Biology subjects

Herzog, N.

Publications and source records attributed to Herzog, N..

7 recordsLinked to original sources

bioRxiv2024

Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes

IntroductionThe endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which constitute a large fraction of the total protein output of a mammalian cell. Striated muscle cells contain a specialized membrane system known as the sarcoplasmic reticulum (SR) that controls calcium homeoastasis and contraction, however the biochemical and physiological relationship between the ER and SR and how both compartments participate in protein synthesis remains incompletely understood. MethodsProtein quantification and imaging of selected marker proteins for ER and SR functions was performed to characterize the relationship of the ER and SR and its individual involvement in protein synthesis in neonatal and adult cardiac myocytes. Superresolution microscopy was used to examine the interaction of ribosomes and the SR in adult cardiac myocytes. ResultsQuantification of ER and SR-associated proteins of isolated ventricular cardiac myocytes showed that relative expression of ER/SR resident protein quality elements, as well as relative ribosome levels are decreased in adult cells, whereas SR-associated Ca2+ handling proteins increase. Immunocytoflourescence revealed that the membrane compartment that exists in early postpartum resembles mostly the ER and decreases in postnatal development. The SR is the main membrane network that exists in the adult cardiac myocytes, replacing the ER, in all but the perinuclear region. Immunocytoflourescence staining further indicated that both networks perform overlapping but distinct, specialized functions, such as localization of excitation-contraction coupling exclusively to the SR or initiation of secretion via the classical secretory pathway mainly from the ER. Ribosomes and mRNA were localized both in close proximity to the ER and the SR of adult ventricular cardiac myocytes. Superresolution microscopy confirmed that both the ER as well as the developed SR bind ribosomes and are direct sites of protein synthesis and protein homeostasis in adult cardiac myocytes. ConclusionOur findings suggest molecular differentiation and structural organization of the ER/SR in cardiac muscle development, resulting in the development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.

cell biology↗

bioRxiv2024

Validating genuine changes in Heartbeat Evoked Potentials using Pseudotrials and Surrogate Procedures

The brain continuously receives interoceptive information about the state and function of our internal organs. For instance, each time the heart beats, the brain responds by generating time-locked activity, known as heartbeat evoked potentials (HEP). When investigating HEPs, it is essential to adequately control for heartbeat-independent confounding activity to avoid false interpretation. In the present study, we highlight the pitfalls of uncontrolled analyses and advocate for the use of surrogate heartbeat analysis and pseudotrial correction, which are promising tools to control for spurious results. Surrogate heartbeat analysis involves shuffling the timing of heartbeats to verify the time-locking of HEP effects. Pseudotrial correction works by subtracting heartbeat-independent activity from HEPs. In this study we employ both procedures, validate them in simulations and apply them to real EEG data. Using EEG recordings obtained during the performance of an auditory novelty oddball task in a large population, we show that, without control analyses, pre-stimulus HEPs appear inversely related to task-related measures such as P300 event-related potential amplitudes and reaction time speed. However, these effects disappear after carefully controlling for heartbeat-unrelated EEG activity. Additionally, in real and simulated data, we show that pseudotrial correction has the potential to remove task-related confounds from HEPs, thereby uncovering real heartbeat-related effects that otherwise could be missed. This study therefore highlights issues that can arise when analyzing HEPs during tasks, provides solutions to overcome them, and gives recommendations for future studies to avoid pitfalls when analyzing and designing behavioral paradigms with HEPs.

neuroscience↗

bioRxiv2023

Impaired updating of working memory representations in individuals with high BMI: evidence for dopaminergic mechanisms

Everyday life requires an adaptive balance between distraction-resistant maintenance of information and the flexibility to update this information when needed. These opposing mechanisms are proposed to be balanced through a working memory gating mechanism. Prior research indicates that obesity may elevate the risk of working memory deficits, yet the underlying mechanisms remain elusive. Dopaminergic alterations have emerged as a potential mediator. However, current models suggest these alterations should only shift the balance in working memory tasks, not produce overall deficits. The empirical support for this notion is currently lacking, however. To address this gap, we pooled data from three studies (N = 320) where participants performed a working memory gating task. Higher BMI was associated with overall poorer working memory, irrespective of whether there was a need to maintain or update information. However, when participants, in addition to BMI level, were categorized based on certain putative dopamine-signaling characteristics (Single Nucleotide Polymorphisms; specifically, Taq1A and DARPP-32), distinct working memory gating effects emerged. These SNPs, primarily associated with striatal dopamine transmission, appear to be linked with differences in updating, specifically, among high-BMI individuals. Moreover, blood amino acid ratio, which indicates central dopamine synthesis capacity, combined with BMI, shifted the balance between distractor-resistant maintenance and updating. These findings suggest that both dopamine-dependent and dopamine-independent cognitive effects exist in obesity. Understanding these effects is crucial if we aim to modify maladaptive cognitive profiles in individuals with obesity.

neuroscience↗

bioRxiv2022

Cortical grey matter mediates increases in model-based control and learning from positive feedback from adolescence to adulthood

