Een korte biografie van Oss-Horzak, een lokale gemeenschap tussen Maaskant en Heikant

Wetensch. publicatieFaculty of Archeolog

2000 Jaar bewoningsdynamiek Thema's in het metaaltijdenonderzoek

Wetensch. publicatieFaculty of Archeolog

Het vorstengraf van Oss re-reconsidered. Archeologisch onderzoek Oss-Vorstengrafdonk 1997-2005.

Prehistoric farming communities in NW Europ

Vee en voorouders, centrale elementen uit het dagelijks leven in de bronstijd

Prehistoric farming communities in NW Europ

Archeologisch onderzoek in de gemeente Oss in 1998

Wetensch. publicatieFaculty of Archeolog

Bouwen aan het verleden: vijfentwintig jaar archeologisch onderzoek in de gemeente Oss

Wetensch. publicatieFaculty of Archeolog

Systematic analysis of PINK1 variants of unknown significance shows intact mitophagy function for most variants

Pathogenic variants in PINK1 cause early-onset Parkinson’s disease. Although many PINK1 variants have been reported, the clinical significance is uncertain for the majority of them. To gain insights into the consequences of PINK1 missense variants in a systematic manner, we selected 50 PINK1 missense variants from patient- and population-wide databases and systematically classified them using Sherloc, a comprehensive framework for variant interpretation based on ACMG-AMP guidelines. We then performed functional experiments, including mitophagy and Parkin recruitment assays, to assess the downstream consequences of PINK1 variants. Analysis of PINK1 missense variants based on Sherloc showed that the patient databases over-annotate variants as likely pathogenic. Furthermore, our study shows that pathogenic PINK1 variants are most often linked to a loss-of-function for mitophagy and Parkin recruitment, while this is not observed for variants of unknown significance. In addition to the Sherloc framework, the added layer of evidence of our functional tests suggests a reclassification of 9/50 missense variants. In conclusion, we suggest the assessment of multiple layers of evidence, including functional data on top of available clinical and population-based data, to support the clinical classification of a variant and show that the presence of a missense variant in PINK1 in a Parkinson’s disease case does not automatically imply pathogenicity

Parkinson's disease-associated VPS35 mutant reduces mitochondrial membrane potential and impairs PINK1/Parkin-mediated mitophagy

BACKGROUND: Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease (PD), and several genes linked to familial PD, including PINK1 (encoding PTEN-induced putative kinase 1 [PINK1]) and PARK2 (encoding the E3 ubiquitin ligase Parkin), are directly involved in processes such as mitophagy that maintain mitochondrial health. The dominant p.D620N variant of vacuolar protein sorting 35 ortholog (VPS35) gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2. METHODS: To better mimic and study the patient situation, we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35. These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce the PINK1/Parkin-mediated mitophagy, which was assessed using biochemical and microscopy approaches. RESULTS: Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state. As a result, the mitochondria of these cells were desensitized to the CCCP-induced collapse in mitochondrial potential, as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult. Consequently, Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired. CONCLUSION: Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35, PINK1 and Parkin in PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40035-021-00243-4

Viscosity Is Not a Parameter of Postdeglutitive Pharyngeal Residue: Quantification and Analysis with Scintigraphy

The aim of this study was to explore the influence of viscosity on pharyngeal residue in normal healthy volunteers. Scintigraphy was used to measure pharyngeal residue in 11 healthy volunteers after swallowing three different substances (age = 20.2–48.3 years). The first substance was a 10-ml solution of tap water with 0.5% xanthan with a viscosity of 4500 mPa s, comparable to a yogurt drink. The second and third substances were a 0.75% xanthan and a 1.00% xanthan solution, with viscosities of 10,500 and 21,000 mPa s, comparable to low-fat yogurt and 3% fat yogurt, respectively. Tap water was used as the control substance. Mean pharyngeal residue after swallowing tap water was 2.3% (SD = 1.2) of the initial volume in the oral cavity. Pharyngeal residue after swallowing 0.5% xanthan solution was 1.8% (SD = 0.8), after swallowing 0.75% xanthan solution 2.6% (SD = 2.2), and after swallowing 1.00% xanthan solution 2.8% (SD = 1.7). No significant correlation between increase of viscosity and pharyngeal residue was found. In healthy persons viscosity does not seem to be a significant parameter for pharyngeal residue for boluses with viscosities ranging from tap water to solutions having a viscosity comparable to 3% fat yogurt