Biology subjects

Powell, K.

Publications and source records attributed to Powell, K..

At least 19 recordsLinked to original sources

bioRxiv2026

An Innate Neuroprotective Reflex Activates NRF2 via Phosphorylation of p62 at Ser351 to Mitigate Traumatic Brain Injury

Rationale: The oxidative crisis in traumatic brain injury (TBI) has remained therapeutically intractable to direct antioxidant therapies. Activating nuclear factor erythroid 2-related factor 2 (NRF2) offers a promising strategy, but its translation is hindered by a key question: whether TBI's depleted antioxidant reserves can accommodate canonical electrophilic activation. The diving reflex (DR) is a potential non-electrophilic alternative, but its efficacy in TBI is unknown and its natural induction is clinically impractical. This study tests whether artificial DR, induced by trigeminal nerve stimulation (TNS), can safely engage this non-electrophilic NRF2 pathway and exert a protective role in the acutely injured brain. Methods: In a rat model of severe TBI, we compared TNS-induced DR, natural DR, and exogenous calcitonin gene-related peptide (CGRP) against the electrophilic NRF2 activator dimethyl fumarate (DMF). To define the mechanism of action, we quantified p62 phosphorylation at Ser351 (NRF2-activating) versus Ser403 (autophagy-related), alongside redox homeostasis, lesion volume, and multi-domain functional outcomes. Results: TNS-induced DR fully recapitulated the neuroprotection of natural DR, an effect mimicked by exogenous CGRP, and prevented by CGRP inhibition, confirming a shared, neuropeptide-driven mechanism. This non-electrophilic pathway operated by selectively phosphorylating p62 at Ser351, which preserved glutathione reserves, halted lipid peroxidation, and reduced chronic lesion volume. In contrast, while DMF activated NRF2, its electrophilic mechanism was associated with a further reduction in the brain's already compromised glutathione pools and increased lipid peroxidation. This mechanistic difference was functionally significant, as only the non-electrophilic approaches delivered multi-domain recovery. Conclusion: The TNS-evoked artificial DR is a mechanistically tailored strategy for activating NRF2 in acute TBI. By engaging the endogenous CGRP-p62-KEAP1 pathway, it circumvents the fundamental limitations of both passively consumed direct antioxidants and redox-costly electrophilic activators. Our findings establish a clear translational roadmap for harnessing an innate reflex as a clinically deployable therapy for hyper-oxidative states.

neuroscience↗

bioRxiv2026

Trigeminal Nerve Stimulation Attenuates Traumatic Brain Injury-Induced Neuronal Damage via CGRP-PINK1 Mitophagy Axis

Secondary damage after traumatic brain injury (TBI) is driven by progressive mitochondrial failure, yet clinically viable strategies to directly safeguard mitochondrial networks remain a major therapeutic gap. Here, we show that non-invasive trigeminal nerve stimulation (TNS), which engages the brain's endogenous oxygen-conserving diving reflex, preserves neuronal survival by directly regulating the mitochondrial PINK1/Parkin quality-control pathway. We demonstrate that TBI induces the pathological aggregation of the outer mitochondrial membrane receptor TOM20, in a CGRP-dependent manner, which affects binding of the damage-sensor PINK1 and renders downstream Parkin-mediated rescue ineffective. TNS-induced neuronal CGRP release prevents this TOM20 aggregation, restoring proper PINK1 function and downstream Parkin activation. This preservation of mitochondrial architecture reinforces the outer membrane's barrier function, limiting pro-apoptotic cytochrome c leakage and supporting NRF2 antioxidant defenses, ultimately reducing progressive infarct expansion and recovering sensorimotor functions. The significance of this work lies in bridging physical neuromodulation directly to the preservation of organelle-level architecture. By demonstrating that stimulation of trigeminal afferents to recruit an oxygen-conserving reflex can stabilize outer membrane signaling architecture and preserve mitochondrial survival machinery, this study outlines a non-pharmacological strategy to protect mitochondrial function and inhibit acute post-traumatic neurodegeneration.

neuroscience↗

bioRxiv2026

MAIT cells derived ligands signal via VEGFR2 to promote tissue repair and liver regeneration

