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Muscarinic receptor antagonism activates TRPM3 channels to augment mitochondrial function and provide neuroprotection
Full text linkPeripheral neuropathy, commonly associated with diabetes, chemotherapy, and HIV- induced nerve damage, leads to progressive sensory deficits and nerve dysfunction. While muscarinic acetylcholine type 1 receptor (M1R) antagonism promotes sensory axon repair, the mechanisms underlying its neuroprotective effects remained unclear. Transient receptor potential melastatin-3 (TRPM3), a heat-sensitive cation channel, plays a crucial role in calcium signaling, mitochondrial function and neuronal metabolism, positioning it as a potential mediator of M1R antagonist-driven neuroprotection. This thesis investigated the mechanistic link between M1R antagonism and TRPM3 activation and explored the therapeutic potential of TRPM3 modulation in sensory axon regeneration.
M1R antagonists pirenzepine (PZ) and muscarinic toxin 7 (MT7) enhanced TRPM3-mediated Ca²⁺ influx in dorsal root ganglion (DRG) neurons, an effect that was abolished by TRPM3 inhibitors or extracellular Ca²⁺ removal. TRPM3 activation using CIM0216 and pregnenolone sulfate (PS) elevated intracellular Ca2+, promoted AMP-activated protein kinase (AMPK) phosphorylation via the Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKKβ) pathway, leading to enhanced mitochondrial function, glycolysis, and tricarboxylic acid (TCA) cycle activity. Further analysis established that M1R antagonism stimulated TRPM3 by inhibiting phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, facilitating sustained calcium signaling and metabolic enhancement. TRPM3 knockdown via adeno-associated virus (AAV)-mediated shRNA suppressed the neurite-promoting effects of M1R antagonists, confirming its essential role in axonal plasticity.
To assess whether these findings translated to an in vivo setting, the streptozotocin (STZ)-induced diabetic neuropathy model was utilized, which recapitulated key sensory impairments such as mechanical allodynia, slowed motor nerve conduction velocity (MNCV), and thermal hypoalgesia. PZ treatment restored sensory function in diabetic mice, but co-administration of TRPM3 inhibitors (isosakuranetin and primidone) abolished these improvements, confirming that M1R-mediated neuroprotection was TRPM3-dependent. Despite the emergence of sensory impairments at 16 weeks post-STZ induction, corneal nerve loss was less pronounced than expected, suggesting a gradual progression of neuropathy, where functional impairments preceded structural degeneration. However, TRPM3 inhibition significantly reduced corneal nerve density, further highlighting its potential role in sensory fiber maintenance. This thesis established TRPM3 as a key modulator of sensory axon regeneration via Ca²⁺-dependent AMPK signaling, demonstrating its potential as a therapeutic target for peripheral neuropathy and neurodegenerative disorders.October 202
“Our needs, our priorities, listen to us!” recommendations for improving HIV prevention and the cascade of care from people living with HIV in Manitoba, Canada: a qualitative study
Full text linkAbstract Background The Canadian province of Manitoba has reported a 52% increase in HIV diagnoses during the past 5 years. Females are disproportionately affected by HIV and multiple intersecting health and social challenges, including houselessness, injection drug use, sexually transmitted and blood borne infections, and mental health conditions. Program and service development often ignore people’s complex lived experiences. Our aim was to describe recommendations made by people living with HIV (PLHIV) to inform a person-centred HIV cascade of care valuing the needs and ideas from PLHIV. Methods This qualitative study was conducted between October 2022 and May 2023. Thirty-two women, men, and gender-diverse participants completed a semi-structured interview. Interviews were recorded, transcribed, and analyzed using NVivo 12, deploying thematic analysis to understand major themes related to recommendations to care. This manuscript focuses on questions related to recommendations for the HIV cascade of care. Results Recommendations fell within two major themes: ‘Meeting people where they are at’ and an HIV educational strategy. The first theme included three main categories to make HIV services more accessible. (1) psychological (social programming, peer support during diagnosis, increased mental health services), (2) biomedical (HIV outreach, HIV services outside 9 –5 h, specialized care outside metropolitan areas, universal coverage for HIV medicines), and (3) social (transportation support, emergency housing, financial support) supports. The HIV educational strategy included five major categories: (1) physical posters and billboards in highly transited areas; (2) community meetings with peer-led education; (3) comprehensive sex education in schools; (4) training primary healthcare providers on stigma and discrimination; (5) and social media campaigns to reach younger audiences. We report on gender differences for recommendations where they arose. The themes described by PLHIV suggest a need to implement HIV care delivery models that will connect and maintain people in HIV care in Manitoba. Conclusions This study provides practical and person-centred strategies that could bridge the barriers PLHIV face when accessing and remaining in HIV care and expanding education and prevention about HIV in Manitoba
