Biology subjects

Harris, S. C.

Publications and source records attributed to Harris, S. C..

7 recordsLinked to original sources

bioRxiv2025

Partial Input Loss Differentially Modifies Neural Pathways

Following input loss from degeneration, injury, and/or aging, downstream circuits undergo modifications that can impact neural computations. How neural computations across different pathways are affected by common input loss remain understudied. To leverage known cell types, well-defined circuitry, and molecular tools, we use the mouse retina to show how multiple pathways adjust their functional properties differently to common input loss and further locate these changes within each pathway. Specifically, we asked if two OFF ganglion cell types, alpha OFF-sustained (AOFF-S) and OFF-transient (AOFF-T) cells, and their respective dominant presynaptic partners, type 2 and type 3a cone bipolar cells, respond differentially to partial cone loss. We find that AOFF-T ganglion cells exhibit more circuit changes than AOFF-S ganglion cells, resulting in altered spatiotemporal tuning following partial cone loss. We show that the underlying mechanisms include changes in glutamatergic, GABAergic, and glycinergic circuits in the pathway of AOFF-T ganglion cells. In response to common input loss, our study finds different locations of circuit modifications across OFF pathways. These findings provide insight into how sensory pathways can compensate differentially to common input loss.

neuroscience↗

bioRxiv2024

Tau P301S Transgenic Mice Develop Gait and Eye Movement Impairments That Mimic Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available. The contribution of Tau pathology to the symptoms of patients with PSP is poorly understood, in part due to lack of a rodent model that recapitulates characteristic aspects of PSP. Here, we assessed the hTau.P301S mouse for key clinical features of PSP, finding progressive impairments in balance and gait coordination. Additionally, we found impairments in fast vertical eye movements, one of the most distinctive features of PSP. Across animals, we found that Tau pathology in motor control regions correlated with motor deficits. These findings highlight the utility of the hP301S mouse in modeling key aspects of PSP.

neuroscience↗

bioRxiv2024

Evolution is coupled with branching across many granularities of life

Across many different scales of life, the rate of evolutionary change is often accelerated at the time when one lineage splits into two. The emergence of novel protein function can be facilitated by gene duplication (neofunctionalisation); rapid morphological change is often accompanied with speciation (punctuated equilibrium); and the establishment of cultural identity is frequently driven by sociopolitical division (schismogenesis). In each case, the change resists rehomogenisation; promoting assortment into distinct lineages that are susceptible to different selective pressures, leading to rapid divergence. The traditional gradualistic view of evolution struggles to detect this phenomenon. We have devised a probabilistic framework that constructs phylogenies, tests hypotheses, and improves divergence time estimation when evolutionary bursts are present. As well as assigning a clock rate of gradual evolution to each branch of a tree, this model also assigns a spike of abrupt change, and independently estimates the contributions arising from each process. We provide evidence of abrupt evolution at the time of branching for proteins (aminoacyl-tRNA synthetases), animal morphologies (cephalopods), and human languages (Indo-European). These three cases provide unique insights: for aminoacyl-tRNA synthetases, the trees are substantially different from those obtained under gradualist models; Cephalopod morphologies are found to evolve almost exclusively through abrupt shifts; and Indo-European dispersal is estimated to have started around 6000 BCE, corroborating the recently proposed hybrid explanation. This work demonstrates a robust means for detecting burstlike processes, and advances our understanding of the link between evolutionary change and branching events. Our open-source code is available under a GPL license.

evolutionary biology↗

bioRxiv2024

An expanded metabolic pathway for androgen production by host-associated bacteria

A growing body of literature implicates host-associated microbiota in the modulation of circulating androgen levels in the host, which could have far-reaching implications for androgen-mediated diseases. However, the microbial genetic pathways involved in androgen production remain unknown. Here, we report the first host-associated microbial gene (desF) encoding an enzyme that catalyzes conversion of androstenedione to epitestosterone (epiT) in the gut bacterium, Clostridium scindens. Despite current dogma that epiT is a nuclear androgen-receptor (AR) antagonist, we demonstrate that epiT is a potent androgen, as assessed by its ability to promote prostate cancer cell growth and expression of prostate specific antigen (PSA). We then quantified the desF gene in fecal samples collected from individuals with advanced prostate cancer (rising blood PSA) undergoing androgen deprivation therapy combined with abiraterone acetate and prednisone (AA/P). Strikingly, fecal desF levels were elevated in a subset of individuals progressing on AA/P versus samples taken during AA/P response (stable). Importantly, we observed that AA does not inhibit the bacterial desmolase enzyme that is analogous to the human drug target of AA. We then determined that bacterial isolates from urine or prostatectomy tissue are capable of androgen production. From these isolates we detected 17{beta}-hydroxysteroid dehydrogenase (17{beta}-HSDH) activity, which has not been previously reported in urinary tract bacteria, and discovered the desG gene in urinary isolates encoding 17{beta}-HSDH that catalyzed conversion of androstenedione to testosterone. Applying advanced artificial intelligence and molecular dynamics, we predict the structures and ligand binding to DesF and DesG. Using a novel bioengineered microencapsulation technique, we demonstrate that urinary androgen-producing bacterial strains can also promote prostate cancer cell growth through steroid metabolism. Taken together, our results are a significant advance for steroid microbiology in humans and suggest that these microbial biotransformations should be further studied in the context of androgen-mediated physiological processes and diseases.

