Biology subjects

Hoffman, C.

Publications and source records attributed to Hoffman, C..

8 recordsLinked to original sources

bioRxiv2025

Aminopeptidase N is a receptor for hedgehog merbecoviruses

Merbecoviruses, closely related to the highly pathogenetic Middle East Respiratory Syndrome Coronavirus (MERS-CoV), circulate in hedgehogs throughout Europe and Asia, raising concerns about zoonotic transmission to humans and domestic animals. Unfortunately, how these viruses enter host cells remains unknown, hindering experimental studies. Here, we tested known coronavirus receptor orthologues from European hedgehogs (Erinaceus europaeus) and identified Aminopeptidase N (APN) as an entry receptor for hedgehog merbecoviruses. We confirm this result with single-cycle pseudotype and replication-competent virus experiments as well as protein binding assays. A screen of 30 mammalian APN orthologues reveals restricted cross-species receptor use. Cryo-electron microscopy analysis of the viral glycoprotein-receptor complex shows a unique interface distinct from known coronavirus spike:APN interactions, providing a molecular basis for species barriers. These findings expand the known range of receptor use not only within merbecoviruses but also betacoronaviruses, improving our understanding of betacoronavirus receptors, and informing risk assessments for viral emergence.

microbiology↗

bioRxiv2025

Design and Biological Activity of a Novel Brain Penetrant Urea Compound Against Glioblastoma

Glioblastoma (GBM) remains the most lethal primary brain tumor, largely due to therapy-resistant glioma stem cells (GSCs) and the ability of non-stem cells to dedifferentiate under therapeutic pressure. We developed MXC-017, a novel urea-based compound that crosses the blood-brain-barrier, directly targets GSCs, and prevents radiation-induced GSC formation. Using click chemistry pull-down and mass spectrometry, we identified vimentin as the target of MXC-017, further validated by in silico docking. Global transcriptomic profiling (bulk RNA-seq) and single-cell RNA-seq analyses revealed MXC-017s efficacy with minimal off-target effects, supported by metabolic and kinome assays. Normal cell toxicity was negligible in fibroblasts, microglia, astrocytes, and murine neural progenitors. Maximum tolerated dose was identified and we observed significantly extended median survival in 17 PDOX GBM models when treated with MXC-017 plus radiation, benchmarked against standard-of-care temozolomide. These findings underscore the therapeutic potential of vimentin-targeting agents to overcome radiation resistance and improve outcomes for GBM patients. Statement of SignificanceGlioblastomas distinctive nature and the blood-brain barrier hamper therapies targeting therapy-resistant GSCs. We developed a novel urea-based agent that crosses the barrier, targets GSCs, and prevents radiation-induced GSC formation. With minimal off-target effects, reduced toxicity, and superior survival in PDOX models, it offers potential to improve outcome in GBM.

neuroscience↗

bioRxiv2025

Active DNA demethylation is upstream of rod-photoreceptor fate determination and required for retinal development

Retinal cell fate specification from multipotent retinal progenitors is governed by dynamic changes in chromatin structure and gene expression. Methylation at cytosines in DNA (5mC) is actively regulated for proper control of gene expression and chromatin architecture. Numerous genes display active DNA demethylation across retinal development; a process that requires oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and is controlled by the ten-eleven translocation methylcytosine dioxygenase (TET) enzymes. Using an allelic series of conditional TET enzyme mutants, we determine that DNA demethylation is required upstream of NRL and NR2E3 expression for the establishment of rod-photoreceptor fate. Using histological, behavioral, transcriptomic, and base-pair resolution DNA methylation analyses, we establish that inhibition of active DNA demethylation results in global changes in gene expression and methylation patterns that prevent photoreceptor precursors from adopting a rod-photoreceptor fate, instead producing a retina in which all photoreceptors specify as cones. Our results establish the TET enzymes and DNA demethylation as critical regulators of retinal development and cell fate specification, elucidating a novel mechanism required for the specification of rod-photoreceptors.

developmental biology↗

bioRxiv2024

Theta oscillons in behaving rats

Recently discovered constituents of the brain waves--the oscillons--provide high-resolution representation of the extracellular field dynamics. Here we study the most robust, highest-amplitude oscillons that manifest in actively behaving rats and generally correspond to the traditional{theta} -waves. We show that the resemblances between{theta} -oscillons and the conventional{theta} -waves apply to the ballpark characteristics--mean frequencies, amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the{theta} -rhythms structure, origins and functions. We demonstrate that oscillons are frequency-modulated waves, with speed-controlled parameters, embedded into a noise background. We also use a basic model of neuronal synchronization to contextualize and to interpret the observed phenomena. In particular, we argue that the synchronicity level in physiological networks is fairly weak and modulated by the animals locomotion.

