Biology subjects

Stanley, J.

Publications and source records attributed to Stanley, J..

9 recordsLinked to original sources

bioRxiv2026

Mapping Alzheimer's neuropathology signatures to the whole brain transcriptome using machine learning data fusion

In Alzheimer's disease (AD), misfolded proteins emerge across the entire brain in structured, yet not rigid, spatiotemporal patterns. Yet, a systematic bias of single-cell genomics toward sampling mostly cortical tissue limits our understanding of the whole-brain transcriptomic vulnerability to AD. Here, we develop a machine learning method to extrapolate local AD neuropathology signatures to the whole brain. By analyzing gene expression profiles of over two million cortical cells from 427 humans spanning the AD-pathology spectrum, we derive transcriptomic estimators of AD neuropathology. After extensive validations on datasets with known ground truth, we apply this framework to three million cells from 108 brain regions in the Siletti whole human brain atlas and derive an anticipated brain map of transcriptomic signatures indexing AD neuropathology. This interrogation of regions spanning the cortical, subcortical, and brainstem structures uncovers transcriptomic signatures associated with hyperphosphorylated tau in the medulla oblongata, dorsal raphe nucleus, and the tuberal and mammillary regions of the hypothalamus. At the cellular level, assessments of these signatures across 31 cell populations identify VGLUT1/2 expressing neurons, astrocytes, and microglia as key neuropathology-resembling populations. Within the hippocampus, pathology signatures surface in the rostral cornu ammonis (CA) subfields, particularly in the CA1 pyramidal neurons and dentate granule cells. {beta}-amyloid-like signatures localize to the neocortex with laminar selectivity--most prominently in upper layer somatostatin+ intratelencephalic neurons (L2-L3), but also in deep layer intratelencephalic and corticothalamic neurons (L5-L6). Neocortical astrocytes and microglia exhibiting disease associated signatures similarly demonstrate a unique laminar preference. Together, this study provides the first whole human brain map of AD pathology-associated transcriptomic signals, and exposes cell type, region, and cortex layer specific vulnerabilities.

neuroscience↗

bioRxiv2026

PCR-based assays for determining mating status in field-weathered Ceratitis capitata with enhanced precision across conventional, quantitative, and droplet digital platforms

Accurately determining the mating status of the agricultural fruit fly pest Ceratitis capitata, commonly known as Medfly, is essential for timely and effective eradication efforts. To overcome the limitations of subjective DAPI-based staining assessments of females captured in Jackson dry traps and Multilure liquid traps, we developed a multi-tier molecular diagnostic method that unequivocally detects mating status using DNA probes targeting the male-specific Y114 locus on the Y-chromosome of the species. Our protocol integrates morphological evaluation with increasingly sensitive molecular assays through the following steps: 1) A preliminary quality assessment of the specimens physical condition, DNA preservation, and mating status using conventional PCR followed by agarose electrophoresis (cPCR); 2) Quantification and real-time detection of sperm presence via quantitative PCR (qPCR); and 3) Detection of trace sperm amounts through droplet digital PCR (ddPCR). This PCR-based framework is designed for samples collected in the field, enabling accurate analysis of specimens exposed to adverse environmental conditions and varying levels of preservation after 2- and 3-weeks weathering times in traps. It allows quantitative determination of mating status even when sperm concentrations are extremely low, such as during transient copulation, and achieves detection limits down to approximately 14 spermatozoa in a mated female. By accounting for variable specimen quality and the performance characteristics of each molecular platform, this tiered approach ensures highly sensitive and unequivocal detection of mated females. The methodology can be used to assist eradication efforts across the C. capitata geographic range through the timely detection of mated females, halting their expansion and establishment into novel regions reducing control and eradication costs.