Evaluating factors that influence appetite and glycemic response to wild rice and wild rice blends in humans
Full text linkBackground: Wild rice (WR) has been reported to have better nutritional profile compared to white rice (WhR) and brown rice (BR). It has also shown numerous health benefits in animal models and in vitro studies. But no study has reported the effects of WR consumption on postprandial appetite and glycemic response (PPGR) in humans.
Objectives: To investigate the effects of cooked Canadian WR and wild rice blends consumption on palatability, postprandial appetite and PPGR in adults and evaluate the nutritional components that could be responsible for the study outcomes.
Design: The acute trial followed a randomized crossover controlled design. Participants (n=19, 10 males and 9 females) consumed 140 g of treatment; stovetop cooked WR, BR, WhR (control), a wild rice blend of 15% wild rice and 85% brown rice (WRB), and microwaved WRB with 250 mL water. Their blood glucose concentration and appetite were measured at intervals from 0 to 120 min. Palatability of the treatments was measured following consumption. To explore the potential impact of parboiling on blood glucose results, WR was parboiled and nutritional composition of the treatments used in the study and the parboiled WR were analyzed and compared.
Results: From the trial, it was observed that the stovetop cooked WR had about 32.7% increase in the PPGR when compared to parboiled WhR (p ≤ 0.05). No differences were observed for appetite among the treatments. Parboiled WhR (70.7%) and BR (72.4%) were more palatable than WR (61.3%) and WRB (57.1% for microwave and 64.0% for stovetop). Based on these results we explored the impact of parboiling on WR. We found that parboiling improved the protein, dietary fibre, amylose, total phenolic content, fat, and reduced the rapidly and slowly digestible starch, starch damage, total flavonoid content, and carbohydrates in WR. Also, the cooked parboiled WR showed intermediate estimated glycemic index (eGI) of 64 in in vitro digestion calculation compared to cooked non-parboiled WR with eGI of 77.
Conclusion: Short-term consumption of 140 g of cooked non- parboiled WR led to higher PPGR compared to parboiled BR and WhR in adults, despite WR having better nutritional profile than WhR and BR. Parboiling WR could be an excellent method to reduce blood glucose response to WR consumption, without meaningfully decreasing its positive nutritional properties. Further studies are needed to investigate insulin response following WR consumption and the effects of cooked parboiled WR on postprandial appetite and PPGR in humans.May 202
The Ideal and the Real: Epistemic and practice tensions in renovating long-term residential care settings for persons with advanced dementia
Full text linkAlthough existing research suggests the importance of physical environments on persons living with dementia in residential settings, less is known about whether and how this evidence, among other factors, shapes design processes in long-term residential care. Using process evaluation methods to explore the redesign of one residential dementia care setting in mid-Western Canada pre-pandemic, we identified and explored how the renovation of a residential dementia care setting reveals deeper epistemic and practice tensions. Qualitative data included five years of textual project documentation, and stakeholder interviews. Inductive thematic analysis was used to identify and explore three key tensions. First, complex, shifting and sometimes contradictory design goals reflected broader tensions between major goals of care. Second, multiple meanings of ‘best practice evidence’ and ‘innovation’ reflected tensions between scientific and practice knowledge, which were compounded by organizational communications strategies. Third, differing perceptions of the capabilities of persons living with advanced dementia reflected tensions between types of knowledge that may be particularly pronounced in the context of heavy workloads in these settings. We discuss the need for designers and facilities to more fully engage with evidence reviews and formative process evaluations, and to promote transparency among stakeholders about practical limitations and types of evidence.Mitac
Horizontal grain aeration testing and measurement system
Full text linkFarmers around Canada, specifically in Manitoba, predominantly utilize vertical grain aeration in their post-harvest grain storage systems to extend the storage life of the grain. Using horizontal aeration presents a more energy-efficient alternative to vertical aeration. However, manufacturers lack the information and theoretical calculations necessary to optimize the design of horizontal aeration systems. This means that despite its advantages, manufacturers remain hesitant to adopt horizontal systems due to insufficient data to inform their design.
