Biology subjects

Brown, D. A.

Publications and source records attributed to Brown, D. A..

9 recordsLinked to original sources

bioRxiv2026

EEG Oscillations in Guided Mindfulness versus Mind-Wandering in Young Adults: Effects of Auditory Task Instruction and Naturalistic Video

Alpha and theta band EEG oscillations have been implicated in states of mindfulness meditation. However, results are inconsistent and the influence of testing environment variables is not well-characterized. We used EEG to measure the amplitude of brain oscillations in a mindful-attention versus mind-wandering condition, in which guided auditory instructions were interleaved with periods of silence, with and without accompanying naturalistic video projections. We generated precise measures of alpha and theta in a sample of 20 young-adult non-expert meditators, by identifying each participant's individual alpha peak frequency (IAF) from posterior EEG electrodes and using it to define four individualized frequency bands: two low alpha bands (in 2 Hz increments below the IAF), one upper alpha band (from IAF to 2 Hz above IAF), and one theta band (4 Hz - 6 Hz below IAF). We found that the mindfulness manipulation significantly increased power in alpha ranging between 2 Hz below to 2 Hz above IAF, including peak alpha amplitude, compared with mind-wandering. Meanwhile, central theta amplitude was larger when auditory instructions were on versus off, and naturalistic video did not reliably modulate the EEG effects of mindfulness. We conclude that the acute effects of mindfulness in non-expert meditators are most consistently observed as increases of posterior alpha-band activity, and that auditory task-instructions should be accounted for in studies of guided meditation. Observed alpha increases may reflect induced states of calm or relaxation induced by mindfulness practice, as proposed in previous studies. These results may apply to mindfulness training or biofeedback therapies.

neuroscience↗

bioRxiv2026

BacPROTACs outperform inhibitors in Mycobacterium tuberculosis

Antibiotic discovery has long relied on occupancy-driven inhibition, leaving a vast number of potential bacterial targets undrugged.1 Targeted protein degradation offers a mechanistically distinct alternative to inhibition, yet its application to antibacterial drug discovery remains largely unexplored.2-4 Here we describe the development of first-in-class heterobifunctional bacterial proteolysis targeting chimeras (BacPROTACs) directed against an essential Mycobacterium tuberculosis protein, 4-phosphopantetheinyl transferase (PptT).5 Leveraging the modular architecture of BacPROTACs, we repurposed PptT inhibitors by incorporating them into degraders, yielding compounds with markedly improved antimycobacterial activity. Integrating in vitro and cellular approaches, we developed a characterisation pipeline to assess protein degradation in bacteria, applicable to future BacPROTAC programmes. Our study establishes targeted protein degradation as a strategy for antibacterial drug discovery.

microbiology↗

bioRxiv2025

Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors

Limb loss remains a significant clinical challenge, but regenerative medicine approaches such as gene therapy offer a promising strategy to trigger endogenous regeneration programs. Optimal vector configurations and molecular targets for appendicular skeletal repair are not well defined. Here, we leveraged insights from species with a high endogenous capacity for appendage regeneration to design an enhancer-directed gene delivery platform that functions during mouse digit regeneration, a well characterized model for partial limb regeneration in mammals. Single-cell RNA sequencing of zebrafish caudal fin regeneration, combined with expression data in regenerating salamander limbs and mouse digit tips, implicated the SP family of transcription factors as conserved, epidermally-expressed mediators of appendage regrowth. Null mutants of Sp8 demonstrated impaired limb regeneration in salamanders, while conditional knockout of Sp6 and/or Sp8 in the mouse basal epidermis resulted in defective bony digit tip regeneration, involving an IL-17 mediated osteoclastogenic program. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wildtype mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like SP transcription factors conserved across multiple contexts of appendage regeneration. Significance StatementInstructing regeneration of complex structures in mammals remains an unsolved problem. Gene therapy offers a compelling approach to foster endogenous regeneration by delivering therapeutic gene products to specific cells post injury. We identified a conserved regeneration-linked epidermal transcriptional program in mouse digit regeneration centered on the SP6 and SP8 transcription factors, involving inflammatory responses from osteoclasts. We engineered AAVs harboring a zebrafish tissue regeneration enhancer to direct FGF8 expression in the epidermis after amputation. This enhancer directed delivery partially rescued impaired digit regeneration in Sp6 and Sp8 conditional knockout mice and accelerated regrowth in wildtype digits. Our work links developmental signaling to adult regeneration and establishes a modular, injury site specific gene therapy framework that enables new interventions for limb healing.

genetics↗

bioRxiv2025

"Awe-scillations": EEG spectral and complexity representations of awe

Awe is a positive emotion often accompanied by sensations of vastness and unity, with known benefits for well-being and social behavior. However, its neural underpinnings remain poorly understood. We recorded electroencephalography (EEG) and autonomic physiology in 23 healthy older participants while they watched a nature-based audiovisual film and subjectively rated awe events. Awe was the predominant emotion reported - though other positive emotions (e.g., joy) were also highly rated. Awe events were associated with decreased skin conductance level (SCL), and decreased EEG alpha and theta spectral power - physiological changes associated with low arousal and positively valenced emotional states. Interestingly, awe events exhibited increased Lempel Ziv Complexity (LZC) - indicating heightened neural signal entropy and increased richness of the conscious experience. LZC was also positively associated with the intensity of the awe ratings and negatively associated with SCL. Three additional datasets with separate independent induction methods (video clips and pharmacological induction via N,N-dimethyltryptamine) also showed positive occipital LZC associations with awe - suggesting some generalizability of LZC as a neurophysiological marker of awe. These results suggest that awe evokes neurophysiological states linked to the subjective affective experience. Impact StatementAwe, an emotion of increasing interest, has been studied with fMRI and peripheral physiology - but few studies have used electroencephalography (EEG). In this EEG study, we utilize a movie-watching paradigm to explore potential physiological correlates of awe. The results present EEG-based complexity increases as a potential correlate of awe, though showing limited generalization to independent datasets and limited uniqueness compared to joy, another positive emotion.

