Biology subjects

Hanson, L.

Publications and source records attributed to Hanson, L..

10 recordsLinked to original sources

bioRxiv2026

Cooperative processing of visual threat across collicular pathways

Rapid defensive actions require the transformation of sensory cues into appropriate motor responses. The superior colliculus is central to this transformation, containing defined cell-types that form parallel output pathways linking visual inputs to distinct behaviors. However, whether these pathways act independently or cooperate remains unclear. Here we combine cell-type-specific inhibition, large-scale electrophysiology, and functional ultrasound imaging to determine how these pathways contribute to visually evoked defensive behaviors. Inhibiting either narrow-field or wide-field neurons impaired escape to overhead visual threats, demonstrating that both pathways contribute to escape. Recordings from downstream targets revealed a compact representation in the deeper layers of the superior colliculus that selectively distinguished visual stimuli associated with escape, whereas the lateral posterior thalamus contained a broader representation of visual stimuli. The representation of visual threat in the deeper layers of the superior colliculus predicted escape initiation and vigor in freely moving animals. Across the brain, functional ultrasound imaging showed that visual stimuli recruited distinct patterns of activity that could not be explained by response magnitude alone or by the contribution of single cell-types. Together, these results reveal a cooperative circuit architecture in which parallel pathways carry distinct but complementary signals that jointly support visually evoked escape.

neuroscience↗

bioRxiv2026

A Candida glabrata adhesin-like effector drives fitness and immunogenicity in the gut

Candida glabrata is a leading cause of invasive candidiasis. The gut serves as its primary reservoir, yet factors governing colonization and pathogenic potential remain poorly defined. Here, we identify immunoglobulin A (IgA) as a key regulator of C. glabrata within the intestinal microbiome. We found that C. glabrata induces an IgA response in a strain-specific manner. Comparative transcriptional and proteomic analyses of IgA-inducing and non-inducing strains identified a putative adhesin, Awp11, whose expression correlated with IgA induction. Awp11 is directly targeted by IgA and is required for inducing C. glabrata-specific IgA and Th17 responses in vivo. Functionally, Awp11 promotes colonization of a complex intestinal microbiome, and intestinal IgA limits this advantage. In most strains, AWP11 transcription is dynamic and limited by IgA in the gut. This identifies Awp11 as a key determinant of strain-dependent immunogenicity and gut colonization that C. glabrata may dynamically regulate to balance colonization and immune evasion.

immunology↗

bioRxiv2024

Stress-driven emergence of heritable non-genetic drug resistance

Drug resistance is the chief cause of treatment failure for therapies targeting chronic and infectious diseases. Whether the emergence of resistance is accelerated by environmental exposure to low levels of therapeutics remains controversial. Here, we report a non-genetic mechanism of stress adaptation that promotes heritable resistance to the widely used antifungal drug fluconazole. In the human fungal pathogen Candida albicans, transient exposure to subtherapeutic fluconazole doses induces a protective response that we term para-resistance. Like conventional resistance mechanisms, para-resistance is heritable. However, it does not arise from genetic mutations and can revert spontaneously. Systematic analyses of para-resistant isolates suggest that its key regulators include the stress-activated MAP kinase Hog1, the histone deacetylase subunit Snt1, the chromatin regulator Rap1, and the Sko1 transcriptional factor. Notably, molecules that disrupt biomolecular condensation and prion propagation - crucial for the inheritance of protein assemblies - block the induction of para-resistance, whereas inhibiting histone deacetylases facilitates its induction. We find that para-resistance is common in clinical isolates and, remarkably, passage through the mammalian gut triggers its acquisition, compromising fluconazoles therapeutic efficacy. Our work defines a pervasive, prion-like epigenetic mechanism of stress adaptation and highlights potential strategies to mitigate the rapid emergence of drug resistance.

microbiology↗

bioRxiv2024

A standard area diagram for Fusarium yellows rating in sugar beet (Beta vulgaris L.)

Members of the Fusarium oxysporum species complex are pathogens of sugar beet causing Fusarium yellows. Fusarium yellows can reduce plant stand, yield, and extractable sugar. Improving host plant resistance against Fusarium-induced diseases, like Fusarium yellows, represents an important long-term breeding target in sugar beet breeding programs. Current methods for rating Fusarium yellows disease severity rely on an ordinal scale, which limits precision for intermediate phenotypes. In this study, we aimed to improve the accuracy and precision of rating Fusarium yellows by developing a standard area diagram (SAD). Two SAD versions were created using images of sugar beets infected with Fusarium oxysporum strain F19. Each version was tested using inexperienced raters. Comparing both the pilot and improved version showed no statistical differences in Lins Concordance Correlation Coefficient (LCC) values to assess accuracy and precision between the two versions (Cb = 0.99 for both versions, {rho}c = 0.97 and 0.96 for version 1 and 2, respectively). In addition, five naive Bayesian machine learning models which used pixel classification to determine disease score, were tested for congruency to human estimates in version 2. Root mean square error was lowest compared to the "true" values for the unweighted model and a model where necrotic tissue was given a 2x weight (12.4 and 12.6, respectively). The creation of this standard area diagram enables breeding programs to make consistent, accurate disease ratings regardless of personnels previous experience with Fusarium yellows. Additionally, more iterations of pixel quantification equations may overcome accuracy issues for rating Fusarium yellows.

plant biology↗

bioRxiv2023

Registration of sugar beet genetic stocks FC308 (PI701378) and FC309 (PI700990)