Adolescents undergo maturation in cognition and brain structure. Model-based (MB) control is known to increase from childhood to young adulthood, which is mediated by cognitive abilities. Here, we asked two questions unaddressed in previous developmental studies: Firstly, what are the brain structural correlates of age-related increases in MB control? Secondly, how are age-related increases in MB control from adolescence to adulthood influenced by motivational context? A developmental sample (n=103, age: 12-42) completed structural MRI and an established task to capture MB control. The task was modified with respect to outcome valence by including (1) reward and punishment blocks to manipulate the motivational context and (2) an additional choice test to assess learning from positive vs. negative feedback. After replicating that an age-dependent increase in MB control is mediated by cognitive abilities, we demonstrate first-time evidence that grey matter density (GMD) in the parietal cortex mediates the increase of MB control with age. While motivational context did not relate to age-related changes in MB control, learning from positive feedback improved with age. Meanwhile, negative feedback learning showed no age effects. We present a first report that an age-related increase in learning from positive feedback was mediated by reduced GMD in the parietal, medial and dorsolateral prefrontal cortex. Our findings indicate that efficient brain maturation, as putatively reflected in lower GMD, in distinct and partially overlapping brain regions is a key developmental step towards age-related increases in planning and value-based choice. Significance StatementAdolescents undergo extensive maturation in cognition and brain structure. Interestingly, model-based decision-making is also known to increase from childhood to adulthood. Here, we demonstrate for the first time that grey matter density in the parietal cortex mediates an age-dependent increase in model-based control. An age-related increase in positive feedback learning was mediated by reduced grey matter density in the parietal, medial and dorsolateral prefrontal cortex. Interestingly, a manipulation of motivational context (gain reward vs. avoid punishment) did not impact age-related changes in model-based control. These findings highlight that efficient brain maturation in distinct and overlapping cortical brain regions constitutes a key developmental step towards increases in model-based planning and value-based choice.

neuroscience↗

bioRxiv2021

Age-related decline of the unfolded protein response in the heart promotes protein misfolding and cardiac pathology

Cardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases. HighlightsO_LIThe unfolded protein response (UPR) declines as a function of age in adult mammalian tissues with low mitotic activity, such as the heart C_LIO_LIDecreases in the UPR in adult cardiac myocytes is associated with impaired survival during ER stress C_LIO_LIATF6 loss of function in adult hearts increases protein misfolding and cardiac disfunction during stress C_LI

molecular biology↗

bioRxiv2020

Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint.

Tumor emboli - aggregates of tumor cell within vessels - pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modelled a lymphatic vessel as a 200 m-diameter channel in either a stiff or soft, bioinert agarose matrix, and we modelled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff vessel model constrained the tumor emboli to the cylindrical geometry, which led to continuous growth of the emboli, in contrast to the growth plateau that unconstrained spheroids exhibit. Emboli morphology in the soft vessel model, however, was dependent on the magnitude of mechanical mismatch between the vessel matrix and the cell aggregates. In general, when the elastic modulus of the vessel was greater than the emboli (Eves / Eemb > 1), the emboli were constrained to grow within the vessel geometry, and when the elastic modulus of the vessel was less than the emboli (0 < Eves / Eemb < 1), the emboli bulged into the matrix. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the vessel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen. INSIGHT BOXThe growth of tumor emboli--aggregates of tumor cells within vessels--is associated with aggressive cancer progression and metastasis. Models of their growth have not taken into account their biomechanical context, where radial expansion is constrained, but lengthwise expansion is free in the vessel. Here, we modelled the vessel geometry with a cylindrical microchannel in a hydrogel. In contrast to unconstrained or fully embedded aggregates, vessel-like constraint promotes growth of emboli in our model. The growth advantage is increased when the matrix is stiffened or actomyosin contractility weakened, both of which effectively increase the magnitude of mechanical constraint. This study sheds light on increased tumor burden in vessel-based growth and indicates a need to study tumor progression in similar environments.

cell biology↗

bioRxiv2018

Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Fibrosis and inflammation promote atrial fibrillation (AF) and worsen its clinical outcome. The underlying molecular mechanisms, that are relevant for effective antifibrotic drug development, are still under debate. This study deciphers a novel mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-inflammatory cytokine osteopontin (OPN) in the pathogenesis of atrial fibrosis. Compared to sinus rhythm (SR) controls, right atrial appendages and isolated right atrial fibroblasts from AF patients showed downregulation of PLK2 mRNA and protein levels, which were accompanied by remarkable hypoxia-sensitive DNA-methylation of the PLK2 promotor. In an experimental setting, both, genetic deletion and pharmacological inhibition of PLK2 induced myofibroblast differentiation and reduced fibroblast proliferation. Notably, proteomics from PLK2-deleted fibroblasts revealed de novo secretion of OPN. Accordingly, we observed higher OPN plasma levels in AF patients with atrial fibrosis compared to non-fibrosis AF patients. Hence, we provide evidence for PLK2 reactivation and/or OPN inhibition as potential novel targets to prevent fibrosis progression in AF.

pharmacology and toxicology↗