genetics↗

bioRxiv2026

HKDC1 contributes to aberrant lysosome-mitochondria contact in Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder comprising two clinically indistinguishable but genetically distinct subtypes caused by mutations in NPC1, or NPC2. The specific impact of each deficiency on cellular homeostasis remains poorly defined due to the phenotypic heterogeneity of patient-derived models and a lack of isogenic platforms for comparative study. Here we established isogenic ARPE19 models of NPC1 and NPC2 deficiency that faithfully recapitulate hallmark pathologies, including homogeneous lysosomal expansion and lipid sequestration. Direct comparison of these isogenic lines revealed a fundamental divergence in organelle crosstalk: while both genotypes exhibit comparable lipid accumulation, expanded mitochondria-lysosome contact sites (MLCs) are observed exclusively in NPC1-/- cells. Using StARD3-targeted proximity labelling and quantitative proteomics, we identified the mitochondrial protein HKDC1 as an MLC regulator. We demonstrate that HKDC1 is markedly upregulated in NPC1-/- cells and that its overexpression drives MLC expansion in wild-type cells. Thus our study uncovers a homeostatic role for HKDC1-mediated organelle remodelling and demonstrates the power of isogenic modelling for identifying novel regulators of organelle architecture and potential therapeutic targets.

cell biology↗

bioRxiv2025

Learning evoked centrality dynamics in the schizophrenia brain: Entropy, heterogeneity and inflexibility of brain networks

BackgroundBrain network dynamics are responsive to task induced fluctuations, but such responsivity may not hold in schizophrenia (SCZ). We introduce and implement Centrality Dynamics (CD), a method developed specifically to capture task-driven dynamic changes in graph theoretic measures of centrality. We applied CD to fMRI data in SCZ and Healthy Controls (HC) acquired during a learning paradigm. MethodsfMRI (3T Siemens Verio) was acquired in 88 participants (49 SCZ). Time series were extracted from 246 functionally defined cerebral nodes. We applied a dynamic widowing technique to estimate 280 partially overlapping connectomes (30,135 region-pairs in each connectome). In each connectome we calculated every nodes Betweenness Centrality (BC) before building 246 unique time series (representing a nodes CD) from a nodes BC in successive connectomes. Next, in each group nodes were clustered based on similarities in CD. ResultsClustering gave rise to fewer sub-networks in SCZ, and these were formed by nodes with greater functional heterogeneity. These sub-networks also showed greater ApEn (indicating greater stochasticity) but lower amplitude variability (suggesting less adaptability to task-induced dynamics). Higher ApEn was associated with worse clinical symptoms. LimitationsCentrality Dynamics is a new method for network discovery in health and schizophrenia but will need further extension to other tasks and psychiatric conditions, before we achieve a fuller understanding of its promise. ConclusionThe brains functional connectome is not static under task-driven conditions, and characterizing the dynamics of the connectome will provide new insight on the dysconnection syndrome that is schizophrenia. Centrality Dynamics provides novel characterization of task-induced changes in the brains connectome and shows that in the schizophrenia brain, learning-evoked sub-network dynamics were less responsive to learning evoked changes and showed greater stochasticity.

neuroscience↗

bioRxiv2025

Cell type transcriptomics reveal shared genetic mechanisms in Alzheimer's and Parkinson's disease

Historically, Alzheimers disease (AD) and Parkinsons disease (PD) have been investigated as two distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single gene-centric genetic studies, including GWAS and differential gene expression analyses, have struggled to unravel the molecular links between AD and PD. To address this, we tailor a pattern-learning framework to analyze synchronous gene co-expression at sub-cell-type resolution. Utilizing recently published single-nucleus AD (70,634 nuclei) and PD (340,902 nuclei) datasets from postmortem human brains, we systematically extract and juxtapose disease-critical gene modules. Our findings reveal extensive molecular similarities between AD and PD gene cliques. In neurons, disrupted cytoskeletal dynamics and mitochondrial stress highlight convergence in key processes; glial modules share roles in T-cell activation, myelin synthesis, and synapse pruning. This multi-module sub-cell-type approach offers insights into the molecular basis of shared neuropathology in AD and PD.

neuroscience↗

bioRxiv2024

Physiological Processing of Aversiveness in the Mind's Ear: Comparing Audiovisual, Auditory and Imagined Auditory Affective Stimuli