This project aimed to address this issue on behalf of Dr. Fuji Jian and the grain storage research group at the University of Manitoba. The project focused on creating a bench-scale device for testing and measuring air resistance in horizontal grain aeration systems. The device measures the performance of horizontal airflow through an aeration system that results from different types of grain and system configurations. Project deliverables included the constructed and verified device, and preliminary testing and data collection for future Ph.D. research and eventual industry application.
The project's technical specifications were verified to ensure that the final prototype would meet the client's demands for a grain bin that could hold a load of grain and measure the performance of horizontal grain aeration. A structural design was carried out to ensure that the grain bin could hold a whole load of grain during operation. Other verifications included testing the radial airflow uniformity, whether vertical airflow is negligible, and adapting the grain bin to be used with various system configurations. The grain bin was found to satisfy all the criteria required by the client. The overall project successfully provided a method to measure horizontal grain aeration performance from the data collected.
There are several recommendations for how to improve this project further. The main recommendation is to minimize instrumentation in the grain bin. A combination of pitot tubes and mass flow sensors were used to measure airflow. This combination provides highly detailed measurements, but the consequence is several disruptions to the airflow. Replacing or reducing the instrumentation disruption to the airflow would be reduced, producing higher quality results. Additionally, some operation procedure improvements are recommended to help future researchers transition to working with pilot-scale prototypes
Contextual factors related to aging determine force-based manipulation dosage: a prospective cross-sectional study
Full text linkAbstract Background Contextual factors influence clinicians’ delivery of force-based manipulation (FBM), like spinal manipulative therapy (SMT). It is particularly important to discern how contextual factors interact with therapeutic forces delivered to an older adult population, to minimize risk and identify ideal dosage. This study aimed to determine whether contextual factors pertaining to aging result in the modulation of kinetic and kinematic parameters used by experienced clinicians when delivering SMT. Methods Participants were randomly presented with a series of 12 AI-generated patient vignettes, featuring both visual and auditory content and representing varying age-related contextual factors. Factors included chronological (35-, 65- and 85-year-old), pathological (“healthy” vs degenerative spine), and felt (perceived as “young” vs. “old”) age. Participants delivered SMT to a human analogue manikin based on each vignette, presented six times in randomized order. Kinetic and kinematic parameters were collected and analyzed for differences between “young” and “old” contextual factors of age, using a 3-way repeated measures ANOVA model. Results Sixteen licensed chiropractors (8 female, 8 male) participated, with an average age of 45.4 (SD = 9.7, range 34–64) years and 18.3 (SD = 10.8, range 5–39) years of experience. A main effect in peak force was found for both chronological (F(2,30) = 26.18; p <.001, ηp2 = 0.636) and pathological age (F(1,15) = 11.58; p =.004, ηp2 = 0.436), following a stepwise progression of decreased force with increased age and with pathology. No statistically significant differences were found in peak force based on felt age, or in time to peak force for any factor. A main effect was found for chronological age with peak acceleration (F(2,20) = 9.50; p <.001, ηp2 = 0.487) and peak velocity (F(2,20) = 7.20; p =.004, ηp2 = 0.419), but not for pathological or felt age. There was a significant difference in time to peak velocity for felt age (F(1,10) = 12.23; p =.006, ηp2 = 0.550), with a shorter time to peak velocity in response to vignettes with older felt age. Conclusion Contextual factors of aging modulated certain kinetic and kinematic characteristics when delivering SMT. This provides evidence that practitioners differentially discern aspects of aging to inform how they deliver FBM dosage. Future research is needed to identify ideal kinetic and kinematic characteristics based on considerations of aging
