Biology subjects

Larson, E.

Publications and source records attributed to Larson, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Noise Optimization of Basic Signal Component Extraction for Cryogenic and On-Scalp Magnetoencephalography (MEG)

Magnetoencephalography (MEG) measures human neural activity non-invasively with spatio-temporal precision, and has been foundational in enabling impactful discoveries in cognitive neuroscience. New on-scalp MEG sensor technologies, such as OPM-MEG, offer the opportunity to capture more information about the neuronal magnetic fields with higher sensitivity to more complex, higher order spatial components, leading to improved source localization. The accuracy of MEG and OPM-MEG source localization relies on data preprocessing techniques to isolate the neuronal fields from other magnetic and biomagnetic sources through signal space separation, rejection, and suppression methods. Current preprocessing methods risk rejecting brain signals of interest, or can spread sensor noise artifacts unknowingly. Here we propose a novel preprocessing method for MEG, and test the extent to which it overcomes limitations of prior methods. Specifically, we derive, apply, and assess a novel signal space separation (SSS) method with Fosters inverse, a weighted matrix inversion protocol that can utilize information about the MEG sensor noise and artifacts to reconstruct neuronal activity. With simulations, phantom head cryogenic MEG recordings, and subject recordings with two OPM-MEG systems, we show that Fosters inverse with SSS offers a more robust and stable reconstruction of the neuronal magnetic fields, especially in the face of sensor noise and artifacts. As the field of cognitive neuroscience continues to embrace MEG and OPM-MEG, Fosters inverse with SSS offers a robust and powerful data preprocessing technique for reducing noise and improving source localization of the underlying neuronal currents.

neuroscience↗

bioRxiv2026

EMG-BIDS: an extension to the Brain Imaging Data Structure for electromyography

Electromyography (EMG) is fundamental to clinical assessment, rehabilitation, neuromuscular research, and human-machine interfaces. Despite decades of use, no widely adopted standard exists for organizing and sharing EMG data, limiting reusability and large-scale data aggregation. We present EMG-BIDS, an extension to the Brain Imaging Data Structure (BIDS) that standardizes the organization of EMG recordings. EMG-BIDS addresses challenges unique to EMG, including diverse electrode types (surface or intramuscular, single channel to high-density arrays), heterogeneous electrode placements across anatomical locations, montages (e.g., monopolar or bipolar sensor designs), and the critical need for transparent documentation of sensor positioning. The specification introduces hierarchical coordinate systems that link local electrode grids to anatomical landmarks, enabling precise and reproducible placement documentation. EMG-BIDS is now part of BIDS as of version 1.11.0, supported by existing tools, including MNE-BIDS and EEGLAB. We demonstrate the specification through public datasets, including high-density surface EMG recordings. EMG-BIDS provides the foundation for FAIR (Findable, Accessible, Interoperable, Reusable) EMG data sharing, enabling meta-analyses, multi-site studies, and machine learning applications that require standardized, well-documented datasets.

neuroscience↗

bioRxiv2025

Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation

Protein aggregation drives many neurodegenerative diseases, including Parkinsons disease, where misfolded -synuclein (Syn) forms fibrillar assemblies that accumulate as Lewy bodies. Although Syn aggregation has been extensively characterized, its evolutionary origins and sequence determinants remain unresolved. Here, we use ancestral sequence reconstruction (ASR) to trace the emergence of fibril-forming ability in the synuclein family. We inferred synuclein phylogeny and experimentally resurrected common ancestors, including ROOT synuclein, the last common ancestor of all synucleins, and key intermediates along the Syn lineage. Strikingly, ROOT synuclein is non-aggregating, demonstrating that fibril formation is an evolved, rather than ancestral property. Aggregation first emerges at the ancestral {beta} node, is retained in Syn, and suppressed in {beta}-synuclein. Biophysical analyses including mass spectrometry and NMR reveal that aggregation aligns with greater complexity and heterogeneity in the monomer conformational ensemble, suggesting that evolutionary sequence changes progressively remodel monomer landscapes to favor fibril formation. Complementing these insights, comparative sequence analysis reveals that the transition from ROOT to -WT is marked by the stepwise acquisition of residues critical for stabilizing the fibril core. Early mutations stabilized the {beta}-arch core, enabling the onset of fibril formation, followed by substitutions that reinforce protofilament-protofilament interactions. Together, ASR defines an evolutionary framework for synuclein aggregation linking progressive sequence evolution and conformational complexity to the molecular origins of Syn fibril formation.