Sugar beet (Beta vulgaris L.) genetic stock lines FC308 (PI701378) and FC309 (PI700990) are two highly homozygous and phenotypically homogenous sources of resistance to two sugar beet pests. FC308 is resistant to sugar beet cyst nematode (Heterodera schachtii), but susceptible to Fusarium yellows, while FC309 is Fusarium yellows resistant, but sugar beet cyst nematode susceptible. These two populations were developed by the USDA-ARS in Fort Collins, CO, derived from unreleased USDA-ARS Salinas germplasm lines. Multiple field and greenhouse trials for Fusarium yellows and nematode resistance confirmed the uniform phenotypes of both lines for each disease. To enable molecular breeders to rapidly screen proprietary markers in silico, gene space assemblies for each line were also developed. Genome sequencing of individual plants from each line, as well as pooled sequencing of sub-populations of both lines indicated fixation of a previously reported genetic variant linked to sugar beet cyst nematode resistance in FC308. However, two previously reported variants linked to Fusarium resistance appear to be unlinked to the resistance found in FC309. Collectively, these two new genetic stocks should prove useful as sources of resistance to Fusarium yellows and sugar beet cyst nematode, as model genetic backgrounds for studying plant-pathogen interactions, and for mapping the resistance genes present in these lines.

plant biology↗

bioRxiv2022

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.

PurposeNovel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Experimental designSmall molecule KRASG12C inhibitors AZ1569 and AZ8037 were employed. To identify novel candidate combination strategies for AZ1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ1569-resistant CRC cells were generated and characterised. ResultsResponse to AZ1569 was heterogeneous across the KRASG12CMT models. AZ1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. ConclusionsCombinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients.

cancer biology↗

bioRxiv2021

Gain control by sparse, ultra-slow glycinergic synapses

SO_SCPLOWUMMARYC_SCPLOWRetinal ON starburst amacrine cells (SACs) play a critical role in computing stimulus direction, partly in service of image stabilization by optokinetic nystagmus. ON SAC responses are sculpted by rich GABAergic innervation, mostly from neighbouring SACs. Surprisingly, however, we find that glycinergic narrow field amacrine cells (NACs) serve as their dominant source of inhibition during sustained activity. Although NAC inputs constitute only [~]5% of inhibitory synapses to ON SACs, their distinct input patterns enable them to drive glycine inhibition during the both light increments and decrements. NAC-to-ON-SAC inhibition appears to be mediated by ultra-slow non-canonical glycine receptors containing the 4 subunit, which effectively summate during repetitive stimulation. Glycinergic inhibition strongly decreases the output gain of the SACs, ensuring that their direction-selective output is maintained over their operating range. These results reveal an unexpected role for glycinergic pathways and receptor kinetics in modulating direction selectivity in the retina.

neuroscience↗

bioRxiv2019

Magnetic manipulation of axonal endosome transport in live neurons

Noninvasive control of axonal cargos in live neurons is a challenging prospect that can enable novel research on the mechanisms of axonal cargo transport, cargo-mediated signaling and axonal traffic jams in neurons. However, conventional techniques for force manipulation such as optical traps are limited to a few micron-sized cargos and are not applicable to the small axonal cargos in live neurons. Here, we present a new methodology that permits the external control of axonal endosome transport via tailored magnetic forces. By culturing neurons in a microfluidic device made up of microfabricated magnetic arrays, we can exert 3 - 48 pN forces on retrograde axonal endosomes carrying fluorescent magnetic nanoparticles, 100 - 260 nm in size. The magnetic force counters the forces exerted by molecular motors driving the endosomes and results in a wide range of perturbations on endosome transport in axons. These perturbations, captured by oblique illumination fluorescence imaging, reveal new insights on the collective function of dyneins and the nature of paused and stationary states during retrograde endosome transport in axons. Most notably, we demonstrate controllable capture and release of retrograde endosomes in axons by toggling the external magnetic field. This technical advance has great potential to elucidate the spatiotemporal origins of long-distance endosome signaling pathways as well as the ramifications of axonal traffic jams in neurons.

biophysics↗

bioRxiv2018

Retinal direction selectivity in the absence of asymmetric starburst amacrine cell responses

SO_SCPLOWUMMARYC_SCPLOWIn the mammalian retina, asymmetric inhibitory signals arising from the direction-selective dendrites of GABAergic/cholinergic starburst amacrine cells are thought to be crucial for originating direction selectivity. Contrary to this notion, however, we found that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst output is rendered non-directional (using a novel strategy combining a conditional GABAA 2 receptor knockout mouse with optogenetics). We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cells receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that shape directional responses in ganglion cells are shaped by two core mechanisms, both arising from distinct specializations of the starburst network.

neuroscience↗

bioRxiv2017

Nanoscale Manipulation Of Membrane Curvature For Probing Endocytosis In Live Cells

Clathrin-mediated endocytosis (CME) involves nanoscale bending and inward budding of the plasma membrane, by which cells regulate both the distribution of membrane proteins and the entry of extracellular species1,2. Extensive studies have shown that CME proteins actively modulate the plasma membrane curvature1,3,4. However, the reciprocal regulation of how plasma membrane curvature affects the activities of endocytic proteins is much less explored, despite studies suggesting that membrane curvature itself can trigger biochemical reactions5-8. This gap in our understanding is largely due to technical challenges in precisely controlling the membrane curvature in live cells. In this work, we use patterned nanostructures to generate well-defined membrane curvatures ranging from +50 nm to -500 nm radius of curvature. We find that the positively curved membranes are CME hotspots, and that key CME proteins, clathrin and dynamin, show a strong preference toward positive membrane curvatures with a radius < 200 nm. Of ten CME related proteins we examined, all show preferences to positively curved membrane. By contrast, other membrane-associated proteins and non-CME endocytic protein, caveolin1, show no such curvature preference. Therefore, nanostructured substrates constitute a novel tool for investigating curvature-dependent processes in live cells.

cell biology↗