Biology subjects

Dickson, T.

Publications and source records attributed to Dickson, T..

4 recordsLinked to original sources

bioRxiv2025

Early Antibody-Mediated Immunity to Tuberculosis in Mice Requires NLRP3

While antibodies have emerged as potential mediators of protective immunity against Mycobacterium tuberculosis (Mtb), their mechanisms of action remain incompletely understood. Here, we demonstrate that immune complexes of Mtb and monoclonal antibodies targeting the Mtb phosphate transporter subunit PstS1 robustly activate the NLRP3 inflammasome in human and murine macrophages, leading to enhanced interleukin-1{beta} secretion. Surprisingly, antibody-mediated inflammasome activation occurred independently of cell-surface Fc{gamma} receptors, as confirmed using Fc-domain glycosylation mutant mAbs and macrophages from Fc{gamma} receptor-deficient mice. Crucially, NLRP3 is indispensable for early antibody-mediated protection in vivo, as both pharmacological inhibition, and genetic deletion of NLRP3 completely abolished protective effects of PstS1-specific antibodies in Mtb-infected mice. This mechanism extends beyond monoclonal antibodies, as polyclonal sera from intravenously BCG-immunized rhesus macaques also required NLRP3 for protective efficacy. Our findings reveal a previously unrecognized mechanism by which Mtb-specific antibodies enhance host defense through inflammasome activation, potentially informing novel approaches for tuberculosis vaccine development.

immunology↗

bioRxiv2024

Biological sex determines skeletal muscle atrophy in response to cortical TDP-43 pathology

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative condition. In ALS, wasting of skeletal muscle causes weakness, paralysis and ultimately, death due to respiratory failure. Diagnosis of ALS is a long process and delays in diagnosis are common, which impedes rapid provision of patient care and treatment. Additional tools or methodologies that improve early detection might help overcome the diagnostic delays and enhance survival and quality of life for people with ALS. In this study, we used a transgenic mouse model to create a detailed catalogue of skeletal muscle wasting with the goal of finding muscles that can be examined to enhance early diagnosis of ALS. MethodsCortical pathology was induced by crossing CaMKIIa-tTA and tetO-hTDP-43{Delta}NLS transgenic mice ({Delta}NLS). Transgenic expression was induced at 30-days postnatal via removal of doxycycline diet. Mice were aged to 15-, 20-, 30- and 45-days post transgene induction. Microdissection was applied to isolate 22 individual hindlimb muscles for measurement of weight. Both males and females were used at all timepoints. ResultsWe found that male and female {Delta}NLS mice exhibited hindlimb skeletal muscle atrophy relative to controls. Multiply innervated muscles, also known as series-fibered muscles, were especially vulnerable to atrophy. The strongest predictor of the atrophic response across all hindlimb muscles was the extent to which any individual muscle was larger in males than females, known also as sexual dimorphism. In males, muscles that are usually larger in males compared to females experienced the most atrophy. Conversely, in females, muscles that are usually of similar size between males and females experienced the most atrophy. Segregating muscles based on whether they were more affected in males or females revealed that hip extensors, knee flexors, knee extensors, ankle dorsiflexors and ankle evertors were more affected in males. Hip adductors, hip rotators, hip flexors and ankle plantarflexors were more affected in females. ConclusionsOur results demonstrate that the difference in the size of skeletal muscles in males compared to females is the most powerful predictor of muscle atrophy in response to dying forward pathology. This indicates that sex is a strong determinant of skeletal muscle vulnerability in ALS. Our results provide new insights into determinants of skeletal muscle atrophy and may help inform selection of muscles for diagnostic testing of ALS patients.

neuroscience↗

bioRxiv2020

Human muscle stem cells are refractory to aging

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle micro-environment such as to disfavor the myogenic function of these cells.

cell biology↗

bioRxiv2020

Quantifying the wave resistance of a swimmer

AbstractQuantifying the wave resistance of a swimmer as a function of depth assists in identifying the optimum depth for the glide phases of competition. Previous experiments have inferred how immersed depth influences the drag acting on a swimmer [1], but have not directly quantified the magnitude of wave resistance. This research experimentally validates the use of thin-ship theory for quantifying the wave resistance of a realistic swimmer geometry. The drag and wave pattern of a female swimmer mannequin were experimentally measured over a range of depths from 0.05m to 1.00m at a speed of 2.50 m/s. Numerical simulations agree with experiment to confirm that there were negligible reductions in wave resistance below a depth of 0.40m. Larger swimming pool dimensions are shown to be significant at reducing wave resistance at speeds above 2.0 m/s and depths below 0.40m. Truncating the swimmer’s body at the upper thigh increases the wave resistance at speeds below 2.0m/s but is not significant at higher speeds, indicating that the upper body is the main contributor to the wave system. Numerical experiments indicate that rotating the shoulders towards the surface is more influential than the feet, demonstrating the impact of the upper body on wave resistance.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