biophysics↗

bioRxiv2024

Nonlinear thinking in ecology and evolution: The case for ecological scaling of the Threshold Elemental Ratio

Nonlinear dynamics govern ecological processes, thus understanding thresholds is important for measuring and forecasting effects of climate change and management of natural resources. However, identifying whether and how such thresholds scale across biological levels of organization remains challenging. Ecological stoichiometry, the study of the balance of multiple elements and energy in ecological systems, provides a framework for scaling thresholds. We broaden a key organismal concept from ecological stoichiometry theory, the Threshold Elemental Ratio (TER), to study how nonlinear dynamics operate in evolutionary and ecological processes across the organizational hierarchy. Traditionally, TERs are used to describe the elemental ratio at which the limitation of organismal growth shifts from one element to another. Following this definition, we make a case for broadening the ecological scale of the TER beyond organisms to include populations, clades, communities, and ecosystems. We show how TERs can be detected and translated across different scales of biological and evolutionary organization through simulation modeling, literature review, and synthesis of empirical examples from diverse systems and ecological scales including: cyanotoxin production in lakes, alder-salmon dynamics, and the Cambrian explosion. Collectively, we demonstrate that TERs are widespread and consequential across levels of biological organization and that such thresholds manifest from a diversity of mechanisms. Thus, scaling of the TER concept holds promise for advancing our understanding of nonlinear dynamics from the micro-evolutionary to macro-ecological.

ecology↗

bioRxiv2023

Identification of Natural Antiviral Drug Candidates Against Tilapia Lake Virus: Computational Drug Design Approaches

Tilapia Lake Virus (TiLV) is a disease that affects tilapia fish, causing a high rate of sudden death at any stage of their growth. Unfortunately, there are currently no effective antiviral drugs or vaccines to control the progression of this disease. Researchers have discovered that the CRM1 protein plays a critical function in the development and spreading of animal viruses. By inhibiting CRM1, the viruss spread in commercial fish farms can be suppressed. With this in mind, this study intended to identify potential antiviral drugs from two different tropical mangrove plants from tropical regions: Heritiera fomes and Ceriops candolleana. To identify promising compounds that target the CRM1 protein, a computer-aided drug discovery approach is employed containing molecular docking, ADME (absorption, distribution, metabolism and excretion) analysis, toxicity assessment as well as molecular dynamics (MD) simulation. To estimate binding affinities of all phytochemicals, molecular docking is used and the top three candidate compounds with the highest docking scores were selected, which are CID107876 (-8.3), CID12795736 (-8.2), and CID12303662 (-7.9). We also evaluated the ADME and toxicity properties of these compounds. Finally, molecular dynamics simulation was conducted to analyze the stability of the protein-ligand complex structures and confirm the suitability of these compounds. The computational study demonstrated that the phytochemicals found in H. fomes and C. candolleana could potentially serve as important inhibitors of TiLV, offering practical utility. However, further in vivo investigations are necessary to investigate the effectiveness of these compounds as antiviral drugs against the virus TiLV.

pharmacology and toxicology↗

bioRxiv2023

Regional vulnerability in a neurodegenerative disease: Delineating SCA1 CNS and muscle therapeutic targets using a conditional mutant ATXN1 mouse

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model (f-ATXN1146Q/2Q) having mouse Atxn1 coding exons replaced by human exons encoding 146 glutamines. F-ATXN1146Q/2Q mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using ATXN1146Q/2Q;Nestin-Cre mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using f-ATXN1146Q/2Q;Rgs9-Cre mice. Mice lacking striatal ATXN1146Q/2Q had improved rotarod performance late in disease. Muscle contributions to disease were revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice which lacked muscle pathology and kyphosis seen in f-ATXN1146Q/2Q mice. Kyphosis was not improved in f-ATXN1146Q/2Q;Nestin-Cre mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.