neuroscience↗

bioRxiv2024

A Systematic Review of the Neuroprotective Role and Biomarker Potential of GDF15 in Neurodegeneration

Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.

neuroscience↗

bioRxiv2024

Cerebrospinal fluid proteome profiling using machine learning shows a unique protein signature associated with APOE4 genotype

INTRODUCTIONProteome changes associated with APOE4 variant carriage that are independent of Alzheimers disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. METHODSClinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. RESULTSWe found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. DISCUSSIONAPOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers vulnerability to cognitive decline and AD.

neuroscience↗

bioRxiv2022

The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury

Spinal cord injury (SCI) occurs when the spinal cord is damaged from either a traumatic event or disease. SCI is characterised by multiple injury phases that affect the transmission of sensory and motor signals and lead to temporary or long-term functional deficits. There are few treatments for SCI. Estrogens and estrogenic compounds, however, may effectively mitigate the effects of SCI and therefore represent viable treatment options. This review systematically examines the pre-clinical literature on estrogen and estrogenic compound neuroprotection after SCI. Several estrogens were examined by the included studies: estrogen, estradiol benzoate, Premarin, isopsoralen, genistein, and selective estrogen receptor modulators. Across these pharmacotherapies, we find significant evidence that estrogens indeed offer protection against myriad pathophysiological effects of SCI and lead to improvements in functional outcomes, including locomotion. A STRING functional network analysis of proteins modulated by estrogen after SCI demonstrated that estrogen simultaneously upregulates known neuroprotective pathways, such as HIF-1, and downregulates pro-inflammatory pathways, including IL-17. These findings highlight the strong therapeutic potential of estrogen and estrogenic compounds after SCI.

neuroscience↗

bioRxiv2019

Evaluation of the psychometric properties of the HIV Disability Questionnaire among adults living with HIV in the United Kingdom

ObjectiveTo evaluate the psychometric properties of the HIV Disability Questionnaire (HDQ) among adults living with HIV in London, United Kingdom (UK). MethodsThis is a cross-sectional measurement study. We recruited and administered the self-reported HDQ, seven criterion measures, and a demographic questionnaire with adults living with HIV accessing HIV care. We determined median and interquartile ranges (IQR) for disability presence, severity and episodic scores (range 0-100). We calculated Cronbachs alpha () Kuder-Richardson-20 (KR-20) statistics for disability and episodic scores respectively (internal consistency reliability), smallest detectable change (SDC) for each HDQ severity item and domain (precision), and tested 36 a priori hypotheses assessing correlations between HDQ and criterion scores (construct validity). ResultsOf N=243 participants, all were male, median age 40 years, 94% currently taking antiretroviral therapy, and 22% living with [≥]2 concurrent health conditions. Median HDQ domain scores ranged from 0 (IQR: 0,7) (difficulties with day-to-day activities domain) to 27 (IQR: 14, 41) (uncertainty domain). Cronbachs alpha for the HDQ severity scale ranged from 0.85 (95% Confidence Interval (CI): 0.80-0.90) in the cognitive domain to 0.93 (95%CI: 0.91-0.94) in the mental-emotional domain. The KR-20 statistic for the HDQ episodic scale ranged from 0.74 (95%CI: 0.66-0.83) in the cognitive domain to 0.91 (95%CI: 0.89-0.94) in the uncertainty domain. SDC ranged from 7.3-15.0 points on the HDQ severity scale for difficulties with day-to-day activities and cognitive symptoms domains, respectively. The majority of the construct validity hypotheses (n=30/36, 83%) were confirmed. ConclusionsThe HDQ possesses internal consistency reliability and construct validity with varied precision when administered to males living with HIV in London, UK. Clinicians and researchers may use the HDQ to measure the nature and extent of disability experienced by PLHIV in the UK, and to inform HIV service provision to address the health-related challenges among PLHIV.

epidemiology↗

bioRxiv2018

Genetic evidence that the latency III stage of Epstein-Barr Virus infection is a therapeutic target for Multiple Sclerosis

Genome wide association studies have identified >200 susceptibility loci accounting for much of the heritability of Multiple Sclerosis (MS). Epstein Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS, with evidence for disease causation. The molecular and immunological basis for this has not been established. LCL proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. We show that the CD40 ligand, CD40L, potentially through competitive signalling with LMP1, reduces LCL proliferation (p<0.001). The MS risk variants of the LMP1 signalling inhibitor, TRAF3, had altered expression in B cells and LCLs. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2. We have investigated transcriptomes of B cells and EBV infected B cells at Latency III (LCLs) and identified 47 MS risk genes with altered expression, associated with the risk genotype. Overall these MS risk SNPs were overrepresented in target loci of the EBV transcription factor EBNA2 (p<10-16), in genes dysregulated between B and LCLs (p<10-5), and as targets for EBV miRNAs (p<10-4). The risk gene ZC3HAV1 is the putative target for multiple EBV miRNAs. It amplifies the interferon response, and was shown to have reduced expression in LCLs for the risk allele. These data indicate targeting EBV EBNA2, miRNAs, and MS risk genes on the LMP1/LMP2 pathways, and the pathways themselves, may be of therapeutic benefit in MS.

genomics↗