Biology subjects

Schmidt, S.

Publications and source records attributed to Schmidt, S..

77 records · Page 5Linked to original sources

bioRxiv2019

Structural elements that modulate the substrate specificity of plant purple acid phosphatases: avenues for improved phosphorus acquisition in crops

Phosphate acquisition by plants is an essential process that is directly implicated in the optimization of crop yields. Purple acid phosphatases (PAPs) are ubiquitous metalloenzymes, which catalyze the hydrolysis of a wide range of phosphate esters and anhydrides. While some plant PAPs display a preference for ATP as the substrate, others are efficient in hydrolyzing phytate or 2-phosphoenolpyruvate (PEP). PAP from red kidney bean (rkbPAP) is an efficient ATP- and ADPase, but has no activity towards phytate. The crystal structure of this enzyme in complex with an ATP analogue (to 2.20 [A] resolution) provides insight into the amino acid residues that play an essential role in binding this substrate. Homology modelling was used to generate three-dimensional structures for the active sites of PAPs from tobacco (NtPAP) and Arabidopsis thaliana (AtPAP12 and AtPAP26) that are efficient in hydrolyzing phytate and PEP as substrates, respectively. In combination with substrate docking simulations and a phylogenetic analysis of 49 plant PAP sequences (including the first PAP sequences reported from Eucalyptus), several active site residues were identified that are important in defining the substrate specificities of plant PAPs. These results may inform bioengineering studies aimed at identifying and incorporating suitable plant PAP genes into crops to improve phosphorus use efficiency. Organic phosphorus sources increasingly supplement or replace inorganic fertilizer, and efficient phosphorus use of crops will lower the environmental footprint of agriculture while enhancing food production.

biochemistry↗

bioRxiv2019

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinsons disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, {beta}-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.

neuroscience↗

bioRxiv2019

A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation

Recurrent MI is common in patients with coronary artery disease and associates with high mortality. Here we developed a surgical mouse model in which two subsequent MIs affect different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex followed by the left anterior descending branch of the coronary artery. We characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac MRI. We report that a first MI induces bone marrow \"memory\" via a circulating signal, thereby affecting hematopoietic factor expression in bone marrow macrophages. This altered the organisms reaction to subsequent events. Inspite at least similar extent of injury reported by blood troponin, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. Our data suggest that hematopoietic and innate immune responses are shaped by a preceding MI.

physiology↗

bioRxiv2019

YAP controls cell migration and invasion through a Rho-GTPase switch

Delineating the mechanisms controlling the invasive spread of non-diseased and transformed cells is central to understanding diverse processes including cancer progression. Here, we found that Yes-associated protein (YAP), a central transcriptional regulator implicated in controlling organ and body size, modulated a Rho-GTPase switch that drives cellular migration by transactivating the Rac1-GEF protein TRIO through direct modulation of its intronic enhancer. Additionally, YAP and TRIO may promote invasive behavior through putative crosstalk with STAT3 signaling, a potential downstream target. Although we found this YAP-dependent infiltrative program in many cell types, it was particularly enhanced in a patient-specific manner in the most common malignant brain tumor, glioblastoma (GBM), where hyperactivation of the YAP, TRIO, and STAT3 signatures also conferred poor clinical outcome. Our analysis suggests that the YAP-TRIO-Rho-GTPase signaling network identified in this study is a ubiquitous regulator of invasive cell spread in both physiological and pathological contexts.

cancer biology↗

bioRxiv2018

Virtual navigation tested on a mobile app (Sea Hero Quest) is predictive of real-world navigation performance: preliminary data

Virtual reality environments presented on smart-phone and tablet devices have potential to aid the early diagnosis of conditions such as Alzheimers dementia by quantifying impairments in navigation performance. However, it is unclear whether performance on mobile devices can predict navigation errors in the real-world. In a preliminary study we tested 30 participants (15 female, 18-30 years old) on their wayfinding ability in our mobile app Sea Hero Quest and on novel real-world wayfinding task in London (UK). We find a significant correlation between virtual and real-world navigation performance and a male advantage on both tasks, although smaller in the real-world environment. These results are consistent with prior studies which have reported navigation in the virtual environments are predictive of real-world navigation performance and a consistent male advantage. Future research will need to test a larger sample size and older participants.

neuroscience↗