MAIT are a highly versatile population of innate-like T cells that have been implicated in promoting tissue repair-associated process in a variety of tissue and diseases settings in the last years. While certain specific effector molecules responsible for MAIT-cell mediated have been identified, the mechanisms by which MAIT cells exert repair functions remain incompletely understood. Here, we show that hepatic MAIT cells express VEGFA, VEGFB and vimentin, an alternative ligand for the VEGFA-receptor VEGFR2 in both, regenerating and heathy tissue. Expression and secretion of these factors were induced in vitro by combined T cell receptor and cytokine stimulation. Supernatants of activated MAIT cells were able to promote proliferation of different epithelial and endothelial cells, including a liver sinusoidal endothelial-derived cell line in an VEGFR2-dependent manner. Together, our findings expand our understanding of MAIT cell function, especially in the liver and open new opens avenues for exploring MAIT therapeutic potential in modulating tissue repair.

immunology↗

bioRxiv2025

A modified cyclosporine enhances lentivector transduction ex vivo and in vivo by degrading IFITM3

Intrinsic innate immune barriers have evolved to suppress viral infection and can reduce effective gene delivery in gene therapy. We have developed BG147, a novel cyclosporine A analogue, optimised via structure-guided design to prevent inhibition of HIV cofactor Cyclophilin A and to specifically inhibit interferon-induced transmembrane proteins (IFITM1-3). BG147 enhances VSV-G pseudotyped lentiviral vector transduction ex vivo in hematopoietic stem and progenitor cells (HSPCs) and in in vivo ocular gene therapy of photoreceptor cells in mice. Upon BG147 treatment, IFITM proteins are mislocalised and degraded through lysosomal acidification-dependent pathways. IFITM3 levels functionally return in cells 96 h after BG147 washout. BG147 promises to transform ex vivo and in vivo eye gene therapies by transiently inhibiting intrinsic immune barriers mediated by IFITM proteins to enhance a wide range of protocols. One Sentence SummaryModified cyclosporine, BG147, enhances lentivector gene therapy transduction, ex vivo in HSPC and in vivo in mouse photoreceptors, by degrading IFITM3.

cell biology↗

bioRxiv2025

Vasoactive Neuropeptide Dysregulation: A Novel Mechanism of Microvascular Dysfunction in Vascular Cognitive Impairment

INTRODUCTIONNeuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODSWe investigated pathological mediators across varying severities of VCI in a rat model of chronic cerebral hypoperfusion (CCH). Proteomic analysis guided the evaluation of neuropeptide and non-neuropeptide markers associated with vascular and nonvascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTSProteomic analysis revealed vasomotor dysfunction as the primary pathological pathway in VCI. Microvascular vasoconstriction was the earliest and most persistent event, initiating a cascade of both microvascular and nonvascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. CGRP supplementation effectively prevented vasoconstriction, and improving cognitive function in CCH. DISCUSSIONThis study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. HIGHLIGHTSO_LINeuropeptides are the primary drivers of dominant pathomechanisms underlying CCH. C_LIO_LIEarly vasoactive neuropeptides dysregulation is a key driver of cognitive decline. C_LIO_LIMicrovascular dysfunction precedes classical non-vascular pathologies in CCH. C_LIO_LICapillary constriction precedes and drives amyloid accumulation in CCH. C_LIO_LICGRP mitigates microvascular constriction, enhancing cognitive function in VCI. C_LI Research in ContextO_LISystematic review: The authors reviewed literature from PubMed and Google Scholar, as well as meeting abstracts and presentations. Neuropeptide dysregulation and microvascular injury are increasingly recognized for involvement in the pathogenesis of VCID; however, the underlying etiology of this pathological axis remains unclear. C_LIO_LIInterpretation: Our evidence shows that early, progressive vasoactive neuropeptide dysregulation drives microvascular constriction, constituting a pivotal mechanism in microvascular dysfunction and subsequent cognitive deterioration in chronic cerebral hypoperfusion. The data further elucidate the significant therapeutic efficacy of pharmacological and non-pharmacological interventions directed at vasoactive neuropeptide pathways, which resulted in marked enhancement of cognitive function. C_LIO_LIFuture directions: Our results indicate that aberrant vasoactive neuropeptide regulation constitutes a fundamental pathophysiological mechanism underlying the development and clinical manifestation of VCID. These findings have potentially substantial implications for the development of novel therapeutic strategies targeting this disorder, which represents the second most common etiology of cognitive deterioration. C_LI

