Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation.

Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants.

Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits.

Differentiation of human induced pluripotent stem cells into cortical neural stem cells.

Efficient and effective methods for converting human induced pluripotent stem cells into differentiated derivatives are critical for performing robust, large-scale studies of development and disease modelling, and for providing a source of cells for regenerative medicine. Here, we describe a 14-day neural differentiation protocol which allows for the scalable, simultaneous differentiation of multiple iPSC lines into cortical neural stem cells We currently employ this protocol to differentiate and compare sets of engineered iPSC lines carrying loss of function alleles in developmental disorder associated genes, alongside isogenic wildtype controls. Using RNA sequencing (RNA-Seq), we can examine the changes in gene expression brought about by each disease gene knockout, to determine its impact on neural development and explore mechanisms of disease.

Study protocol: establishment of a multicentre pre-eclampsia database and biobank in Sweden: GO PROVE and UP MOST, a prospective cohort study.

Introduction: Pre-eclampsia, a multisystem disorder in pregnancy, is one of the most common causes of maternal morbidity and mortality worldwide. However, we lack methods for objective assessment of organ function in pre-eclampsia and predictors of organ impairment during and after pre-eclampsia. The women's and their partners' experiences of pre-eclampsia have not been studied in detail.

Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation.

Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells.

Signs of neuroaxonal injury in preeclampsia-A case control study.

Background: Cerebral injury is a common cause of maternal mortality due to preeclampsia and is challenging to predict and diagnose. In addition, there are associations between previous preeclampsia and stroke, dementia and epilepsy later in life. The cerebral biomarkers S100B, neuron specific enolase, (NSE), tau protein and neurofilament light chain (NfL) have proven useful as predictors and diagnostic tools in other neurological disorders.

Co-Constructing Universal Design in Citizen Science Workshops.

This paper reports on a series of workshops that took place at two Swedish museums during 2017. The workshops were inspired by a citizen science approach, where the participants were not only on the receiving end but also active in producing new knowledge. The importance of turning to peoples' lived perspectives are often brought forward as crucial to understanding how inclusion and exclusion are played out in real life.

Geosphere-biosphere circulation of chemical elements in soil and plant systems from a 100 km transect from southern central Norway.

Geochemical element separation is studied in 14 different sample media collected at 41 sites along an approximately 100-km long transect north of Oslo. At each site, soil C and O horizons and 12 plant materials (birch/spruce/cowberry/blueberry leaves/needles and twigs, horsetail, braken fern, pine bark and terrestrial moss) were sampled. The observed concentrations of 29 elements (K, Ca, P, Mg, Mn, S, Fe, Zn, Na, B, Cu, Mo, Co, Al, Ba, Rb, Sr, Ti, Ni, Pb, Cs, Cd, Ce, Sn, La, Tl, Y, Hg, Ag) were used to investigate soil-plant relations, and to evaluate the element differentiation between different plants, or between foliage and twigs of the same plant.

Influence of Multiple Environmental Factors on Organic Matter Chlorination in Podsol Soil.

Natural chlorination of organic matter is common in soils. The abundance of chlorinated organic compounds frequently exceeds chloride in surface soils, and the ability to chlorinate soil organic matter (SOM) appears widespread among microorganisms. Yet, the environmental control of chlorination is unclear.

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1.

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear.

Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies.

Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue.

Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas.

Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry.

Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites.

Opioid precursor protein isoform is targeted to the cell nuclei in the human brain.

Background: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms.

Reduced Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption.

The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN.

Quantitative mass spectrometry imaging of small-molecule neurotransmitters in rat brain tissue sections using nanospray desorption electrospray ionization.

Small molecule neurotransmitters are essential for the function of the nervous system, and neurotransmitter imbalances are often connected to neurological disorders. The ability to quantify such imbalances is important to provide insights into the biochemical mechanisms underlying the disorder. This proof-of-principle study presents online quantification of small molecule neurotransmitters, specifically acetylcholine, γ-aminobutyric acid (GABA) and glutamate, in rat brain tissue sections using nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging.

How to measure renal artery stenosis--a retrospective comparison of morphological measurement approaches in relation to hemodynamic significance.

Background: Although it is well known that renal artery stenosis may cause renovascular hypertension, it is unclear how the degree of stenosis should best be measured in morphological images. The aim of this study was to determine which morphological measures from Computed Tomography Angiography (CTA) and Magnetic Resonance Angiography (MRA) are best in predicting whether a renal artery stenosis is hemodynamically significant or not.

Methods: Forty-seven patients with hypertension and a clinical suspicion of renovascular hypertension were examined with CTA, MRA, captopril-enhanced renography (CER) and captopril test (Ctest).

Urban contamination sources reflected in inorganic pollution in urban lake deposits, Bergen, Norway.

The 7000 years transition from a pristine environment towards a modern city has brought a number of chemical changes and effects to urban lake sediments in Bergen. Metals, such as Pb, Hg, Zn, Cu and Fe, display a large anthropogenic influence and reflect historical point sources that existed within the drainage area from approximately AD 1790 until today. The concentration peaks alternate with intervals of lower concentration due to phases of coarser grained sediment input but also periods of potentially reduced metal influx.

Polycyclic aromatic hydrocarbons (PAHs) in sediments from lake Lille Lungegårdsvannet in Bergen, western Norway; appraising pollution sources from the urban history.

This study aims to determine the temporal character and concentration variability of polycyclic aromatic hydrocarbon (PAH) during the last 5,400 years in urban lake sediments through a combination of dating and chemo-stratigraphical correlation. We investigate the chemical history of the city of Bergen and determine the effect of specific point sources, as well as diffuse sources, and also help assess the risk of remediation plans. By using several organic compounds, metals and cyanide, we demonstrate the more accurate timing of sedimentation.

Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA).

Many pathological processes are not directly correlated to dramatic alterations in protein levels. The changes in local concentrations of important proteins in a subset of cells or at specific loci are likely to play a significant role in disease etiologies, but the precise location might be unknown, or the concentration might be too small to be adequately sampled for traditional proteomic techniques. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is a unique analytical method that combines analysis of multiple molecular species and of their distribution in a single platform.

Analysis of neuropeptides by MALDI imaging mass spectrometry.

Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is one of the most effective tools for localizing small molecules and compounds directly in thin tissue sections. MALDI IMS should be used when the distribution of molecular species is not known and to localize changes due to a disease process or a treatment. In recent years it has become increasingly clear that many pathological processes are not readily correlated to dramatic changes in protein levels.

MALDI imaging of post-mortem human spinal cord in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brainstem and the spinal cord. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry is an emerging powerful technique that allows for spatially resolved, comprehensive, and specific characterization of molecular species in situ. In this study, we report for the first time the MALDI imaging-based spatial protein profiling and relative quantification of post-mortem human spinal cord samples obtained from ALS patients and controls.

Neonatal exposure to the cyanobacterial toxin BMAA induces changes in protein expression and neurodegeneration in adult hippocampus.

The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 9-10) with the glutamatergic BMAA.