Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls.

Genomic, molecular, and cellular divergence of the human brain.

While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development.

X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes.

Background: Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines.

Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner.

Background: Development of synaptic activity is a key neuronal characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human- or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known about how human astrocytes influence neuronal activity.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards).

Pairwise association of key lifestyle factors and risk of solid cancers - A prospective pooled multi-cohort register study.

Smoking, alcohol consumption, obesity, and physical inactivity are key lifestyle risk factors for cancer. Previously these have been mostly examined singly or combined as an index, assuming independent and equivalent effects to cancer risk. The aim of our study was to systematically examine the joint pairwise and interactive effects of these lifestyle factors on the risk of a first solid primary cancer in a multi-cohort prospective setting.

Trajectories of hospitalizations after age-based statutory retirement.

Retirement years are ideally spent in good health. We aimed to produce new information using person-oriented methods by identifying groups of statutory retirees who did or did not achieve this objective and the factors that distinguish these groups from each other. Our particular focus was on the years directly after the transition into retirement, and the pre-retirement factors that explained the development of health, using a more severe health-related outcome-hospitalization.

Trajectories of CVD medication after statutory retirement: contributions of pre-retirement sociodemographic, work and health-related factors: a register study in Finland.

Background: Cardiovascular diseases (CVDs) are prevalent in older people, but few studies focus on developmental patterns in CVD medication directly after transition to statutory retirement. We thus aimed to identify trajectories of CVD medication after retirement, and their sociodemographic, work and health-related determinants.

Methods: We used complete register data of former employees of the City of Helsinki, Finland.

Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells.

Emerging evidence of species divergent features of astrocytes coupled with the relative inaccessibility of human brain tissue underscore the utility of human pluripotent stem cell (hPSC) technologies for the generation and study of human astrocytes. However, existing approaches for hPSC-astrocyte generation are typically lengthy or require intermediate purification steps. Here, we establish a rapid and highly scalable method for generating functional human induced astrocytes (hiAs).

Long-term sickness absence trajectories among ageing municipal employees - the contribution of social and health-related factors.

Background: 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.

Methods: Data comprised of municipal employees of the city of Helsinki aged 50-60 years during 2004-2018 (N = 4729, 80% women).

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase.

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.

Trajectories in physical functioning by occupational class among retiring women: the significance of type of retirement and social and health-related factors.

Background: Occupational class inequalities in physical functioning and their changes after retirement are poorly understood. We examined occupational class trajectories in physical functioning 10 years before and after transition to old-age and disability retirement. We included working conditions and behavioural risk factors as covariates, given their established link to health and retirement.

Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages.

Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. Here, we describe a "cell village" experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic variation, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus.

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons.

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.

Changes in occupational class differences in leisure-time physical activity and the contribution of retirement.

Occupational class differences in leisure-time physical activity (LTPA) are well recognized. Less is known about how these differences develop as individuals age, and how retirement is associated with this change. We investigated how occupational class differences in LTPA change in a cohort over a 15-17 years follow-up.

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line.

Joint association of socioeconomic circumstances and minor mental health problems with antidepressant medication.

Background: Disadvantageous socioeconomic circumstances and minor mental health problems have both been associated with mental disorders, such as depression, but their joint contribution remains unknown.

Methods: The Helsinki Health Study baseline survey (2000-02) of 40- to 60-year-old employees was linked with antidepressant medication data from registers of the Social Insurance Institution of Finland. The analyses were made using logistic regression with first prescribed antidepressant medication purchase during a 10-year follow-up as the outcome.

Associations between low parental education, childhood adversities and sickness absence in midlife public sector employees.

Aims: Parental education and childhood adversities are associated with long-term work disability but their contribution to sickness absence is largely unknown. We aimed to examine the associations between parental education, childhood adversities and self-certified and medically-certified sickness absence among midlife employees.

Methods: The Helsinki Health Study baseline survey data (2000-2002) of 40-to-60-year-old municipal employees were linked with sickness absence data from the employer's register.

Trajectories of Insomnia Symptoms Among Aging Employees and Their Associations With Memory, Learning Ability, and Concentration After Retirement - A Prospective Cohort Study (2000-2017).

Objectives: We applied a person-oriented approach and used latent class linear mixed models to identify sleep trajectories that explain memory, concentration, and learning ability problems after retirement.

Methods: Data consist of prospective surveys from four phases of the Helsinki Health Study between 2000-2017 (n = 3748, aged 55-77 years, 80% women). Multinomial regression was used to examine the associations between sleep trajectories and cognitive function, adjusting for sociodemographic, health-related behavior, and health factor covariates.

Pairwise association of key lifestyle factors and risk of colorectal cancer: a prospective pooled multicohort study.

Background: Several lifestyle factors are associated with an increased risk of colorectal cancer (CRC). Although lifestyle factors co-occur, in most previous studies these factors have been studied focusing upon a single risk factor or assuming independent effects between risk factors.

Aim: To examine the pairwise effects and interactions of smoking, alcohol consumption, physical inactivity, and body mass index (BMI) with risk of subsequent colorectal cancer (CRC).

A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development.

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.