neuroscience↗

bioRxiv2022

Chronic obstructive pulmonary disease and cigarette smoke exposure lead to dysregulated MAIT cell activation by bronchial epithelial cells

Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation, increased infiltration by CD8+ T lymphocytes, and infection-driven exacerbations. COPD is most commonly caused by cigarette smoke (CS), however the mechanisms driving development of COPD in some smokers but not others are incompletely understood. Lung-resident mucosal-associated invariant T (MAIT) cells play a role in both microbial infections and inflammatory diseases. MAIT cell frequency is reduced in the peripheral blood of individuals with COPD, however the role of MAIT cells in COPD pathology is unknown. Here, we examined MAIT cell activation in response to CS-exposed primary human bronchial epithelial cells (BEC) from healthy, COPD, or smoker donors. We observed significantly higher MAIT cell responses to COPD BEC than healthy BEC. However, COPD BEC stimulated a smaller fold-increase in MAIT cell response despite increased microbial infection. For all donor groups, CS-exposed BEC elicited reduced MAIT cell responses; conversely, CS exposure increased ligand-mediated MR1 surface translocation in healthy and COPD BEC. Our data demonstrate MAIT cell activation is dysregulated in the context of CS and COPD. MAIT cells could contribute to CS- and COPD-associated inflammation through both inappropriate activation and reduced early recognition of bacterial infection, contributing to microbial persistence and COPD exacerbations.

immunology↗

bioRxiv2022

Reading instruction causes changes in category-selective visual cortex

Education sculpts specialized neural circuits for skills like reading that are critical to success in modern society but were not anticipated by the selective pressures of evolution. Does the emergence of brain regions that selectively process novel visual stimuli like words occur at the expense of cortical representations of other stimuli like faces and objects? To answer this question we conducted a randomized controlled trial with pre-school children (five years of age). We found that being taught reading versus oral language skills induced different patterns of change in category-selective regions of visual cortex. Reading instruction enhanced the response to text but did not diminish the response to other categories. How these changes play out over a longer timescale is still unknown but, based on these data, we can surmise that high-level visual cortex undergoes rapid changes as children enter school and begin establishing new skills like literacy.

neuroscience↗

bioRxiv2021

Oxygenated hemoglobin signal provides greater predictive performance of experimental condition than de-oxygenated

Continuous-wave functional near-infrared spectroscopy (fNIRS) neuroimaging provides an estimate of relative changes in oxygenated and de-oxygenated hemoglobin content, from which regional neural activity is inferred. The relation between both signals is governed by neurovascular coupling mechanisms. However, the magnitude of concentration changes and the contribution of noise sources to each chromophore is unique. Subsequently, it is not apparent if either chromophore signal practically provides greater information about the underlying neural state and relation to an experimental condition. To assess this question objectively, we applied a machine-learning approach to four datasets and evaluated which hemoglobin signal best differentiated between experimental conditions. To further ensure the objective nature of the analysis, the algorithm utilized all samples from the epoched data rather than pre-selected features. Regardless of experimental task, brain region, or stimulus, the oxygenated hemoglobin signal was better able to differentiate between conditions than the de-oxygenated signal. Incorporating both signals into the analysis provided no additional improvement over oxygenated hemoglobin alone. These results indicate that oxyhemoglobin is the most informative fNIRS signal in relation to experimental condition.

neuroscience↗

bioRxiv2021

Genetic coordination of sperm morphology and seminal fluid proteins promotes male reproductive success in Drosophila melanogaster