neuroscience↗

bioRxiv2025

Endogenous CGRP activates NRF2 signaling via non-electrophilic mechanisms

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is crucial for regulating cellular responses to oxidative stress, making it a significant target for therapeutic interventions. While exogenous NRF2 activators offer significant therapeutic potential, their predominantly electrophilic nature poses considerable challenges for clinical use; the heightened electrophilic reactivity required to achieve therapeutic efficacy raises potential safety concerns. Calcitonin gene-related peptide (CGRP) has shown protective effects against oxidative stress and is involved in NRF2 activation; however, the underlying mechanisms are not fully understood. This study explores the mechanisms underlying endogenous CGRP-mediated NRF2 upregulation by inducing acute or chronic CGRP release through diving reflex (DR) in male Sprague-Dawley rats. Brain tissue proteomics confirmed the upregulation of NRF2-dependent antioxidant transcripts-- predominantly glutathione-related genes--without concurrent elevation of oxidative stress markers in both acute and chronic CGRP exposure paradigms. CGRP potently activated NRF2 in brain and peripheral tissues, evidenced by elevated nuclear and phosphorylated NRF2, increased nuclear:cytosolic NRF2 ratios, and enhanced antioxidant gene transcription--effects substantially attenuated by CGRP antagonism. Reduced glutathione levels increased without concurrent elevations in lipid peroxidation, protein oxidation, or evidence of tissue damage, suggesting CGRP avoids side effects characteristic of electrophilic NRF2 activators. Furthermore, our findings suggest that CGRP-mediated NRF2 activation primarily occurs via non-electrophilic mechanisms, with the p62-KEAP1-NRF2 pathway predominantly active in peripheral organs (lung and kidney), and the AMPK-NRF2 pathway more pronounced in the brain, highlighting the organ-specific nature of the response. Time-dependent variations in CGRP-mediated NRF2 activation were also observed, influencing both the response to CGRP and its impact on oxidative stress resistance. These results suggest that targeting NRF2 with endogenous CGRP may offer a promising therapeutic approach for managing oxidative stress-related diseases, both acute and chronic, across multiple organs, by avoiding electrophilic stress. HighlightsO_LIEndogenous CGRP triggers a potent and non-electrophilic activation of NRF2 signaling. C_LIO_LICGRP increases reduced glutathione levels following both acute and chronic exposures, in contrast to the effects of exogenous electrophilic NRF2 activators. C_LIO_LIIn peripheral organs, CGRP predominantly activates the KEAP1-dependent p62-KEAP1-NRF2 pathway. C_LIO_LIIn the brain, CGRP primarily activates the KEAP1-independent AMPK-NRF2 pathway. C_LIO_LICGRP exhibits time-dependent patterns, where acute exposure leads to a more significant upregulation of NRF2-targeted antioxidative gene expression and chronic exposure confers increased resistance to oxidative stress. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/650677v1_ufig8.gif" ALT="Figure 8"> View larger version (44K): org.highwire.dtl.DTLVardef@ae52a3org.highwire.dtl.DTLVardef@b35d1eorg.highwire.dtl.DTLVardef@1a68f31org.highwire.dtl.DTLVardef@31234_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Functional connectivity in the social perception pathway at birth is linked with attention to faces at 4 months

BackgroundProcessing faces and speech is supported by the right-lateralized social visual perception pathway (social pathway) involving medial temporal/visual 5 area (MT/V5) and superior temporal sulcus (STS). Little is known about development of the social pathway and its links with later social outcomes. We examined intrinsic functional connectivity (iFC) in the right social pathway in neurotypical neonates, compared it with iFC in the left social and bilateral dorsal attention pathways, and interrogated prospective links between iFC and social attention in neurodiverse neonates. MethodsiFC in the social and dorsal pathways was measured in 517 full-term neonates from the developing Human Connectome Project (dHCP) and 73 full-term Yale neonates [Mage=41.5 weeks (SD=1.9)]. Social attention was assessed in 36 Yale neonates at Mage=4.2 months (SD=0.4) months. ResultsIn the dHCP sample, the iFC indices were positive in all the pathways (all p-values < 0.001) and did not vary by sex [all p>0.275], but the iFC in the right-lateralized social pathway was higher than in the remaining pathways [all p<0.001] and was positively associated with age at scan [r(517)=0.251, p<0.011]. In the prospective neurodiverse Yale sample, the iFC in the right social pathway was positively associated with social attention at 4 months [p=0.007], and greater social attention at 4 months predicted better social functioning in the second year [p=0.010]. ConclusionsThe early development of intrinsic functional connectivity in the right social perception pathway represents an area of interest for identifying neural mechanisms underlying emergence of atypical social attention associated with autism.

