Biology subjects

Stelzer, J.

Publications and source records attributed to Stelzer, J..

5 recordsLinked to original sources

bioRxiv2026

Hearts may grow concentrically to balance ATP supply and demand and eccentrically to stabilize titin-based stress

Hearts change their wall thickness (concentric growth) and chamber size (eccentric growth) as they adapt to circulatory demands and the intrinsic function of their contractile cells. Factors associated with wall thickening include variants of sarcomeric proteins that enhance contractility, mitochondrial dysfunction, and hypertension. Chambers can dilate due to many factors including sarcomeric variants that depress contractility and aortic and / or mitral valve insufficiency. Despite intensive study, the mechanisms that regulate cardiac growth remain unclear. It is also uncertain whether inherited variants induce growth via the same mechanisms as more common clinical pathologies, such as hypertension. Here we show that computer simulations of a beating left ventricle reproduce both variant and non-variant-related growth patterns when myocytes grow concentrically to regulate intracellular ATP concentration and eccentrically to maintain titin-based intracellular stress. The simulations support the hypothesis that cardiac growth reflects homeostatic feedback through three interacting systems whereby myocytes add or remove mitochondria and sarcomeres (1) in parallel to match ATP generation to myocardial energy demand, and (2) in series to regulate passive tension, while (3) the autonomic nervous system regulates cardiac power, and thus myocardial ATPase, via baroreflex control. The new framework provides a mechanistic basis for the patterns of eccentric and concentric growth induced by a wide range of clinically-relevant conditions and could facilitate in silico testing of potential therapies for cardiac disease. Significance statementHearts grow in response to both physiological and pathological stimuli. The patterns of concentric (wall thickening / thinning) and eccentric (chamber dilation / constriction) induced by different challenges are well recognized but the underlying mechanisms remain unclear. This work presents simulations of a beating left ventricle where (1) concentric growth is regulated by myocytes attempting to stabilize the intracellular ATP concentration and (2) eccentric growth is regulated by titin-mediated stress. The calculations reproduce the growth associated with inherited variants of sarcomeric proteins, mitochondrial dysfunction, hypertension, and both mitral and aortic valve insufficiency. The new ability to predict cardiac growth and its potential modification by treatments, including myotropes, brings the field closer to in silico optimization of therapy for cardiovascular disease.

biophysics↗

bioRxiv2020

Olig3 acts as a master regulator of cerebellar development

The mature cerebellum controls motor skill precision and participates in other sophisticated brain functions that include learning, cognition and speech. Different types of GABAergic and glutamatergic cerebellar neurons originate in temporal order from two progenitor niches, the ventricular zone and rhombic lip, which express the transcription factors Ptf1a and Atoh1, respectively. However, the molecular machinery required to specify the distinct neuronal types emanating from these progenitor zones is still unclear. Here, we uncover the transcription factor Olig3 as a major determinant in generating the earliest neuronal derivatives emanating from both progenitor zones. In the rhombic lip, Olig3 regulates progenitor cell proliferation. In the ventricular zone, Olig3 safeguards Purkinje cell specification by curtailing the expression of Pax2, a transcription factor that we found to impose an inhibitory interneuron identity. Our work thus defines Olig3 as a key factor in cerebellar development.

neuroscience↗

bioRxiv2018

Eigenvector centrality mapping for ultrahigh resolution fMRI data of the human brain

Eigenvector centrality mapping (ECM) is a popular technique for analyzing fMRI data of the human brain. It is used to obtain maps of functional hubs in networks of the brain in a manner similar to Googles PageRank algorithm. ECM attributes a score to the time course of each voxel that reflects its centrality within the network. Voxels that are strongly correlated with many other voxels that are themselves strongly correlated with other voxels receive high scores. Currently, there exist two different implementations ECM, one of which is very fast but limited to one particular type of correlation metric whose interpretation can be problematic. The second implementation supports many different metrics, but it is computationally costly and requires a very large main memory. Here we propose two new implementations of the ECM approach that resolve these issues. The first is based on a new correlation metric that we call \"ReLU correlation (RLC)\". The second method is based on matrix projections. We demonstrate the use of both techniques on standard fMRI data, as well as on high-resolution fMRI data acquired at 9.4 Tesla.

neuroscience↗

bioRxiv2017

Inflated False Negative Rates Undermine Reproducibility In Task-Based fMRI

Reproducibility is generally regarded as a hallmark of scientific validity. It can be undermined by two very different factors, namely inflated false positive rates or inflated false negative rates. Here we investigate the role of the second factor, i.e. the degree to which true effects are not detected reliably. The availability of large public databases and also supercomputing allows us to tackle this problem quantitatively. Specifically, we estimated the reproducibility in task-based fMRI data over different samples randomly drawn from a large cohort of subjects obtained from the Human Connectome Project. We use the full cohort as a standard of reference to approximate true positive effects, and compute the fraction of those effects that was detected reliably using standard software packages at various smaller sample sizes. We found that with standard sample sizes this fraction was less than 25 percent. We conclude that inflated false negative rates are a major factor that undermine reproducibility. We introduce a new statistical inference algorithm based on a novel test statistic and show that it improves reproducibility without inflating false positive rates.

neuroscience↗

bioRxiv2017

Neural decoding of visual stimuli varies with fluctuations in global network efficiency

Functional magnetic resonance imaging (fMRI) studies have shown that neural activity fluctuates spontaneously between different states of global synchronization over a timescale of several seconds. Such fluctuations generate transient states of high and low correlation across distributed cortical areas. It has been hypothesized that such fluctuations in global efficiency might alter patterns of activity in local neuronal populations elicited by changes in incoming sensory stimuli. To test this prediction, we used a linear decoder to discriminate patterns of neural activity elicited by face and motion stimuli presented periodically while participants underwent time-resolved fMRI. As predicted, decoding was reliably higher during states of high global efficiency than during states of low efficiency, and this difference was evident across both visual and non-visual cortical regions. The results indicate that slow fluctuations in global network efficiency are associated with variations in the pattern of activity across widespread cortical regions responsible for representing distinct categories of visual stimulus. More broadly, the findings highlight the importance of understanding the impact of global fluctuations in functional connectivity on specialised, stimulus driven neural processes.

neuroscience↗