Biallelic variants in cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of in mice results in sinus pauses and bradycardia and morpholino knockdown of zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy.

PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD.

Tissue tropism and pathology of highly pathogenic avian influenza H5N6 virus in chickens and Pekin ducks.

The highly pathogenic avian influenza (HPAI) H5N6 virus caused outbreaks on commercial poultry farms in the Netherlands in 2017-2018, holding chickens and Pekin ducks. Intravenous pathogenicity index (IVPI) tests confirmed the high pathogenicity of the virus. Tissues derived from birds from infected farms (natural infection) and IVPI tests (experimental infection) were used to compare histopathology and virus distribution in both poultry species.

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 .

Clinical and Pathological Findings in SARS-CoV-2 Disease Outbreaks in Farmed Mink ().

SARS-CoV-2, the causative agent of COVID-19, caused respiratory disease outbreaks with increased mortality in 4 mink farms in the Netherlands. The most striking postmortem finding was an acute interstitial pneumonia, which was found in nearly all examined mink that died at the peak of the outbreaks. Acute alveolar damage was a consistent histopathological finding in mink that died with pneumonia.

Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with pathogenic/likely pathogenic (P/LP) variants in genes encoding the cardiac desmosomal proteins. Origin of these variants, including de novo mutation rate and extent of founder versus recurrent variants has implications for variant adjudication and clinical care, yet this has never been systematically investigated.

Methods: We identified arrhythmogenic right ventricular cardiomyopathy probands who met 2010 Task Force Criteria and had undergone genotyping that included sequencing of the desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP) from 3 arrhythmogenic right ventricular cardiomyopathy registries in America and Europe.

Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation.

Alzheimer's disease (AD) is a highly prevalent multifactorial disease for which Diabetes Mellitus (DM) is a risk factor. Abnormal phosphorylation and aggregation of tau is a key hallmark of AD. In animal models, DM induces or exacerbates the phosphorylation of tau, suggesting that DM may influence the risk at AD by directly facilitating tau pathology.

Liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide affect Aβ aggregation features and cross the blood-brain-barrier: implications for therapy of Alzheimer disease.

Targeting amyloid-β peptide (Aβ) within the brain is a strategy actively sought for therapy of Alzheimer's disease (AD). We investigated the ability of liposomes bi-functionalized with phosphatidic acid and with a modified ApoE-derived peptide (mApoE-PA-LIP) to affect Aβ aggregation/disaggregation features and to cross in vitro and in vivo the blood-brain barrier (BBB). Surface plasmon resonance showed that bi-functionalized liposomes strongly bind Aβ (kD=0.

Ubiquilin 2 is not associated with tau pathology.

Accumulation of aberrant proteins in inclusion bodies is a hallmark of many neurodegenerative diseases. Impairment of proteolytic systems is a common event in these protein misfolding diseases. Recently, mutations in the UBQLN 2 gene encoding ubiquilin 2 have been identified in X-linked amyotrophic lateral sclerosis (ALS).

Inhibition of endoplasmic reticulum associated degradation reduces endoplasmic reticulum stress and alters lysosomal morphology and distribution.

Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases.

Disturbed Ca2+ homeostasis increases glutaminyl cyclase expression; connecting two early pathogenic events in Alzheimer's disease in vitro.

A major neuropathological hallmark of Alzheimer's disease (AD) is the deposition of aggregated β amyloid (Aβ) peptide in the senile plaques. Aβ is a peptide of 38-43 amino acids and its accumulation and aggregation plays a key role early in the disease. A large fraction of β amyloid is N-terminally truncated rendering a glutamine that can subsequently be cyclized into pyroglutamate (pE).

Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome.

Deposition of aggregated amyloid beta (Aβ) is a major hallmark of Alzheimer's disease (AD)-a common age-related neurodegenerative disorder. Typically, Aβ is generated as a peptide of varying lengths. However, a major fraction of Aβ peptides in the brains of AD patients has undergone posttranslational modifications, which often radically change the properties of the peptides.

Rab6 is a modulator of the unfolded protein response: implications for Alzheimer's disease.

The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients.

Pathogenesis of Herpesvirus anguillae (HVA) in juvenile European eel Anguilla anguilla after infection by bath immersion.

A clinical infection in post-larval (glass) European eels Anguilla anguilla was successfully induced after artificial bath immersion with Herpesvirus anguillae (HVA), isolated from diseased European eel. HVA caused a clinical infection after 7 d post-inoculation (pi); virus was detected by polymerase chain reaction (PCR) from Day 1 pi; virus isolation was positive from Day 7 pi, and HVA antigen was detected by immunohistochemistry in gills and stomach from Day 4 pi. Tissue changes were found by histological examination in gills and skin from Day 4 pi.

Abeta 1-42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner.

Alzheimer's disease (AD) is characterized by the aggregation of misfolded proteins. Previously we reported activation of the unfolded protein response (UPR) in AD neurons. A potential source for UPR activation in AD neurons may be the increased levels of beta-amyloid (Abeta).

Pin1 levels are downregulated during ER stress in human neuroblastoma cells.

Previously, we showed that pretangle neurons in Alzheimer's disease (AD) brain display unfolded protein stress in the endoplasmic reticulum (ER). Others showed that the peptidylprolyl isomerase Pin1 protects against tangle formation by facilitating tau dephosphorylation, corroborating with the lower expression of Pin1 observed in tangle-bearing neurons. In this study, we investigated Pin1 expression under ER stress conditions.

Alternative splicing in the N-terminus of Alzheimer's presenilin 1.

Presenilin 1 (PS1) is mutated in the majority of familial cases of Alzheimer disease (AD). Although it is clear that PS1 is involved in the processing of the amyloid precursor protein (APP), the exact function of PS1 is still elusive. Human presenilin 1 (PS1) is alternatively spliced, resulting in the presence or absence of a four-amino acid motif, VRSQ, in the PS1 N-terminus.

Rab6 membrane association is dependent of Presenilin 1 and cellular phosphorylation events.

Processing of the amyloid precursor protein (APP) by alpha-secretase precludes the formation of beta-amyloid (Abeta). Therefore, the increase of cleavage by alpha-secretase upon stimulation by protein kinase C (PKC) is of potential therapeutic interest for Alzheimer's disease (AD). Unknown is whether phosphorylation by PKC increases alpha-secretase-mediated cleavage directly or indirectly, for example, by modulation of APP trafficking.

Macrophages and MHC class II positive dendritiform cells in the iris and choroid of the pig.

Purpose: Macrophages and dendritic cells (DC) are considered to play an important role in the initiation and propagation of uveitis. Little is known about these cells in the normal pig uveal tract, despite the fact that the pig eye shares many similarities with the human eye and is considered as a suitable species to investigate the pathogenesis of human ocular disease. The aim of this study was to investigate the presence of immunocompetent cells in the uveal tract of the normal pig.

Immune cells in the porcine retina: distribution, characterization and morphological features.

Purpose: To investigate the presence of immunocompetent cells in the porcine retina and to compare the findings with those obtained earlier in human retinas.

Methods: Retinal wholemounts or cryostat sections from outbred Dutch Landrace pigs were analyzed for the presence of microglia (CD45), macrophages-monocytes (SW3, CD163, 2A10, CD14), major histocompatibility complex (MHC) class II-positive cells (MCA1335), granulocytes (MCA1219), B lymphocytes (IgM), and T lymphocytes (CD6, CD4, CD8), by using specific monoclonal antibodies followed by immunohistochemical staining.

Results: A uniform distribution of CD45-positive microglial cells was observed throughout the porcine retina (mean number, 289 +/- 16 cells/mm(2)).