Spermatozoal morphology is highly variable both among and within species and in ways that can significantly impact fertilization success. In Drosophila melanogaster, paternity success depends on sperm length of both competing males and length of the females primary sperm storage organ. We found that genes upregulated in long sperm testes are enriched for lncRNAs and seminal fluid proteins (Sfps). Transferred in seminal fluid to the female during mating, Sfps are secreted by the male accessory glands (AG) and affect female remating rate, physiology, and behavior with concomitant advantages for male reproductive success. Despite being upregulated in long sperm testes, they have no known function in testis tissue. We found that Sex Peptide and ovulin (Acp26Aa) knockouts resulted in shorter sperm, suggesting that Sfps may regulate sperm length during spermatogenesis. However, knockout of AG function did not affect sperm length, suggesting that AG expression has no influence on spermatogenic processes. We also found that long sperm males are better able to delay female remating, suggesting higher Sfp expression in AG. These results might suggest that long sperm males have a double advantage in sperm competition by both delaying female remating, likely through transfer of more Sfps, and by resisting sperm displacement. However, we also found that this extra advantage does not necessarily translate to more progeny or higher paternity success. Thus, we found that multiple components of the ejaculate coordinate to promote male reproductive success at different stages of reproduction, but the realized fitness advantages in sperm competition are uncertain. Significance StatementThe ejaculate is comprised of sperm produced in the testis and seminal fluid primarily produced in the male accessory glands (AG). These complementary components are both critical for male reproductive success, but they are largely considered to be functionally, genetically, and developmentally independent. In a quest to understand genetic mechanisms of sperm length variation, we found that genes upregulated in long sperm testes are enriched for lncRNAs and seminal fluid proteins (Sfps). Knockout of two Sfps, Sex Peptide and ovulin, results in shorter sperm, though knockout of AG function has no effect. Moreover, long sperm males delay female remating longer. These results suggest sophisticated testis-AG coordination that amplifies male reproductive success, with implications for evolutionary integration of sexually selected traits.

genetics↗

bioRxiv2021

Stage-specific disruption of X chromosome expression during spermatogenesis in sterile house mouse hybrids

Hybrid sterility is a complex phenotype that can result from the breakdown of spermatogenesis at multiple developmental stages. Here, we disentangle two proposed hybrid male sterility mechanisms in the house mice, Mus musculus domesticus and M. m. musculus, by comparing patterns of gene expression in sterile F1 hybrids from a reciprocal cross. We found that hybrid males from both cross directions showed disrupted X chromosome expression during prophase of meiosis I consistent with a loss of Meiotic Sex Chromosome Inactivation (MSCI) and Prdm9-associated sterility, but that the degree of disruption was greater in mice with an M. m. musculus X chromosome consistent with previous studies. During postmeiotic development, gene expression on the X chromosome was only disrupted in one cross direction, suggesting that misexpression at this later stage was genotype-specific and not a simple downstream consequence of MSCI disruption which was observed in both reciprocal crosses. Instead, disrupted postmeiotic expression may depend on the magnitude of earlier disrupted MSCI, or the disruption of particular X-linked genes or gene networks. Alternatively, only hybrids with a potential deficit of Sly copies, a Y-linked ampliconic gene family, showed overexpression in postmeiotic cells, consistent with a previously proposed model of antagonistic coevolution between the X and Y-linked ampliconic genes contributing to disrupted expression late in spermatogenesis. The relative contributions of these two regulatory mechanisms and their impact on sterility phenotypes awaits further study. Our results further support the hypothesis that X-linked hybrid sterility in house mice has a variable genetic basis, and that genotype-specific disruption of gene regulation contributes to overexpression of the X chromosome at different stages of development. Overall, these findings underscore the critical role of epigenetic regulation of the X chromosome during spermatogenesis and suggest that these processes are prone to disruption in hybrids.

evolutionary biology↗

bioRxiv2021

A Thermostable, Flexible RNA Vaccine Delivery Platform for Pandemic Response

Current RNA vaccines against SARS-CoV-2 are limited by instability of both the RNA and the lipid nanoparticle delivery system, requiring storage at -20{degrees}C or -70{degrees}C and compromising universally accessible vaccine distribution. This study demonstrates the thermostability and adaptability of a nanostructured lipid carrier (NLC) RNA vaccine delivery system for use in pandemic preparedness and pandemic response. Liquid NLC is stable at refrigerated temperatures for [≥] 1 year, enabling stockpiling and rapid deployment by point-of-care mixing with any vaccine RNA. Alternatively, NLC complexed with RNA may be readily lyophilized and stored at room temperature for [≥] 8 months or refrigerated temperature for [≥] 21 months. This thermostable RNA vaccine platform could significantly improve distribution of current and future pandemic response vaccines, particularly in low-resource settings. One Sentence SummaryAn RNA vaccine delivery system stable at room temperature for 8+ months and refrigerated for 21+ months.