neuroscience↗

bioRxiv2024

Human tonsil organoids reveal innate pathways modulating humoral and cellular responses to ChAdOx1

The COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19. Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN- was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN--dependent and independent manners, indicating intricate signaling interplay. IFN- and IL-6 also regulated the function of vaccine-activated CD4+ T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies. SUMMARYDespite the success of adenovirus vector vaccines, we still lack understanding of the mechanisms regulating immunity induced by this platform. This study utilized human tonsil organoids to provide key insights into innate pathways regulating ChAdOx1-induced humoral and cellular immunity.

immunology↗

bioRxiv2024

Intrinsic diving reflex enhances cognitive performance by alleviating microvascular dysfunction in vascular cognitive impairment

Vascular cognitive impairment (VCI) stands as the second-most prominent contributor to cognitive decline, lacking efficacious interventions. Chronic cerebral hypoperfusion (CCH) triggers microvascular dysfunction, which plays a critical role in VCI pathophysiology, emerging as a pivotal therapeutic target. While interventions addressing facets of microvascular dysfunction like angiogenesis and blood-brain barrier functionality show promise, the evaluation of microvascular constriction, another key component, remains unexplored. The diving reflex (DR) represents an oxygen-conserving response, characterized by robust vasodilation and potentially also inducing angiogenesis. In this investigation, we studied DRs functionality and underlying mechanisms within a rat bilateral common carotid artery occlusion induced CCH model. Remarkably, progressive hippocampal microvascular constriction exhibited strong correlations with short-term memory impairment during both early (R2=0.641) and late phases (R2=0.721) of CCH. Implementation of DR led to a significant reduction in microvascular constriction within the hippocampus ([~]2.8-fold) and striatum ([~]1.5-fold), accompanied by enhanced vasodilatory capacity and heightened expression of vasoactive neuropeptides. Furthermore, DR attenuated microvascular degeneration across various brain subregions affected by CCH, concomitant with increased levels of multiple angiogenic factors. The reinforced microvascular integrity facilitated by DR corresponded with significantly improved short-term recognition memory and long-term spatial memory functions observed during the late phase of CCH. The comprehensive and synergistic effects of DR on various aspects of microvascular function and cognitive preservation highlight its potential as a disease-modifying therapeutic strategy in VCI.

neuroscience↗

bioRxiv2024

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

AimsThis study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses. MethodsMale Sprague-Dawley rats (n=38) underwent either a single diving session to elicit acute diving reflex, or daily diving sessions for 4-weeks to produce chronic diving reflex. NRF2 (total, nuclear, phosphorylated), NRF2-downstream genes, and malondialdehyde were assessed via Western blot, immunofluorescence, RT-PCR, and ELISA in brain, lung, kidney, and serum. ResultsDiving reflex increased nuclear NRF2, phosphorylated NRF2, and antioxidative gene expression, in an organ-specific and exposure time-specific manner. Comparing organs, the brain had the highest increase of phosphorylated NRF2 expression, while kidney had the highest degree of nuclear NRF2 expression. Comparing acute and chronic sessions, phosphorylated NRF2 increased the most with chronic diving reflex, but acute diving reflex had the highest antioxidative gene expression. Notably, calcitonin gene-related peptide appears to mediate diving reflex effects on NRF2 activation. ConclusionsAcute and chronic diving reflex activate potent NRF2 signaling in the brain and peripheral organs. Interestingly, acute diving reflex induces higher expression of downstream antioxidative genes compared to chronic diving reflex. This result contradicts previous assumptions requiring chronic exposure to diving for induction of antioxidative effects and implies that the diving reflex has a strong translational potential during preconditioning and postconditioning therapies. Key PointsO_LIDiving reflex activates potent NRF2 signaling via multiple mechanisms, including phosphorylation, nuclear translocation, and KEAP1 downregulation with both acute and chronic exposure. C_LIO_LIDiving reflex activates NRF2 via differential pathways in the brain and other organs; phosphorylated NRF2 increases more in the brain, while nuclear NRF2 increases more in the peripheral organs. C_LIO_LIAcute diving reflex exposure induces a more pronounced antioxidative effect than chronic diving reflex exposure, indicating that the antioxidative response activated by diving reflex is not dependent upon chronic adaptive responses and supports diving reflex as both a preconditioning and postconditioning treatment. C_LI

physiology↗

bioRxiv2024

Interneuron-like features of microglia in the mouse outer retina

Microglia have recently been associated with complex functionalities both in the brain and the retina, including in synaptic function and plasticity. While investigating the morphology, protein expression profile and connectivity of microglia in the mouse outer retina, we have found that they closely resemble interneurons in the outer retina of other species. We argue that functional studies are needed to reveal whether they also perform an interneuron-like role in vision.

