Biology subjects

Nieminen, T.

Publications and source records attributed to Nieminen, T..

3 recordsLinked to original sources

bioRxiv2021

Epicardial transplantation of autologous atrial appendage micrografts-evaluation of safety and feasibility in pigs after coronary artery occlusion

Several approaches devised for clinical utilization of cell-based therapies for heart failure often suffer from complex and lengthy preparation stages. Epicardial delivery of autologous atrial appendage micrografts (AAMs) with a clinically used extracellular matrix (ECM) patch provides a straightforward therapy alternative. We evaluated the operative feasibility and the effect of micrografts on the patch-induced epicardial foreign body inflammatory response in a porcine model of myocardial infarction. Right atrial appendages were harvested and mechanically processed into AAMs. The left anterior descending coronary artery was ligated to generate acute infarction. Patches of ECM matrix with or without AAMs were transplanted epicardially onto the infarcted area. Four pigs received the ECM and four received the AAMs patch. Cardiac function was studied by echocardiography both preoperatively and at three weeks follow-up. The primary outcome measures were safety and feasibility of the therapy administration and the secondary outcome was the inflammatory response to ECM. Neither AAMs nor ECM patch-related complications were detected during the follow-up time. AAMs patch preparation was feasible according to time and safety. Inflammation was greatly reduced in AAMs as compared to ECM patches as measured by the amount of infiltrated inflammatory cells and area of inflammation. Immunohistochemistry demonstrated an increased CD3+ cell density in the AAMs patch infiltrate. Epicardial AAMs transplantation demonstrated safety and clinical feasibility. The use of micrografts significantly inhibited ECM-induced foreign body inflammatory reactivity. Transplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can suppress acute inflammatory reactivity.

cell biology↗

bioRxiv2020

Determinants for forming a supramolecular myelin-like proteolipid lattice

Myelin protein P2 is a peripheral membrane protein of the fatty acid binding protein family. It functions in the formation and maintenance of the peripheral nerve myelin sheath, and several P2 mutations causing human Charot-Marie-Tooth neuropathy have been reported. Here, electron cryomicroscopy of myelin-like proteolipid multilayers revealed a three-dimensionally ordered lattice of P2 molecules between stacked lipid bilayers, visualizing its possible assembly at the myelin major dense line. A single layer of P2 is inserted between two bilayers in a tight intermembrane space of [~]3 nm, implying direct interactions between P2 and two membrane surfaces. Further details on lateral protein organization were revealed through X-ray diffraction from bicelles stacked by P2. Surface mutagenesis of P2 coupled to structural and functional experiments revealed a role for both the portal region and the opposite face of P2 in membrane interactions. Atomistic molecular dynamics simulations of P2 on myelin-like and model membrane surfaces suggested that Arg88 is an important residue for P2-membrane interactions, in addition to the helical lid domain on the opposite face of the molecule. Negatively charged myelin lipid headgroups anchor P2 stably on the bilayer surface. Membrane binding may be accompanied by opening of the P2 {beta} barrel structure and ligand exchange with the apposing lipid bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step towards deciphering the 3-dimensional assembly of a mature myelin sheath at the molecular level.

biochemistry↗

bioRxiv2019

Automated quantification of small vessel disease brain changes on MRI predicts cognitive and functional decline

Background and purposeCerebral small vessel disease (SVD) is characterized by a wide range of focal and global brain changes. We used automated MRI segmentation to quantify multiple types of SVD brain changes and examined their individual and combined predictive value on cognitive and functional abilities.\n\nMethodsMRI scans of 560 subjects of the Leukoaraiosis and Disability Study (LADIS) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities (WMH), lacunes, cortical infarcts, enlarged perivascular spaces and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years.\n\nResultsThe strongest predictors of cognitive performance and functional outcome over time were total volumes of WMH, grey matter (GM) and hippocampi (p<0.001 for global cognitive function, processing speed, executive functions and memory; and p<0.001 for poor functional outcome). Volumes of lacunes, cortical infarcts and EVPS were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of WMH, lacunes, GM and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on z-scores strongly predicted cognitive and functional outcomes (p<0.001) even above the contribution of the individual brain changes.\n\nConclusionsGlobal burden of SVD-related brain changes as quantified by automated image segmentation is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of WMH, lacunar, GM and hippocampal volumes could be used as an imaging identification model of vascular cognitive impairment.

neuroscience↗