Mb CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 95% CI 0.66-0.89) and lower household income (OR = 0.77 0.66-0.89). Income-associated CNVs also lowered household income (OR = 0.50 0.38-0.66), and CNVs with medical consequences lowered subjective health (OR = 0.48 0.32-0.72). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 0.26-0.37), lower-income (OR = 0.66 0.57-0.77), lower subjective health (OR = 0.72 0.61-0.83), and increased mortality (Cox's HR = 1.55 1.21-1.98). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.
The maturation of neurons and the development of synapses, although emblematic of neurons, also relies on interactions with astrocytes and other glia. Here, to study the role of glia-neuron ...interactions, we analyze the transcriptomes of human pluripotent stem cell (hPSC)-derived neurons, from 80 human donors, that were cultured with or without contact with glial cells. We find that the presence of astrocytes enhances synaptic gene-expression programs in neurons when in physical contact with astrocytes. These changes in neurons correlate with increased expression, in the cocultured glia, of genes that encode synaptic cell adhesion molecules. Both the neuronal and astrocyte gene-expression programs are enriched for genes associated with schizophrenia risk. Our results suggest that astrocyte-expressed genes with synaptic functions are associated with stronger expression of synaptic genetic programs in neurons, and they suggest a potential role for astrocyte-neuron interactions in schizophrenia.
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•Major gene-expression changes occur in neurons and glia on contact•Synaptic gene-expression programs are enhanced in neurons•Expression of genes that encode synaptic cell adhesion molecules is increased in glia•Both programs are enriched for genes associated with schizophrenia risk
Pietiläinen et al. examine gene-expression changes in neuronal and glial cells on contact. By studying 80 human neuronal lines cultured in different formats, they find that synaptic gene-expression programs are enhanced in neurons, whereas synaptic cell adhesion programs are increased in glia. Both are enriched for schizophrenia risk genes.
Early exit from paid employment is a notable public health and societal challenge. Previous research has largely focused on the relationships among variables instead of the relationships among ...individuals with different work participation history. Person-oriented methods enable to identify latent groups of individuals who are likely to follow similar development in their work participation over time. We thus aimed to identify work participation trajectories during early and midlife careers and their social determinants using large nationally representative data comprising over 1 million initially employed individuals and a 10-year follow-up for their work participation. A further aim was to determine the cumulative incidence of sickness absence due to key diagnostic groups, mental disorders and musculoskeletal diseases within the trajectories.
Young (25-38 years at baseline, n = 495,663) and midlife (39-52 years at baseline, n = 603,085) Finnish people, all working in 2004, were followed up through 2013, with registers of the Social Insurance Institution, and the Statistics Finland. The registers provided data for work participation and its determinants, as well as for computing the cumulative incidence of sickness absence. Latent class growth analysis was used to identify trajectories.
Three distinctive trajectories were identified: temporary exit, permanent exit, and continuously employed people. As compared to the other trajectories, those belonging to the permanent exit trajectory were more likely men, manual workers and had a lower income. The cumulative incidence of sickness absence due to mental disorders was highest in the permanent exit trajectory group. For musculoskeletal diseases, the cumulative incidence of sickness absence increased in the permanent exit trajectory mainly in the older age groups.
Distinct group-based trajectories of early work exit can be identified in a representative cohort of initially employed people. Focusing on the determinants of premature exit and early intervention to tackle increasing sickness absence may promote work participation particularly in the most vulnerable groups.
Objectives The mechanisms through which a low socioeconomic position leads to disability retirement are not yet established. We examined, on the one hand, the associations between occupational social ...class and disability retirement due to all causes, musculoskeletal diseases, and mental disorders and, on the other hand, the contribution of health behaviors and working conditions to these associations. Methods Middle-aged municipal employees from the Helsinki Health Study cohort baseline surveys in 2000–2002 (N=6516) were followed up until the end of 2010 for disability retirement. Retirement data were obtained from the registers of the Finnish Centre for Pensions and social class and covariates from the baseline surveys. Social class was categorized into managers and professionals, semi-professionals, routine non-manual employees, and manual workers. Cox regression analysis was used to calculate hazard ratios and their 95% confidence intervals. Results The risk of disability retirement was generally higher among those in lower social classes with a strong gradient for all causes, an even stronger gradient for musculoskeletal diseases, and a weaker non-linear association for mental disorders. These associations were largely mediated through physical workload among both women and men and hazardous exposures particularly among men. In mental disorders, job control also mediated the association. Strenuous desktop work and job demands widened the social class differences particularly among men and in mental disorders. The contribution of health behaviors was modest. Conclusions Improvements particularly in the physical working conditions but also the job control of those in lower social classes are likely to reduce socioeconomic differences in disability retirement.
Objectives The aim of the study was to examine the associations of changes in exposure to physical and psychosocial working conditions on subsequent sickness absence among ageing municipal employees ...of the City of Helsinki, Finland. Methods Changes in exposure to working conditions were assessed between baseline (2000-2002) and followup (2007) surveys. Register-based sickness absence information was linked to the survey data (N=3739) and followed-up from the return of the questionnaire in 2007 to the end of 2010. The study included six measures of physical and two measures of psychosocial working conditions. Negative binomial regression analysis was used to assess the associations and adjust for covariates. Results Favorable changes in physical working conditions lowered the risk for sickness absence whereas adverse changes increased the risk. Adverse changes in psychosocial working conditions only slightly increased the risk for sickness absence whereas favorable changes were unassociated with sickness absence. Conclusions Changes in exposure to physical working conditions in particular are associated with subsequent sickness absence. Preventing an increase in exposure to both psychosocial and physical working conditions and promoting a decrease in exposure to physical working conditions likely helps reduce the risk of sickness absence.
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