Biology subjects

Levine, B.

Publications and source records attributed to Levine, B..

9 recordsLinked to original sources

bioRxiv2026

Naturalistic recall preserves temporal specificity despite cortical feature reorganization

Although sensory input arrives in a largely continuous stream, recall is temporally compressed, discontinuous, and often structured as events. However, the temporal specificity of recall-related neural activity within events, and the separation and cortical organization of recalled features relative to perception, remain poorly characterized. We analyzed functional MRI data recorded during viewing and free recall of an episode of Sherlock. A data-driven alignment between viewing and recall data identified neural recapitulation of corresponding narrative events and revealed information that distinguished moments within events, particularly in the association cortex. Features ranging from low-level visual to semantic information predicted recall reinstatement. However, differences in predictive performance among feature levels became smaller during recall, and their organization along the cortical sensory-to-association gradient reversed relative to viewing. Thus, temporal specificity within events can be preserved despite substantial reorganization of feature representations across the cortex during recall.

neuroscience↗

bioRxiv2024

Remembrance with gazes passed: Eye movements precede continuous recall of episodic details of real-life events

Autobiographical memory entails reconstructing the visual features of past events. Eye movements are associated with vivid autobiographical recollection, but this research has yet to capitalize on the high temporal resolution of eye-tracking data. We aligned eye movement data with participants simultaneous free recall of a verified real-life event, allowing us to assess the temporal correspondence of saccades to production of episodic and non-episodic narrative content at the millisecond level. Eye movements reliably predicted subsequent episodic - but not non-episodic - details by 250-1100 ms, suggesting that they facilitate episodic recollection by reinstating spatiotemporal context during vivid recollection. Assessing the relationship of oculomotor responses to naturalistic memory informs theory as well as diagnosis and treatment of conditions involving pathological recollection, such as Alzheimers disease and post-traumatic stress disorder (PTSD).

neuroscience↗

bioRxiv2024

Sleep selectively and durably enhances real-world sequence memory

Sleep is thought to play a critical role in the retention of episodic memories. Yet it remains unclear whether and how sleep actively transforms memory for specific experiences. More generally, little is known about sleeps effects on memory for multidimensional real-world experiences, both overnight and in the days to months that follow. In an exception to the law of forgetting, we showed that sleep actively and selectively improves retrieval of a one-time real-world experience (a controlled but immersive art tour) - specifically boosting memory for the order of tour items (sequential associations), but not perceptual details from the tour (featural associations). This above-baseline increase in sequence memory was not evident after a matched period of wakefulness. Moreover, the sleep-induced advantage of sequence over featural memory grew over time up to one-year post-encoding. Finally, overnight polysomnography showed that sleep-related memory enhancement was associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to neural replay, particularly spindle-slow wave coupling. These results suggest that sleep serves a crucial and selective role in enhancing sequential organization in episodic memory at the expense of specific details, linking sleep-related neural mechanisms to the transformation and enhancement of memory for complex real-life experiences. Significance StatementSleep affects the retention of episodic memories. Yet, it remains unclear whether sleep active transforms how we remember past experiences, overnight and beyond. We investigated memory for different dimensions underlying a dynamic real-world event - sequential associations versus atemporal featural associations - before and after sleep or wakefulness, and serially up to a year later. Sleep actively and selectively enhanced sequence memory, with this preferential sequence retention growing with time. Overnight memory enhancement is associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to sequential neural replay, particularly spindle-slow wave coupling. Our findings support an active role for sleep in transforming different aspects of real-world memory, with sequence structure coming to dominate long-term memory for dynamic real-world experiences.

neuroscience↗

bioRxiv2023

Reference Sequence Browser: An R application with a User-Friendly GUI to rapidly query sequence databases

Land managers, researchers, and regulators increasingly utilize environmental DNA (eDNA) techniques to monitor species richness, presence, and absence. In order to properly develop a biological assay for eDNA metabarcoding or quantitative PCR, scientists must be able to find not only reference sequences (previously identified sequences in a genomics database) that match their target taxa but also reference sequences that match non-target taxa. Determining which taxa have publicly available sequences in a time-efficient and accurate manner currently requires computational skills to search, manipulate, and parse multiple unconnected DNA sequence databases. Our team iteratively designed a Graphic User Interface (GUI) Shiny application called the Reference Sequence Browser (RSB) that provides users efficient and intuitive access to multiple genetic databases regardless of computer programming expertise. The application returns the number of publicly accessible barcode markers per organism in the NCBI Nucleotide, BOLD, or CALeDNA CRUX Metabarcoding Reference Databases. Depending on the database, we offer various search filters such as min and max sequence length or country of origin. Users can then download the FASTA/GenBank files from the RSB web tool, view statistics about the data, and explore results to determine details about the availability or absence of reference sequences.

bioinformatics↗

bioRxiv2022

CDKL5 regulates p62-mediated selective autophagy and host antiviral defense

Virophagy, the selective autophagosomal engulfment and degradation of viral components, is crucial for antiviral immunity. However, the mechanisms leading to viral antigen recognition and autophagy induction remain poorly understood. Here, we identify a novel kinase, Cyclin-dependent kinase-like 5 (CDKL5), as an essential regulator of virophagy. Deletion of CDKL5 or abrogation of its kinase activity reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid proteins and cellular cytotoxicity. Mechanistically, through direct phosphorylation of the selective autophagy receptor p62, CDKL5 promoted formation of p62 inclusion bodies that bound capsid. Loss of CDKL5 disrupted the capsid-p62 interaction, and a p62 phosphomimetic mutant rescued the interaction. CDKL5 knockout mice demonstrated increased neuronal cell death after SINV infection and enhanced lethality after infection with several human viruses. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear toxic viral capsid aggregates during infection.