Investigating the impact of helminths on mercury in Arctic foxes
Full text linkMercury (Hg) pollution in the Arctic poses a growing threat to the health of local wildlife, yet many factors behind Hg bioaccumulation remain poorly understood. Primarily ingested through diet, Hg bioaccumulates in animal tissues and can impair neurological and reproductive functions. Intestinal helminths have demonstrated the ability to take up Hg while residing in their hosts and have consequently been suggested to benefit their hosts through mitigating toxin exposure. In this study, I used Arctic foxes harvested over five years from Churchill, MB to analyze fox muscle total mercury concentrations ([THg]) (ng/g), intestinal helminth [THg], and helminth biomasses to determine if (i) helminth group (taxa and size)
influences helminth Hg uptake, and (ii) helminths benefit their host by decreasing host Hg uptake. Results showed that [THg] did not significantly vary with fox sex, age, or harvest year. Cestodes demonstrated higher [THg] than nematodes, though size did not influence [THg] for either taxon. Both cestodes and nematodes demonstrated [THg] increases relative to host [THg], though only the cestodes had significantly higher [THg] than their hosts, and no significant effect
was seen for either cestode or nematode biomass on fox [THg]. Overall, this study provides valuable insight into host-helminth-Hg dynamics. Further research is needed to elucidate the mechanisms and significance of helminth Hg uptake to help understand their potential applications in mitigating toxin exposure in wildlife.Manitoba Fish and Wildlife Enhancement Fund,
Natural Sciences and Engineering Research Council of Canada,
University of Manitoba Fieldwork Support Program,
Churchill Northern Studies Centre Northern Research Fun
Acute effects of quinoline and 2-methylquinoline on electrical activity of great pond snail (Lymnaea stagnalis) neurons
Full text linkPolycyclic aromatic compounds (PAC) are organic compounds found ubiquitously in the environment and originate naturally or anthropogenically. They are persistent, bioaccumulative, and toxic (PBT). PACs have been found to modulate voltage gated ion channels in fish cardiomyocytes. Many studies have examined PACs effects, however, there is growing concern about a less studied class of PACs: hetero-polycyclic aromatic compounds (HPACs). Quinoline and its derivative 2-methylquinoline are two-ringed HPACs found in high concentrations in sediment and tissues of fishes from the Great Lakes. Studies investigating synthetic quinoline derivatives used in the pharmaceutical industry have shown HPACs modulate voltage gated sodium, calcium and potassium ion channels in cardiomyocytes of fishes and mollusk neurons. We therefore designed a study investigating the acute neurobiological effects of quinoline and 2-methylquinoline on Great Pond Snail (Lymnaea stagnalis) neurons, a model with a large easily accessible central nervous system and well conserved ion channels. Electrophysiological characteristics were measured by performing suction electrode experiments on the right internal
nerve of the right parietal Lymnaea stagnalis ganglion. Extracellular recordings before and after application of various quinoline or 2-methylquinoline concentrations were used to determine the frequency of right parietal nerve activity which we normalized as percent of control. The extracellular recordings revealed that quinoline affects right parietal nerve activity in a dose dependent manner. Quinoline caused a statistically significant effect on right parietal nerve activity at 1000 nM, but not 100 nM, and 10 nM, with mean percent of control values being 89.2 ± 4.3%, 103.9 ± 4.6% and 99.9 ± 3.5% respectively. 2-Methylquinoline had no statistically significant effect on right parietal nerve activity at 1000 nM. These experiments highlight the importance of understanding the neurobiological effect of PBT environmental contaminants quinoline and 2-methylquinoline, as well as demonstrate the utility of suction electrode recordings as an electrophysiology technique to evaluate acute neurotoxicity of environmental contaminants