bioengineering↗

bioRxiv2020

Analysis methods for measuring fNIRS responses generated by a block-design paradigm

OverviewO_ST_ABSSignificanceC_ST_ABSfNIRS is an increasingly popular tool in auditory research, but the range of analysis procedures employed across studies complicates interpretation of data. AimTo assess the impact of different analysis procedures on the morphology, detection, and lateralization of auditory responses in fNIRS. Specifically, whether averaging or GLM-based analyses generate different experimental conclusions, when applied to a block-protocol design. The impact of parameter selection of GLMs on detecting auditory-evoked responses was also quantified. Approach17 listeners were exposed to three commonly employed auditory stimuli: noise, speech, and silence. A block design was employed, comprising sounds of 5-s duration, and 10-20 s silent intervals. ResultsBoth analysis procedures generated similar response morphologies and amplitude estimates, and both also indicated responses to speech to be significantly greater than to noise and silence. Neither approach indicated a significant effect of brain hemisphere on responses to speech. Methods to correct for systemic hemodynamic responses using short channels improved detection at the individual level. ConclusionsConsistent with theoretical considerations, simulations, and other experimental domains, GLM and averaging analyses generate the same group-level experimental conclusions. We release this dataset publicly for use in future development and optimization of algorithms.

neuroscience↗

bioRxiv2020

Pre-existing SIV infection increases expression of T cell markers associated with activation during early Mycobacterium tuberculosis co-infection and impairs TNF responses in granulomas

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV (PLHIV). PLHIV are more susceptible to contracting Mycobacterium tuberculosis (Mtb) infection and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on Mtb co-infection is critical in combating this global health epidemic. We previously established a model of simian immunodeficiency virus (SIV) and Mtb co-infection in Mauritian cynomolgus macaques (MCM), and showed that SIV/Mtb co-infected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to Mtb infection. To test our hypothesis, we infected MCM with SIVmac239 intrarectally followed by co-infection with a low dose of Mtb Erdman 6 months later. SIV-naive MCM were infected with Mtb alone as controls. Six weeks after Mtb infection, animals were necropsied and immune responses were measured by multiparameter flow cytometry. While the two groups exhibited similar TB progression at time of necropsy (Nx), longitudinal sampling of the blood (PBMC) and airways (BAL) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways following Mtb co-infection of SIV+ animals. Differences in the activation markers CD69, PD-1, and TIGIT were observed. At sites of Mtb infection (i.e. granulomas), SIV/Mtb co-infected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ and CD8+ T cells in granulomas and airways of SIV/Mtb co-infected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of Mtb replication soon after infection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection which promotes TB progression. Author SummaryPeople living with HIV are incredibly susceptible to TB and, when co-infected with Mtb, often develop serious TB disease. We do not yet understand precisely how HIV infection impairs the early stages of the adaptive immune response against Mtb bacilli. We employed a non-human primate model of HIV, using SIV as a surrogate for HIV, followed by Mtb co-infection to investigate the immunologic defects associated with pre-existing SIV infection over the first six weeks of Mtb co-infection. Our study focused on CD4+ and CD8+ T cells as these cells are known to play an important role in Mtb control. We found more CD8+ T cells in granulomas, the sites of Mtb infection, from SIV/Mtb co-infected animals, with little difference in CD4+ T cells. SIV/Mtb co-infected animals and animals infected with SIV alone had a higher proportion of both CD4+ and CD8+ T cells expressing activation markers compared to SIV-naive animals, consistent with SIV-dependent immune activation. Notably, we observed a lower proportion of TNF-producing T cells, a cytokine critical for Mtb control, in granulomas and airways of SIV/Mtb co-infected animals. Taken together, these data show that pre-existing SIV alters T cell phenotypes and reduces TNF responses early in Mtb infection.