microbiology↗

bioRxiv2022

Interaction of surface topography and taper mismatch on head-stem modular junction contact mechanics during assembly in modern total hip replacement

Implant failure due to fretting corrosion at the head-stem modular junction is an increasing problem in modular total hip arthroplasty. The effect of varying microgroove topography on modular junction contact mechanics has not been well characterized. The aim of this work was to employ a novel, microgrooved finite element (FEA) model of the hip taper interface and assess the role of microgroove geometry and taper mismatch angle on the modular junction mechanics during assembly. A two-dimensional, axisymmetric FEA model was created using a modern 12/14 taper design of a CoCrMo femoral head taper and Ti6Al4V stem taper. Microgrooves were modelled at the contacting interface of the tapers and varied based on height and spacing measurements obtained from a repository of measured retrievals. Additionally, taper angular mismatch between the head and stem was varied to simulate proximal- and distal-locked engagement. Forty simulations were conducted to parametrically evaluate the effects of microgroove surface topography and angular mismatch on predicted contact area, contact pressure, and equivalent plastic strain. Multiple linear regression analysis was highly significant (p < 0.001; R2 > 0.74) for all outcome variables. The regression analysis identified microgroove geometry on the head taper to have the greatest influence on modular junction contact mechanics. Additionally, there was a significant second order relationship between both peak contact pressure (p < 0.001) and plastic strain (p < 0.001) with taper mismatch angle. These modeling techniques will be used to identify the implant parameters that maximize taper interference strength via large in-silico parametric studies.

bioengineering↗

bioRxiv2021

Quantitative Phosphoproteomic Analyses Identify STK11IP as a Lysosome-Specific Substrate of mTORC1 that Regulates Lysosomal Acidification

The evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. Through cross-reference analyses of lysosome proteomic with mTORC1-regulated phosphoproteomic, we identified STK11IP as a novel lysosome-specific substrate of mTORC1. mTORC1 directly phosphorylates STK11IP at S404. Knockout of STK11IP led to a robust increase of autophagosome-lysosome fusion and autophagy flux. Dephosphorylation of STK11IP at S404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting and Methionine and Choline-Deficient Diet (MCD) diet induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a novel mechanism for mTORC1 to regulate lysosomal acidification, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.

cell biology↗

bioRxiv2021

RNA sequencing on muscle biopsy from a 5-week bedrest study reveals the effect of exercise and potential interactions with dorsal root ganglion neurons

Lack of physical activity is a predictor of poor health outcomes that can be prevented or reversed by exercise. Sedentary lifestyle, chronic disease or microgravity can cause muscle deconditioning that then has an impact on other physiological systems. An example is the nervous system, which is adversely affected by decreased physical activity resulting in increased incidence of neurological problems such as chronic pain. We sought to better understand how this might occur by conducting RNA sequencing experiments on muscle biopsies from human volunteers in a 5-week bed-rest study with an exercise intervention arm. We also used a computational method for examining ligand-receptor interactions between muscle and human dorsal root ganglion (DRG) neurons, the latter of which play a key role in nociception and are generators of signals responsible for chronic pain. We identified 1352 differentially expressed genes (DEGs) in bed rest subjects without an exercise intervention but only 132 DEGs in subjects with the intervention. Thirty-six genes were shared between the exercise and no intervention groups. Among 591 upregulated muscle genes in the no intervention arm, 26 of these were ligands that have receptors that are expressed by human DRG neurons. We detected a specific splice variant of one of these ligands, placental growth factor (PGF), in deconditioned muscle that binds to neuropilin 1, a receptor that is highly expressed in DRG neurons and known to promote neuropathic pain. We conclude that exercise intervention protects muscle from deconditioning transcriptomic changes, and prevents changes in expression of ligands that might sensitize DRG neurons that promote pain. Our work creates a set of actionable hypotheses to better understand how deconditioned muscle may influence the function of sensory neurons that innervate the entire body.

neuroscience↗

bioRxiv2018

Generalization of the minimum covariance determinant algorithm for categorical and mixed data types

The minimum covariance determinant (MCD) algorithm is one of the most common techniques to detect anomalous or outlying observations. The MCD algorithm depends on two features of multivariate data: the determinant of a matrix (i.e., geometric mean of the eigenvalues) and Mahalanobis distances (MD). While the MCD algorithm is commonly used, and has many extensions, the MCD is limited to analyses of quantitative data and more specifically data assumed to be continuous. One reason why the MCD does not extend to other data types such as categorical or ordinal data is because there is not a well-defined MD for data types other than continuous data. To address the lack of MCD-like techniques for categorical or mixed data we present a generalization of the MCD. To do so, we rely on a multivariate technique called correspondence analysis (CA). Through CA we can define MD via singular vectors and also compute the determinant from CAs eigenvalues. Here we define and illustrate a generalized MCD on categorical data and then show how our generalized MCD extends beyond categorical data to accommodate mixed data types (e.g., categorical, ordinal, and continuous). We illustrate this generalized MCD on data from two large scale projects: the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Alzheimers Disease Neuroimaging Initiative (ADNI), with genetics (categorical), clinical instruments and surveys (categorical or ordinal), and neuroimaging (continuous) data. We also make R code and toy data available in order to illustrate our generalized MCD.

bioinformatics↗