Biology subjects

Hutchinson, J.

Publications and source records attributed to Hutchinson, J..

4 recordsLinked to original sources

bioRxiv2024

Differential expression of sex regulatory genes in gonads of Astyanax mexicanus surface fish and cavefish

BackgroundAstyanax mexicanus is a single species of fish that consists of river-dwelling (surface) and cave-dwelling morphotypes. Little is known about how sexual determination, differentiation or reproduction have evolved in the surface morphs or cavefish, though divergence in reproductive strategy is expected as the latter have adapted to the novel cave environment. Evolution of the gonad transcriptome may underlie the differences in gamete morphology, fertility, and fecundity previously reported between morphotypes. ResultsWe compared the ovary and testis transcriptome of surface fish and cavefish at juvenile and adult stages. We found that samples clustered by developmental stage, sex, and morphotype identity. Several key genes that are typically associated with the female gonad in other vertebrates showed a reversal in sexual dimorphism or were not differentially expressed between sexes in A. mexicanus. In contrast, while gene expression typically associated with male gonads was largely conserved and consistent with vertebrate testicular expression profiles. Transcriptional and physiological differences between surface fish and cavefish morphotypes were observed in gonads from both sexes. Cavefish ovaries exhibited unique upregulation of neuron development and differentiation genes, and extensive innervation of the ovarian epithelium, while cavefish testes showed increased expression of angiogenesis regulating genes, and greater vasculature density compared to surface fish testes. ConclusionsThese results reveal significant gene expression differences between A. mexicanus surface fish and cavefish morphotypes that may have functional consequences in gonad morphogenesis and fertility. Our findings provide a foundation for investigating the evolution of sex regulatory pathways and reproductive strategies in animals adapting to new and challenging environments in which nutrient availability, temperature, and mate selection are suboptimal.

evolutionary biology↗

bioRxiv2024

A novel biomechanical model of the mouse forelimb predicts muscle activity in optimal control simulations of reaching movements

Mice are key model organisms in neuroscience and motor systems physiology. Fine motor control tasks performed by mice have become widely used in assaying neural and biophysical motor system mechanisms. Although fine motor tasks provide useful insights into behaviors which require complex multi-joint motor control, there is no previously developed physiological biomechanical model of the adult mouse forelimb available for estimating kinematics nor muscle activity or kinetics during behaviors. Here, we developed a musculoskeletal model based on high-resolution imaging of the mouse forelimb that includes muscles spanning the neck, trunk, shoulder, and limbs. Physics-based optimal control simulations of the forelimb model were used to estimate in vivo muscle activity present when constrained to the tracked kinematics during reaching movements. The activity of a subset of muscles was recorded and used to assess the accuracy of the muscle patterning in simulation. We found that the synthesized muscle patterning in the forelimb model had a strong resemblance to empirical muscle patterning, suggesting that our model has utility in providing a realistic set of estimated muscle excitations over time when given a kinematic template. The strength of the similarity between empirical muscle activity and optimal control predictions increases as mice performance improves throughout learning of the reaching task. Our computational tools are available as open-source in the OpenSim physics and modeling platform. Our model can enhance research into limb control across broad research topics and can inform analyses of motor learning, muscle synergies, neural patterning, and behavioral research that would otherwise be inaccessible. NEW & NOTEWORTHYInvestigations into motor planning and execution lack an accurate and complete model of the forelimb, which could bolster or expand on findings. We sought to construct such a model using high detail scans of murine anatomy and prior research into muscle physiology. We then used the model to predict muscle excitations in a set of reaching movements and found that it provided accurate estimations and provided insight into an optimal-control framework of motor learning.

bioengineering↗

bioRxiv2021

Low effective mechanical advantage of giraffes' limbs during walking reveals trade-off between limb length and locomotor performance

Giraffes (Giraffa camelopardalis) possess specialised locomotor morphology, namely elongate and gracile distal limbs. Whilst this contributes to their overall height (and enhanced feeding behaviour), we propose that the combination of long limb segments and modest muscle lever arms results in low effective mechanical advantage (EMA, the ratio of in-lever to out-lever moment arms), when compared with other cursorial mammals. To test this, we used a combination of experimentally measured kinematics and ground rection forces (GRFs), musculoskeletal modelling, and inverse dynamics to calculate giraffe forelimb EMA during walking. Giraffes walk with an EMA of 0.34 ({+/-}0.05 S.D.), with no evident association with speed within their walking gait. Giraffe EMA was markedly below the expectations extrapolated from other mammals ranging from 0.03 - 297 kg, and provides further evidence that EMA plateaus or even diminishes in mammals exceeding horse size. We further tested the idea that limb segment length is a factor which determines EMA, by modelling the GRF and muscle moment arms in the extinct giraffid Sivatherium giganteum and the other extant giraffid Okapia johnstoni. Giraffa and Okapia shared similar EMA, despite a 4-6 fold difference in body mass (Okapia EMA = 0.38). In contrast Sivatherium, sharing a similar body mass to Giraffa, had greater EMA (0.59), which we propose reflects behavioural differences, such athletic performance. Our modelling approach suggests that limb length is a determinant of GRF moment arm magnitude, and that unless muscle moment arms scale isometrically with limb length, tall mammals are prone to low EMA. Significance StatementGiraffes are the tallest living animals - using their height to access food unavailable to their competitors. It is not clear how their specialized anatomy impacts their athletic ability. We made musculoskeletal models of the forelimbs from a giraffe and two close relatives, and used motion-capture and forceplate data to measure how efficient they are when walking in a straight line. A horse for example, uses just 1 unit of muscle force to oppose 1 unit of force on the ground. Giraffe limbs however are comparatively disadvantaged - their muscles must develop 3 units of force to oppose 1 unit of force at the ground. This explains why giraffes walk and run at relatively slow speeds.

biophysics↗

bioRxiv2020

Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

Severe 1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant 1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z 1-antitrypsin. The lead compound blocks Z 1-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z 1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z 1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that mutation ameliorating small molecules are a viable approach to treat protein conformational diseases.

pharmacology and toxicology↗