Spastic paraplegia preceding -related familial Alzheimer's disease.

Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 () related familial Alzheimer's disease (AD).

Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where mutation was identified, brain biopsy was performed.

Correction to: Features of intracranial hemorrhage in cerebral venous thrombosis.

The original version of this article unfortunately contained mistakes. The correct information is given below.

Features of intracranial hemorrhage in cerebral venous thrombosis.

Background: Cerebral venous thrombosis (CVT) is associated with intracranial hemorrhage.

Aim: To identify clinical and imaging features of CVT-associated intracranial hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracranial hemorrhage.

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition.

Given the high frequency of activating mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application.

Hospital case-volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage.

Background: Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures.

Aims: To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH).

Methods: We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007-2014.

Outcome After Clipping and Coiling for Aneurysmal Subarachnoid Hemorrhage in Clinical Practice in Europe, USA, and Australia.

Background: Within randomized clinical trials (RCTs), coiling of the ruptured aneurysm to prevent rebleeding results in better outcomes than clipping in patients with aneurysmal subarachnoid hemorrhage (aSAH).

Objective: To study the association of coiling and clipping with outcome after aSAH in daily clinical practice.

Methods: In this controlled, nonrandomized study, we compared outcomes after endovascular coiling and neurosurgical clipping of ruptured intracranial aneurysms in an administrative dataset of 7658 aSAH patients (22 tertiary care hospitals from Europe, USA, Australia; 2007-2013).

Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model.

Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic.

Propofol is the most commonly used general anesthetic in humans. Our understanding of its mechanism of action has focused on its capacity to potentiate inhibitory systems in the brain. However, it is unknown whether other neural mechanisms are involved in general anesthesia.

Defining Y-SNP variation among the Flemish population (Western Europe) by full genome sequencing.

Y-chromosomal single nucleotide polymorphisms (Y-SNPs) represent a powerful tool in forensic research and casework, especially for inferring paternal ancestry of unknown perpetrators and unidentified bodies. However, the wealth of recently discovered Y-SNPs, the 'jungle' of different evolutionary lineage trees and nomenclatures, and the lack of population-wide data of many phylogenetically mapped Y-SNPs, limits the use of Y-SNPs in routine forensic approaches. Recently, a concise reference phylogeny of the human Y chromosome, the 'Minimal Reference Y-tree', was introduced aiming to provide a stable phylogeny with optimal global discrimination capacity by including the most resolving Y-SNPs.

HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls.

Postoperative atrial fibrillation: Target for stroke prevention?

Purpose: A substantial number of patients without a history of atrial fibrillation who undergo surgery develop one or more episodes of atrial fibrillation in the first few days after the operation. We studied whether postoperative transient atrial fibrillation is a risk factor for future atrial fibrillation, stroke and death.

Method: We performed a narrative review of the literature on epidemiology, mechanisms, risk of atrial fibrillation, stroke and death after postoperative atrial fibrillation.

Another piece in the progranulin puzzle: special binding between progranulin and prosaposin creates additional lysosomal access: An Editorial Comment for 'The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C' on page 236.

Loss-of-function mutations in the gene encoding the growth factor progranulin cause degeneration of the ageing brain in a dose-dependent manner. While heterozygous mutations result in adult onset frontotemporal dementia, the much rarer homozygous null mutations cause an early onset lysosomal storage disorder. A better understanding of the biology of progranulin in the central nervous system is needed to find solutions for these incurable diseases.

Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.

Loss of function mutations in progranulin (GRN) cause frontotemporal dementia, but how GRN haploinsufficiency causes neuronal dysfunction remains unclear. We previously showed that GRN is neurotrophic in vitro. Here, we used an in vivo axonal outgrowth system and observed a delayed recovery in GRN-/- mice after facial nerve injury.

The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling.

Loss of ER Ca homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor.

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID.

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models.

High content analysis at single cell level identifies different cellular responses dependent on nanomaterial concentrations.

A mechanistic understanding of nanomaterial (NM) interaction with biological environments is pivotal for the safe transition from basic science to applied nanomedicine. NM exposure results in varying levels of internalized NM in different neighboring cells, due to variances in cell size, cell cycle phase and NM agglomeration. Using high-content analysis, we investigated the cytotoxic effects of fluorescent quantum dots on cultured cells, where all effects were correlated with the concentration of NMs at the single cell level.

Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK.

BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP) consolidation in the dentate gyrus of live rodents requires sustained (hours) BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK).

High-content imaging and gene expression analysis to study cell-nanomaterial interactions: the effect of surface hydrophobicity.

The effects of nanoparticle (NP)-related parameters on cellular interactions are currently uncertain as analysis is complicated by the combinatorial diversity arising from the array of size, shape and surface properties. Here, we present a validated multiparametric high-content imaging method, with the utility of this approach demonstrated by in-depth analysis of the role of hydrophobicity on the interaction of Au NPs with cultured cells. In this methodology, we evaluate cell viability, membrane damage, induction of reactive oxygen species, mitochondrial health, cell area, skewness and induction of autophagy.