Understanding the somatovisceral responses to auditory affective imagery has important implications in disorders like misophonia. The current study compared physiological responses to aversive and nonaversive states across three modalities: audiovisual, auditory, and auditory imagery. Electromyographic activity over corrugator supercilii (EMGc) and zygomaticus major (EMGz), electrodermal activity (EDA), heart rate (HR), and finger skin temperature (SKT) were measured. There was significant differentiation in EMGc, EDA, and HR deceleration between aversive and nonaversive audiovisual stimuli. EMGc potentiation was the only physiological measure showing consistent differentiation across the three modalities. Cross-modal aversiveness classification results revealed a similar physiological response pattern between audiovisual and auditory modalities. The physiological response pattern during auditory affective imagery was useful for predicting the aversiveness in audiovisual modality but not the other way around. Vividness in auditory imagery correlated with subjective hedonic valence ratings, but not physiological responses. Taken together, the current data suggest that the aversiveness of auditory imagery is differentiable in subjective affective experience and facial muscle potentiation. These results of the physiological responses to imagined aversive sounds in nonclinical population would serve as a comparison baseline for the study of misophonia.

physiology↗

bioRxiv2023

Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that significant morphological changes in BAT mitochondria and cristae would be present with aging. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/540609v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@96099borg.highwire.dtl.DTLVardef@50b4f4org.highwire.dtl.DTLVardef@983092org.highwire.dtl.DTLVardef@19ceb9b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Overview of serial block facing-scanning electron microscopy (SBF-SEM) workflow, data segmentation, and 3D analysis of mitochondria using Amira software for murine interscapular BAT. C_FIG

biophysics↗

bioRxiv2022

High-content phenotypic screen to identify small molecule enhancers of parkin-dependent ubiquitination and mitophagy

Mitochondrial dysfunction and aberrant mitochondrial homeostasis are key aspects of Parkinsons disease (PD) pathophysiology. Mutations in PINK1 and Parkin proteins lead to autosomal recessive PD, suggesting that defective mitochondrial clearance via mitophagy is key in PD etiology. Accelerating the identification and/or removal of dysfunctional mitochondria could therefore provide a disease-modifying approach to treatment. To that end, we performed a high-content phenotypic screen (HCS) of ~125,000 small molecules to identify compounds that positively modulate mitochondrial accumulation of the PINK1-Parkin-dependent mitophagy initiation marker p-Ser65-Ub in Parkin haploinsufficiency (Parkin +/R275W) human fibroblasts. Following confirmatory counter-screening and orthogonal assays, we selected compounds of interest that enhance mitophagy-related biochemical and functional endpoints in patient-derived fibroblasts. Identification of inhibitors of the ubiquitin-specific peptidase and negative regulator of mitophagy USP30 within our hits further validated our approach. The compounds identified provide a novel starting point for further investigation and optimisation.

cell biology↗

bioRxiv2020

Phosphine: an eco-friendly alternative for management of wheat storage insects

Methyl bromide (MB) fumigant has been phased out in many countries honouring Montreal Protocol. Reports on phosphine fumigant efficacy under different ecological zones in India are scanty. Field fumigation trials were conducted on 5 Metric Tons of wheat stacks per replication of a treatment for testing phosphine efficacy against laboratory cultured and resident population of Tribolium castanium, Sitophilus oryzae, and Rhyzopertha dominica. The trials were organized in triplicate including control at two locations with varying climate locations namely, Pithoragarh and Delhi using conventional 56% tablet (2 and 3 tablet/MT) and 77.5% granular (1.0 and 1.5 g phosphine/m3) formulations of Aluminium phosphide (AlP) for 7 and 10-days exposure periods for each dosage. Phosphine concentration was monitored every 24 hours till end of the exposure periods. Insect mortality of laboratory culture and resident infestation was observed as 100% in both the exposure periods using all dosages of phosphine. No emergence of insects was observed till 60 days after treatment at both the locations, indicating mortality of all available life stages of insects during the exposure periods. Minimum effective phosphine concentration for controlling all life stages of S. oryzae, R. dominica and T castaneum was observed 500-600 ppm for 7-days exposure at 25{degrees}-27{degrees}C and humidity 38-45%, at 1.5 g phosphine/m3. Hence, phosphine can be an effective alternative to methyl bromide fumigant for wheat stored grain insects at different climatic conditions.

ecology↗