neuroscience↗

bioRxiv2024

Altered patterning of neural activity in a tauopathy mouse model

Alzheimers disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales--spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animals location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions. SignificanceWe expose differences in WT and tau brains, emerging at the circuit level, using a novel, morphological perspective on neural activity. This approach allows identifying qualitative changes in spiking patterns and in extracellular field oscillations, that are not discernible through traditional time-localized or time-averaged analyses. In particular, analyses of activity patterns facilitates detection of neurodegenerative deviations, conspicuously linking their effects to behavior and locomotion, thus opening a new venue for understanding how the architecture of neural activity shifts from normal to pathological.

neuroscience↗

bioRxiv2023

Terrestrial laser scan metrics predict surface vegetation biomass and consumption in a frequently burned southeastern U.S. ecosystem

Fire-prone landscapes found throughout the world are increasingly managed with prescribed fire for a variety of objectives. These frequent low-intensity fires directly impact lower forest strata, and thus estimating surface fuels or understory vegetation is essential for planning, evaluating, and monitoring management strategies and studying fire behavior and effects. Traditional fuel estimation methods have applications for stand-level and canopy fuel loading; however, local-scale understory biomass remains challenging because of complex within-stand heterogeneity and fast recovery post-fire. Previous studies have demonstrated how single location terrestrial laser scanning (TLS) can be used to estimate plot-level vegetation characteristics and impacts from prescribed fire. To build upon this methodology, co-located single TLS scans and physical biomass measurements were used to generate linear models for predicting understory vegetation and fuel biomass as well as consumption by fire in a southeastern U.S. pineland. A variable selection method was used to select the six most important TLS-derived structural metrics for each linear model, where model fit ranged in R2 from 0.61 to 0.74. This study highlights a prospect for efficiently estimating vegetation and fuel characteristics relevant to prescribed burning via the integration of a single-scan TLS method adaptable by managers and relevant for coupled fire-atmosphere models.

ecology↗

bioRxiv2022

Pattern dynamics and stochasticity of the brain rhythms

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored, is the actual structure of the waves--their shapes and patterns over finite timescales. To address this, we used two independent approaches to link wave forms to their physiological functions: the first is based on quantifying their consistency with the underlying mean behavior, and the second assesses "orderliness" of the waves features. The corresponding measures capture the waves characteristic and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns dynamics and the animals location, speed and acceleration. Specifically, we studied patterns of{theta} and{gamma} waves, and Sharp Wave Ripples, and observed speed-modulated changes of the waves cadence, an antiphase relationship between orderliness and acceleration, as well as spatial selectiveness of patterns. Further-more, we found an interdependence between orderliness and regularity: larger deviations from steady oscillatory behavior tend to accompany disarrayed temporal cluttering of peaks and troughs. Taken together, our results offer a complementary--mesoscale--perspective on brain wave structure, dynamics, and functionality.

neuroscience↗

bioRxiv2020

Species level resolution of female bladder microbiota from marker gene surveys

The human bladder contains bacteria in the absence of infection. Interest in studying these bacteria and their association with bladder conditions is increasing. However, the chosen experimental method can limit the resolution of the taxonomy that can be assigned to the bacteria found in the bladder. 16S rRNA amplicon sequencing is commonly used to identify bacteria in urinary specimens, but is typically restricted to genus-level identification. Our primary aim was to determine if accurate species-level identification of bladder bacteria is possible using 16S rRNA amplicon sequencing. We evaluated the ability of different classification schemes, each consisting of combinations of a reference database, a 16S rRNA gene variable region and a taxonomic classification algorithm to correctly classify bladder bacteria. We show that species-level identification is possible, and that the reference database chosen is the most important component, followed by the 16S variable region sequenced. ImportanceSpecies-level information may deepen our understanding of associations between bladder microbiota and bladder conditions, such as lower urinary tract symptoms and urinary tract infections. The capability to identify bacterial species depends on large databases of sequences, algorithms that leverage statistics and available computer hardware, and knowledge of bacterial genetics and classification. Taken together, this is a daunting body of knowledge to become familiar with before the simple question of bacterial identity can be answered. Our results show the choice of taxonomic database and variable region of the 16S rRNA gene sequence makes species level identification possible. We also show this improvement can be achieved through the more careful application of existing methods and use of existing resources.

bioinformatics↗