immunology↗

bioRxiv2020

Structural templates for imaging EEG cortical sources in infants

Electroencephalographic (EEG) source reconstruction is a powerful approach that helps to unmix scalp signals, mitigates volume conduction issues, and allows anatomical localization of brain activity. Algorithms used to estimate cortical sources require an anatomical model of the head and the brain, generally reconstructed using magnetic resonance imaging (MRI). When such scans are unavailable, a population average can be used for adults, but no average surface template is available for cortical source imaging in infants. To address this issue, this paper introduces a new series of 12 anatomical models for subjects between zero and 24 months of age. These templates are built from MRI averages and volumetric boundary element method segmentation of head tissues available as part of the Neurodevelopmental MRI Database. Surfaces separating the pia mater, the gray matter, and the white matter were estimated using the Infant FreeSurfer pipeline. The surface of the skin as well as the outer and inner skull surfaces were extracted using a cube marching algorithm followed by Laplacian smoothing and mesh decimation. We post-processed these meshes to correct topological errors and ensure watertight meshes. The use of these templates for source reconstruction is demonstrated and validated using 100 high-density EEG recordings in 7-month-old infants. Hopefully, these templates will support future studies based on EEG source reconstruction and functional connectivity in healthy infants as well as in clinical pediatric populations. Particularly, they should make EEG-based neuroimaging more feasible in longitudinal neurodevelopmental studies where it may not be possible to scan infants at multiple time points. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/162131v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@8d705dorg.highwire.dtl.DTLVardef@1cc0ac7org.highwire.dtl.DTLVardef@d791caorg.highwire.dtl.DTLVardef@a4707d_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITwelve surface templates for infants in the 0-2 years old range are proposed C_LIO_LIThese templates can be used for EEG source reconstruction using existing toolboxes C_LIO_LIA relatively modest impact of age differences was found in this age range C_LIO_LICorrelation analysis confirms increasing source differences with age differences C_LIO_LISources reconstructed with infants versus adult templates significantly differ C_LI

neuroscience↗

bioRxiv2020

Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

The emergence and reemergence of highly virulent viral pathogens with pandemic potential has created an urgent need for accelerated discovery of antiviral therapeutics. Antiviral human monoclonal (mAbs) are promising drug candidates to prevent or treat severe viral diseases, but the long timelines needed for discovery limits their rapid deployment and use. Here, we report the development of an integrated sequence of technologies incorporating advances in single-cell mRNA sequence analysis, bioinformatics, synthetic biology, and high-throughput functional analysis that allowed us to discover highly potent antiviral human mAbs and validate their activity in vivo at an unprecedented scale, speed, and efficiency. In a 78-day study, modeling deployment of a rapid response platform to an outbreak, we isolated >100 individual Zika virus (ZIKV) specific human mAbs, assessed their function, identified 29 broadly-neutralizing mAbs, and verified therapeutic potency of lead candidates with antibody-encoding mRNA formulation and/or IgG protein delivery in mice and nonhuman primates. Our work provides a roadmap for the rapid antibody discovery programs against viral pathogens of global concern.

immunology↗

bioRxiv2019

SSnet - Secondary Structure based End-to-End Learning model for Protein-Ligand Interaction Prediction

Computational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-machine learning models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure based deep learning, which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research while being readily accessible for de novo drug designers as a standalone package.

bioinformatics↗

bioRxiv2019

Long-Term Aberrations To Cerebellar Endocannabinoids Induced By Early-Life Stress

Studies of early-life stress traditionally focus on glucocorticoid signaling as a modulator of neurodevelopmental risk, but emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling. Existing studies on stress-induced endocannabinoid dysregulation have focused on changes to cerebrum that are temporally proximal to stressors, but little is known about temporally distal effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Further, sex-specific effects of stress on cerebellar endocannabinoid tone are understudied. Following a naturalistic rodent model of early-life stress, limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids and related lipids and mRNA were assessed, and behavioral performance was evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar deep nuclei in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Transcriptomics for cerebellar interpositus nucleus revealed substantial sex effects, with minimal effects of stress. Stress did impair novel object recognition in both sexes and social preference in females. Taken together, the cerebellar endocannabinoids system exhibits robust sex-specific differences, malleable through early-life stress and perhaps also contributing to sexual differentiation of the brain. The current study may foster future research into stress as a risk factor for cerebellar-related dysfunctions.

neuroscience↗