Biology subjects

Edwards, B.

Publications and source records attributed to Edwards, B..

3 recordsLinked to original sources

bioRxiv2022

Introduction of a condensed, reverse tricarboxylic acid cycle for additional CO2 fixation in plants

Plants employ the Calvin-Benson cycle (CBC) to fix atmospheric CO2 for the production of biomass. The flux of carbon through the CBC is limited by the activity and selectivity of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO). Alternative pathways that do not use RuBisCO to fix CO2 exist but occur only in anaerobic microorganisms. Rather than modifying existing routes of carbon metabolism in plants, we have developed a synthetic carbon fixation cycle that does not exist in nature, but is inspired by metabolisms of bacterial autotrophs. This synthetic cycle uses endogenous plant metabolites to fix CO2 and yield glyoxylate as a product. In this work, we build and characterize a condensed, reverse tricarboxylic acid (crTCA) cycle in vitro and in planta. We demonstrate that a simple, synthetic cycle can be used to fix carbon in vitro under aerobic and mesophilic conditions and that these enzymes retain activity when expressed transiently in planta. We then evaluate stable transgenic lines of Camelina sativa that have both phenotypic and physiologic changes. Transgenic C. sativa are shorter than controls with increased rates of photosynthetic CO2 assimilation and changes in photorespiratory metabolism. This first iteration of a build-test-learn phase of the crTCA cycle provides promising evidence that this pathway can be used to increase photosynthetic capacity in plants.

plant biology↗

bioRxiv2022

Dogma and belief: the primary lesion in age-related hearing loss is old news

Presbycusis, or age-related hearing loss, is the most common sensory deficit globally, and the biggest modifiable risk factor for a later dementia diagnosis. Despite its ubiquity, however, the primary pathology contributing to presbycusis is reportedly contentious, particularly the relative role of damage to the sensory outer hair cells compared to the stria vascularis, an important inner ear structure that maintains the ionic concentration of inner ear fluids that surround it. To determine what might be the "dogma" of the field regarding the primary pathology in presbycusis, we conducted an online Google survey (https://forms.gle/GPreoePmRxBBkchc7) asking relevant respondents in the field their opinions on the matter. In Question (Q1), respondents were asked to rate in your opinion from least likely to most likely (on a scale 1 to 4 [being most likely]) what is the primary pathology contributing to presbycusis? in terms of damage to: i) the inner hair cells, ii) outer hair cells (OHCs), iii) spiral ganglion, iv) stria vascularis. The term dogma suggests that the proportion of people in the field who believe that the main cause of presbycusis is damage to the stria vascularis is at least 50%. The results of our survey estimated this proportion to be 19/101 = 0.188 (95% CI [0.124 0.275]) and a two-sided test of the null hypothesis that this proportion is at least 0.5 was rejected (p < 10-10). When it came to opining what other professionals in the field consider to be the primary pathology contributing to presbycusis (Q2), the tendency to rank damage to OHCs as being the primary pathology was 45%. Stria vascularis was least likely to be ranked 4 (11%) by professionals in the field opining about the beliefs of others. Even when noise damage was excluded as a factor (Q3), the most likely contributing factor to presbycusis was stated to be damage to the OHCs (42%). Our data suggest the dogma of the field is that damage to outer hair cells is the primary pathology in presbycusis.

neuroscience↗

bioRxiv2021

Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.

pathology↗