neuroscience↗

bioRxiv2023

Primed to resolve: A single cell atlas of the shoulder capsule reveals a cellular basis for resolving inflammatory fibrosis

Fibrotic conditions are a significant global disease burden. While some therapies delay disease progression, none reverse fibrosis. To gain insights into how fibrosis might resolve, we developed a comparative single cell atlas of frozen shoulder capsule tissue; a chronic inflammatory fibrotic human disease that resolves spontaneously. We identified both a population of pro-inflammatory MERTKlowCD48+ macrophages (M{varphi}) and a population of MERTK+LYVE1+MRC1+M{varphi} enriched for negative regulators of inflammation. Micro-cultures of patient-derived cells identified cell-matrix interactions between MERTK+M{varphi} and DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in the resolution of frozen shoulder. Cross-tissue analysis revealed a shared gene expression cassette between MERTK+M{varphi} in the shoulder capsule and a similar cell population enriched in synovial tissues from rheumatoid arthritis patients in disease remi ssion, supporting the concept that MERTK+M{varphi} provide a cellular basis for the resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identified MERTK+LYVE1+MRC1+M{varphi} and DKK3+ and POSTN+ fibroblast populations analogous to those identified in adult shoulder capsule, suggesting that the template to resolve fibrosis is established during development. Therapeutic enhancement of crosstalk between MerTK+M{varphi} and pro-resolving DKK3+ and POSTN+ fibroblasts could accelerate resolution of frozen shoulder and resolve persistent inflammatory fibrotic disease in other tissues.

cell biology↗

bioRxiv2022

Complex multiple introductions drive fall armyworm invasions into Asia and Australia

The fall armyworm (FAW) Spodoptera frugiperda is thought to have undergone a rapid west-to-east spread since 2016 when it was first identified in western Africa. Between 2018 and 2020, it was also recorded from South Asia (SA), Southeast Asia (SEA), East Asia (EA), and Pacific/Australia (PA). Population genomic analyses enabled the understanding of pathways, population sources, and gene flow in this notorious agricultural pest species. Using neutral single nucleotide polymorphic (SNP) DNA markers, we detected genome introgression that suggested most populations were overwhelmingly C- and R-strain hybrids. SNP and mitochondrial DNA markers identified multiple introductions that were most parsimoniously explained by anthropogenic-assisted spread, i.e., associated with international trade of live/fresh plants and plant products, and involved bridgehead populations in countries to enable successful pest establishment in neighbouring countries. Distinct population genomic signatures between Myanmar and China do not support the African origin spread nor the Myanmar source population to China hypotheses. Significant genetic differentiation between populations from different Australian states supported multiple pathways involving distinct SEA populations. Our study identified Asia as a biosecurity hotspot and a FAW genetic melting pot, and demonstrated the use of genome analysis to disentangle preventable human-assisted pest introductions from unpreventable natural pest spread.

evolutionary biology↗

bioRxiv2022

ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using cortical organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with idiopathic ASD and their unaffected fathers in thirteen families. Alterations in the transcriptome suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between the excitatory neurons of the dorsal cortical plate and other lineages such as the early-generated neurons from the putative preplate. The imbalance stemmed from a divergent expression of transcription factors driving cell fate during early cortical development. While we did not find probands genomic variants explaining the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and developmental transcriptome in idiopathic ASD.

neuroscience↗

bioRxiv2021

An efficient and robust HPLC method to determine the sialylation levels of human epithelial cells

Sialyltransferase, an enzyme responsible for attaching sialic acid to the cell surface, is reported to play a key role in cancer, making sialyltransferase a potent therapeutic target in drug development for cancer. Hence, this paper aimed to develop a simple method to detect and quantify sialic acids in cancer cells. An efficient method was developed using a reverse-phase ion-pairing HPLC-UV using triisopropanolamine as the ion-pairing agent with a C18 column. Neu5Ac was successfully eluted with the retention time 6.344 min with a flow rate of 0.4 mL/min. The proposed method was validated appropriately according to the AOAC guidelines (2013). This work demonstrates that the proposed method is not only relatively simple but also cost and time effective compared to pre-existing methods to successfully determine both free and protein-bound Neu5Ac in a complex cancer cell matrix. Furthermore, by applying the proposed method, a statistically significant decrease was observed for both HeLa and HuCCT1 cell lines with the application of deoxycholic acid - a known sialyltransferase inhibitor. Hence, the proposed method may be applicable to evaluate the effectiveness of sialyltransferase inhibitors.