The Role of Physical Movement in Spinal Cord Repair Using an Adult Zebrafish Model
Full text linkSpinal cord injury (SCI) is a debilitating medical condition that can lead to lifelong paralysis. Failure to regain mobility and restore neurons can be attributed to the non-permissive microenvironment within the mammalian spinal cord that is characterized by prolonged inflammation and glial scarring. Unlike mammals, the zebrafish has a remarkable ability to regenerate neurons in the spinal cord following a complete transection. Aside from the activation of chemical pathways that promote growth, zebrafish also have ependymoglial (stem) cells surrounding the central canal that can proliferate and differentiate into all cell types of the spinal cord. Previous studies have investigated factors that promote neuronal regeneration, yet the contribution of locomotion remains unevaluated. Thus, we aimed to explore the role of physical movement in spinal cord repair by developing a swim column that elicited swimming activity (exercise treatment) from injured fish. This apparatus was developed using an aquarium pump to direct flow into a PVC tube placed within an acrylic tank. Adult male zebrafish from motor neuron reporter line, Tg(hb9:eGFP), were used. Results showed that the exercise treatment slowed the rate of recovery and diminished normal swimming behaviour. Downstream analysis of distance travelled, mean velocity, and mobility state duration revealed that SCI fish treated with exercise had delayed recovery compared to SCI fish that were untreated. Contrary to previous studies using mammalian models, we found that functional mobility was hindered, and swim restoration was limited. Furthermore, our findings contrast other zebrafish exercise studies that demonstrated increased neurogenesis in larvae, and attenuation of age-related diseases such as sarcopenia and cardiac failure. These contradictions may be attributed to sample size, experimental timeline, treatment duration, and stress levels. Although the current study did not yield statistically significant results, these preliminary findings lay the groundwork for deeper exploration of movement in regenerative model
Impacts of a flea beetle double-stranded RNA-based insecticide on the ground beetle Pterostichus melanarius
Full text linkFlea beetles (Phyllotreta cruciferae and P. striolata) are the most damaging insect pests of canola, one of Canada’s most economically valuable crops. Chemical insecticides are currently the primary method of flea beetle control, but concerns about their impact on non-target organisms highlight the need for safer alternatives. RNA interference (RNAi) has been recognized for its ability to selectively kill insect pests by silencing target genes through sequence-specific exogenous double-stranded RNA (dsRNA). However, sequence similarity between pest and beneficial insects continue to pose risks about potential off-target effects.
In this study, two dsRNAs targeting the UBE2L3 and Snf7 gene in P. cruciferae were evaluated for off-target effects in the predatory ground beetle Pterostichus melanarius. A bioinformatic analysis was used to identify the similarity between the dsRNA sequences and their respective orthologs in P. melanarius. Beetles were then injected with the dsRNAs, and relative gene expression and mortality were measured.
Following injection of the UBE2L3 dsRNA, which shares 83.4% similarity and a 29 bp matching segment with P. melanarius, target gene expression was reduced by 69.9%. Conversely, injection of the Snf7 dsRNA, which only shares 62.6% similarity, did not induce gene knockdown. Despite the knockdown of UBE2L3, no significant mortality was observed in any treatment group, including the positive control, suggesting that an insufficient dose of dsRNA was used. These findings demonstrate that sequence similarity influences the off-target effects of dsRNA, which can be predicted using a bioinformatic assessment. Continued sequencing of beneficial insects is required so that dsRNA can be designed to have minimal similarity with other species to reduce off-target effects