microbiology↗

bioRxiv2024

Modelling the gut microbiota of children with malnutrition: in vitro models reveal differences in fermentability of widely consumed carbohydrates

There is increasing evidence in children suffering from Severe Acute Malnutrition (SAM) that there is disruption of the gut microbiome and low gut microbiota diversity, which may be contributing factors to poor outcomes during nutritional treatment and recovery. The gut microbiome of children with SAM has been demonstrated to have a lower production of beneficial short chain fatty acids, which may contribute to impaired gut barrier function. Recently, several microbiota-directed therapies have been tested in clinical trials in children with SAM. Among them we hypothesized that feeds containing fermentable carbohydrates from various sources (legumes, chicory, milk oligosaccharides) would be fermented to produce beneficial microbial metabolites by the microbiota of children with SAM. In this study we used an in vitro model system inoculated with stool from children with SAM to investigate the fermentability of four substrates; inulin (a chicory-derived fructan), two milk powders (one supplemented with a human milk oligosaccharide) and a chickpea enriched feed. We demonstrated that while the milk powders and chickpea feed were fermented to produce short chain fatty acids, inulin was only fermented to a very limited degree. Through 16S rRNA sequencing we demonstrated that the samples inoculated with inulin had low microbial diversity and linked this to the limited ability to metabolise inulin. Through revealing the fermentability of different complementary feeds, the findings of this study will be of use for the design of future therapeutic feeds for treatment of SAM. ImportanceMalnutrition is a major contributor to childhood mortality globally and is a major public health problem primarily affecting Lower- and Middle-Income Countries. Despite the development of nutritional recovery therapies, for those with the severe and complicated form of malnutrition (SAM), mortality and relapse rates remain high. Emerging evidence suggests a role for the gut microbiome in these poor outcomes, which is known to be significantly altered in children in SAM, compared to healthy age matched controls. To aid in recovery from SAM, nutritional interventions should be designed to support the gut microbiome, using a range of ingredients targeted for colonic fermentation. It is important to understand the fermentation capacity of the gut microbiome of children with SAM, to design future nutritional interventions. In this work, we demonstrate that inulin, a widely used chicory-derived prebiotic, is not a suitable fermentation substrate for the gut microbiome of SAM children, while legume-based formulations and milk oligosaccharides result in increased production of beneficial metabolites.

microbiology↗

bioRxiv2023

A semi-automated method for quantifying optokinetic reflex tracking acuity

The study of murine behavioral responses to visual stimuli is a key component of understanding mammalian visual circuitry. One notable response is the optokinetic reflex (OKR), a highly conserved innate behavior necessary for image stabilization on the retina. The OKR provides a robust readout of image tracking ability and has been extensively studied to understand the logic of visual system circuitry and function in mice from different genetic backgrounds. The OKR consists of two phases: a slow tracking phase as the eye follows a stimulus to the edge of the visual plane, and a compensatory fast phase saccade that maintains the image within the visual field. Assessment of the OKR has previously relied on counting individual compensatory eye saccades to estimate tracking speed. To obtain a more direct quantification of tracking ability, we have developed a novel, semi-automated analysis program that allows for rapid and reproducible quantification of unidirectional tracking gains, in addition to being adaptable to any video-oculography equipment. Our analysis program allows for the selection of slow tracking phases, modeling of the vertical and horizontal eye vectors, quantification of eye movement relative to the stimulus, and organization of resultant data into a usable spreadsheet for statistical and graphical comparisons. This quantitative and streamlined analysis pipeline provides a faster and more direct measurement of OKR responses, thereby facilitating further study of visual behavior responses. SUMMARYWe describe here a semi-automated quantitative analysis method that directly measures eye tracking resulting from murine visual system responses to two-dimensional image motion. A Python-based user interface and analysis algorithm allows for higher throughput and more quantitative measurements of eye tracking parameters than previous methods.

neuroscience↗

bioRxiv2022

Asymmetric retinal direction tuning predicts optokinetic eye movements across stimulus conditions

Across species, the optokinetic reflex (OKR) stabilizes vision during self-motion. OKR occurs when ON direction-selective retinal ganglion cells (oDSGCs) detect slow, global image motion on the retina. How oDSGC activity is integrated centrally to generate behavior remains unknown. Here, we discover mechanisms that contribute to motion encoding in vertically-tuned oDSGCs, and leverage these findings to empirically define signal transformation between retinal output and vertical OKR behavior. We demonstrate that motion encoding in vertically-tuned oDSGCs is contrast-sensitive and asymmetric for oDSGC types that prefer opposite directions. These phenomena arise from the interplay between spike threshold nonlinearities and differences in synaptic input weights, including shifts in the balance of excitation and inhibition. In behaving mice, these neurophysiological observations, along with a central subtraction of oDSGC outputs, accurately predict the trajectories of vertical OKR across stimulus conditions. Thus, asymmetric tuning across competing sensory channels can critically shape behavior.

neuroscience↗