biochemistry↗

bioRxiv2021

An Orally Available Cathepsin L Inhibitor Protects Lungs Against SARS-CoV-2-Induced Diffuse Alveolar Damage in African Green Monkeys

The COVID-19 pandemic resulted from global infection by the SARS-CoV-2 coronavirus and rapidly emerged as an urgent health issue requiring effective treatments. To initiate infection, the Spike protein of SARS-CoV-2 requires proteolytic processing mediated by host proteases. Among the host proteases proposed to carry out this activation is the cysteine protease cathepsin L. Inhibiting cathepsin L has been proposed as a therapeutic strategy for treating COVID-19. SLV213 (K777) is an orally administered small molecule protease inhibitor that exhibits in vitro activity against a range of viruses, including SARS-CoV-2. To confirm efficacy in vivo, K777 was evaluated in an African green monkey (AGM) model of COVID-19. A pilot experiment was designed to test K777 in a prophylactic setting, animals were pre-treated with 100mg/kg K777 (N=4) or vehicle (N=2) before inoculation with SARS-CoV-2. Initial data demonstrated that K777 treatment reduced pulmonary pathology compared to vehicle-treated animals. A second study was designed to test activity in a therapeutic setting, with K777 treatment (33 mg/kg or 100 mg/kg) initiated 8 hours after exposure to the virus. In both experiments, animals received K777 daily via oral gavage for 7 days. Vehicle-treated animals exhibited higher lung weights, pleuritis, and diffuse alveolar damage. In contrast, lung pathology was reduced in K777-treated monkeys, and histopathological analyses confirmed the lack of diffuse alveolar damage. Antiviral effects were further demonstrated by quantitative reductions in viral load of samples collected from upper and lower airways. These preclinical data support the potential for early SLV213 treatment in COVID-19 patients to prevent severe lung pathology and disease progression.

immunology↗

bioRxiv2020

Implementation of a pre- and in-scan system to minimize head motion in pediatric participants undergoing fMRI scans

BackgroundPerforming fMRI scans of children can be a difficult task, as participants tend to move while being scanned. Head motion represents a significant confound in functional magnetic resonance imaging (fMRI) connectivity analyses, and methods to limit the impact of movement on data quality are needed. One approach has been to use shorter MRI protocols, though this potentially reduces the reliability of the results. ObjectiveHere we describe steps we have taken to limit head motion in an ongoing fMRI study of children undergoing a 60 minute MRI scan protocol. Specifically, we have used a mock scan protocol that trains participants to lie still while being scanned. We provide a detailed protocol and describe other in-scanner measures we have implemented, including an incentive system and the use of a weighted blanket. Materials and methodsParticipants who received a formal mock scan (n = 12) were compared to participants who had an informal mock scan (n = 7). A replication group of participants (n = 16), including five with autism spectrum disorder, who received a formal mock scan were also compared to the informal mock scan group. The primary measure of interest was the mean frame-to-frame displacement across eight functional runs during the fMRI protocol. ResultsParticipants in the formal mock scan and replication group tended to exhibit more low-motion functional scans than the informal mock scan group (P < 0.05). Across different functional scan conditions (i.e. while watching movie clips, performing an attention task, and during resting-state scans), effect sizes tended to be large (Hedges g > 0.8). ConclusionResults indicate that with appropriate measures, it is possible to achieve low-motion fMRI data in younger participants undergoing a long scan protocol.

neuroscience↗

bioRxiv2020

Targeting lateral inhibition to improve vision following macular degeneration

Macular degeneration is the leading cause of blindness in the developed world. Whilst most patients lose sight owing to atrophic changes, no treatments currently exist that improve the vision deficit due to atrophy. Here, we identify loss of lateral inhibition as a specific mechanism by which photoreceptor degeneration reduces visual function beyond the atrophic area. We find that this inhibition is adaptive, and that if modulated can improve visual function, making inhibitory circuits an unexpected therapeutic target for age related macular degeneration and related disorders.

neuroscience↗