Biology subjects

Schafer, M.

Publications and source records attributed to Schafer, M..

5 recordsLinked to original sources

bioRxiv2023

Neural Trajectories of Social Relationships on a Map-like Manifold

In a series of conceptually related episodes, meaning arises from the link between these events rather than from each event individually. How does the brain keep track of conceptually related sequences of events (i.e., conceptual trajectories)? In a particular kind of conceptual trajectory--a social relationship--meaning arises from a specific sequence of interactions. To test whether such abstract sequences are neurally tracked, we had participants complete a naturalistic narrative-based social interaction game, during functional magnetic resonance imaging. We modeled the simulated relationships as trajectories through an abstract affiliation and power space. Using two independent samples (n = 50), we found evidence of both the underlying social dimensions of affiliation and power and the evolving social relationships themselves as being tracked by the hippocampus. These results suggest that our evolving relationships with others, despite being composed of isolated events that occur independently across time and space (i.e., spatially and temporally non-consecutive events), but are nevertheless related conceptually, are represented in trajectory-like neural patterns in the human hippocampus.

neuroscience↗

bioRxiv2022

Hippocampal Place-like Signal in Latent Social Space

During navigation, the hippocampus represents physical places like coordinates on a map; similar location-like signals have been seen in sensory and concept spaces. It is unclear just how general this hippocampal place code is, however: does it map places in wholly non-perceivable spaces, without locations being instructed or reinforced and during navigation-like behavior? To search for such a signal, we imaged participants brains while they played a naturalistic, narrativebased social interaction game, and modeled their relationships as a kind of navigation through social space. Two independent samples showed hippocampal place-like signals in both region-based and whole-brain representational similarity analyses, as well as decoding and average pattern similarity analyses; the effects were not explained by other measures of the behavior or task information. These results are the first demonstration of complete domain generality in hippocampal place representation. One-Sentence Summaryhippocampal place-like signal in non-perceivable and unreinforced space during naturalistic navigational behavior. Significance statementThe hippocampus is a brain structure known to encode maps of physical spaces; this study shows that it also maps fully abstract, latent and uninstructed spaces. People played a naturalistic social interaction game while their brains were scanned. Hippocampal brain activity correlated with the fictional characters locations in an abstract social space framed by axes of affiliation and power, despite the participants never being exposed to a perceivable spatial representation. This mapping was present across multiple analyses and two samples, demonstrating that the brain system responsible for spatial mapping maps our social interactions too.

neuroscience↗

bioRxiv2021

Genome-scale CRISPR Screens Identify Host Factors that Promote Human Coronavirus Infection

The COVID-19 pandemic has resulted in 153 million infections and 3.2 million deaths as of May 2021. While effective vaccines are being administered globally, there is still a great need for antiviral therapies as potentially antigenically distinct SARS-CoV-2 variants continue to emerge across the globe. Viruses require host factors at every step in their life cycle, representing a rich pool of candidate targets for antiviral drug design. To identify host factors that promote SARS-CoV-2 infection with potential for broad-spectrum activity across the coronavirus family, we performed genome-scale CRISPR knockout screens in two cell lines (Vero E6 and HEK293T ectopically expressing ACE2) with SARS-CoV-2 and the common cold-causing human coronavirus OC43. While we identified multiple genes and functional pathways that have been previously reported to promote human coronavirus replication, we also identified a substantial number of novel genes and pathways. Of note, host factors involved in cell cycle regulation were enriched in our screens as were several key components of the programmed mRNA decay pathway. Finally, we identified novel candidate antiviral compounds targeting a number of factors revealed by our screens. Overall, our studies substantiate and expand the growing body of literature focused on understanding key human coronavirus-host cell interactions and exploit that knowledge for rational antiviral drug development. One Sentence SummaryGenome-wide CRISPR screens identified host factors that promote human coronavirus infection, revealing novel antiviral drug targets.

microbiology↗

bioRxiv2021

An interpretable connectivity-based decoding model for classification of chronic marijuana use

BackgroundPsychiatric neuroimaging typically proceeds with one of two approaches: encoding models, which aim to model neural mechanisms, or decoding models, which aim to predict behavioral or clinical characteristics from brain imaging data. In this study, we seek to combine these aims by developing interpretable decoding models that offer both accurate prediction and novel neural insights. We demonstrate the effectiveness of this combined approach in a case study of chronic marijuana use. MethodsChronic marijuana (MJ) users (n=195) and non-using healthy controls (n=128) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic MJ users and non-users based on task-evoked, whole-brain functional connectivity. We then used graph theoretic analyses to identify predictive functional connectivities among brain regions that contributed most substantially to the classification of chronic marijuana use. ResultsWe obtained high (~80% out-of-sample) accuracy across four different classification models, demonstrating that task-evoked, whole-brain functional connectivity can successfully differentiate chronic marijuana users from non-users. Subsequent network analyses revealed key predictive regions (e.g., anterior cingulate cortex, dorsolateral prefrontal cortex, and precuneus) that are often implicated in neuroimaging studies of substance use disorders, as well as some key exceptions. We also identified a core set of networks of brain regions that contributed to successful classification, comprised of many of the same predictive regions. ConclusionsOur dual aims of accurate prediction and interpretability were successful, producing a predictive model that also provides interpretability at the neural level. This novel approach may complement other predictive-exploratory approaches for a more complete understanding of neural mechanisms in drug use and other neuropsychiatric disorders.

neuroscience↗

bioRxiv2018

Length-independent telomere damage drives cardiomyocyte senescence

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

cell biology↗