Biology subjects

Hanson, S.

Publications and source records attributed to Hanson, S..

8 recordsLinked to original sources

bioRxiv2025

Non-segmented unsupervised learning of multispectral whole slide images for robust analysis of tissue repair and regeneration

Analyzing whole tissue architecture remains challenging due to the inherent complexity of multicellular organization, variable morphology, and the limitations of conventional segmentation-based image analysis. Traditional approaches often rely on partial sampling or nuclear/cytoplasmic boundaries, which risk introducing bias and fail to capture the contextual interplay of diverse tissue compartments. To overcome these barriers, we developed a segmentation free framework for analyzing multispectral whole slide images (WSIs). By tiling WSIs into fixed sized regions and extracting quantitative tile features, we applied unsupervised machine learning to systematically reveal patterns of tissue organization at scale. This approach preserved spatial context without the need for cell-level delineation, recapitulating expected compartments such as epidermis, adipose, and scab, while also revealing subtle but coherent substructures within stromal and granulation regions. Applied to murine wound healing, the method distinguished wild type from diabetic repair dynamics without prior labels, uncovering both gross and nuanced differences in tissue composition. Together, this work establishes a robust, unbiased strategy for whole-tissue analysis that circumvents the limitations of segmentation, leverages unsupervised learning for discovery, and advances the study of tissue repair and regenerative pathology.

cell biology↗

bioRxiv2025

Correlates of head-fixed orienting movements in mouse superior colliculus and substantia nigra pars reticulata

Orienting movements are a critical component of the natural behavioral repertoire, but their underlying neural bases are not well understood. The deep superior colliculus (dSC) integrates input from several brain regions that influence the selection of targets for orienting movements and coordinates activity among brainstem motor nuclei to initiate and execute movement. Evidence suggests that one prominent dSC input, the substantia nigra pars reticulata (SNr), permits movement by disinhibiting its targets, but much is unknown about the relationship between SNr activity, dSC activity, and movement. Building on increasing application of the head-fixed mouse model to elucidate the neural basis of behavior, we examined neural activity recorded in dSC and SNr with high-density probes in mice performing several variants of a sensorimotor orienting task, from our labs and in data sets curated by the International Brain Laboratory. We found that dSC and SNr were active preceding and throughout movement, across task variants, suggesting that they were engaged by the required movements. Prior to movement, SNr activity reflected the outcome of the previous trial, consistent with a role in biasing movements towards the highest value target. However, the dependence of dSC activity on movement direction was weaker than in other directional orienting behaviors, and we found little evidence for strong suppression of dSC by SNr. These results complement and extend previous findings from other orienting tasks and suggest diverse roles for modulatory input from SNr to dSC in shaping motor behavior.

neuroscience↗

bioRxiv2024

Neural substrates for saccadic modulation of visual representations in mouse superior colliculus

How do sensory systems account for stimuli generated by natural behavior? We addressed this question by examining how an ethologically relevant class of saccades modulates visual representations in the mouse superior colliculus (SC), a key region for sensorimotor integration. We quantified saccadic modulation by recording SC responses to visual probes presented at stochastic saccade-probe latencies. Saccades significantly impacted population representations of the probes, with early enhancement that began prior to saccades and pronounced suppression for several hundred milliseconds following saccades, independent of units visual response properties or directional tuning. To determine the cause of saccadic modulation, we presented fictive saccades that simulated the visual experience during saccades without motor output. Some units exhibited similar modulation by fictive and real saccades, suggesting a sensory-driven origin of saccadic modulation, while others had dissimilar modulation, indicating a motor contribution. These findings advance our understanding of the neural basis of natural visual coding.

neuroscience↗

bioRxiv2024

Multimodal classification of neurons in the lateral septum

The lateral septum (LS) is a ventral forebrain nucleus that modulates complex social and affective behaviors. These behaviors emerge from heterogeneous neuronal populations whose molecular identity and developmental origins remain poorly defined. We profiled the transcriptional identity of mature LS neurons derived from two progenitor lineages distinguished by their embryonic origin and Nkx2.1 expression history, identifying 22 molecularly distinct subtypes. Nkx2.1-lineage neurons are enriched for select cell adhesion and communication molecules; however, subtypes from distinct developmental origins can converge onto similar molecular profiles when residing within the same LS subregion. The graded expression of genes related to synaptic signaling is a primary axis defining the taxonomy of LS neurons. Using transcriptional markers, we labeled non-overlapping neuronal populations and characterized their connectivity, morphology, and electrophysiology. Together, these findings define the extent of LS neuronal diversity and provide a framework for understanding how complex behaviors are regulated by the LS.

neuroscience↗

bioRxiv2023

A spatially resolved single cell genomic atlas of the adult human breast

The adult human breast comprises an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue. While previous studies have mainly focused on the breast epithelial system, many of the non-epithelial cell types remain understudied. Here, we constructed a comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics data profiled 535,941 cells from 62 women, and 120,024 nuclei from 20 women, identifying 11 major cell types and 53 cell states. These data revealed abundant pericyte, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Our spatial mapping using three technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells in the ducts and lobules, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide an unprecedented reference of adult normal breast tissue for studying mammary biology and disease states such as breast cancer.

genomics↗

bioRxiv2023

Temporal Dynamics of Activity in Default Mode Network Suggests a Role in Top-down processing

The default mode network (DMN) is a collection of brain regions including midline frontal and parietal structures, medial and lateral temporal lobes, and lateral parietal cortex. Although there is evidence that the network can be subdivided into at least two subcomponents, the network reliably exhibits highly correlated activity both at rest and during task performance. Current understanding regarding the function of the DMN rests on a large body of research indicating that activity in the network decreases during task epochs of experimental paradigms relative to inter-trial intervals. A seeming contradiction arises when the experimental paradigm includes tasks involving autobiographical memory, thinking about ones self, planning for the future, or social cognition. In such cases, the DMNs activity increases and is correlated with attentional networks. Some have therefore concluded that the DMN supports advanced human cognitive abilities such as interoceptive processing and theory of mind. This conclusion may be called into question by evidence of correlated activity in homologous brain regions in other, even non-primate, species. Thus, there are contradictory findings related to the function of the DMN that have been difficult to integrate into a coherent theory regarding its function. Using data from the Human Connectome Project, we explore the temporal dynamics of activity in different regions of the DMN in relation to stimulus presentation. We show that generally the dorsal portion of the network exhibits only a transient initial decrease in activity at the start of trials that increases over trial duration. The ventral component often has more similarity in its time course to that of task-activated areas. We propose that task-associated ramping dynamics in the network are incompatible with a task-negative view of the DMN and propose the dorsal and ventral sub-components of network may rather work together to support bottom-up salience detection and subsequent top-down voluntary action. In this context, we re-interpret the body of anatomical and neurophysiological experimental evidence, arguing that this interpretation can accommodate the seeming contradictions regarding DMN function in the extant literature.

neuroscience↗

bioRxiv2022

Specificity, synergy, and mechanisms of splice-modifying drugs

Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5 splice site sequences, suggest that branaplam recognizes 5 splice sites via two distinct interaction modes, and disprove the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.

biophysics↗

bioRxiv2018

Whole Genome Sequencing of Primary Immunodeficiency reveals a role for common and rare variants in coding and non-coding sequences

Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

immunology↗