Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.

Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to its extreme hydrophobicity and high molecular weight. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium. Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.

Hem25p is required for mitochondrial IPP transport in fungi.

Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor composed of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for haem biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p failed to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enabled robust IPP uptake and incorporation into the CoQ biosynthetic pathway. HEM25 orthologues from diverse fungi, but not from metazoans, were able to rescue hem25∆ CoQ deficiency. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in fungi.

TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes.

Background: Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated as a cause of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates transcription of TOMM40 and TOMM22 , genes that encode major subunits of the translocase of outer mitochondrial membrane (TOM) complex which is responsible for importing nuclear-encoded proteins and maintaining mitochondrial function. We therefore investigated the role of TOMM40 and TOMM22 in mediating statin effects on mitochondrial function, dynamics, and mitophagy. Methods: Cellular and biochemical assays and transmission electron microscopy were used to investigate effects of simvastatin and TOMM40 and TOMM22 expression on measures of mitochondrial function and dynamics in C2C12 and primary human skeletal cell myotubes. Results: Knockdown of TOMM40 and TOMM22 in skeletal cell myotubes impaired mitochondrial oxidative function, increased production of mitochondrial superoxide, reduced mitochondrial cholesterol and CoQ levels, disrupted mitochondrial dynamics and morphology, and increased mitophagy, with similar effects resulting from simvastatin treatment. Overexpression of TOMM40 and TOMM22 in simvastatin-treated muscle cells rescued statin effects on mitochondrial dynamics, but not on mitochondrial function or cholesterol and CoQ levels. Moreover, overexpression of these genes resulted in an increase in number and density of cellular mitochondria. Conclusion: These results confirm that TOMM40 and TOMM22 are central in regulating mitochondrial homeostasis and demonstrate that downregulation of these genes by statin treatment mediates disruption of mitochondrial dynamics, morphology, and mitophagy, effects that may contribute to statin-induced myopathy.

Hem25p is a mitochondrial IPP transporter.

Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor comprised of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing, and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for heme biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p fail to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enables robust IPP uptake demonstrating that Hem25p is sufficient for IPP transport. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in yeast.

The Role of the Athletic Trainer in Providing Care to Transgender and Gender Diverse Patients: Considerations for Medical Affirmation - Part II.

Recently, there has been an increase in media attention surrounding transgender and gender-diverse (TGD) individuals between discriminatory legislation efforts and changing participation policies within organized sports. These changes and the historical lack of competence and education regarding the transgender patient population have resulted in sub-par patient care, and a misunderstanding of the athletic trainer's (AT) role within the healthcare and compliance systems. This literature review is the second part of a two-paper series and the objective of this paper was to educate ATs on the processes relevant to medical affirmation including compliance considerations regarding medical eligibility and to establish the AT's role. The gender affirmation framework includes social and legal components which are discussed in part one of this literature, and the medical component is thoroughly discussed in part two. AT's and all health care providers involved in the patient care of TGD individuals should work collaboratively on an interprofessional care team and have a general knowledge of the gender affirmation process including GAHT, surgical options, known risks and complications, and the general health needs of TGD patients. By being more knowledgeable, ATs are uniquely positioned to help reduce health and healthcare disparities as they are point-of-care providers as well as members of the interprofessional care team. Furthermore, ATs can use their knowledge to facilitate medical compliance and eligibility within the evolving policies of sporting organizations.

The Role of the Athletic Trainer in Treating Transgender and Gender Non-Conforming Patients: Foundational Knowledge and Disparities - Part I.

Transgender and Gender Diverse (TGD) patients experience discrimination, harassment, marginalization, and minority stress at greater rates than their cisgender counterparts leading to numerous health and healthcare disparities that negatively impact wellbeing and access to quality healthcare.1 While in an opportune position to improve health equity for TGD patients under their care, many athletic trainers (ATs) report having little to no formal education on TGD patient care leading to a reduction in self-reported competence. As such, to fill this knowledge gap, the purpose of the first part of this two-part narrative literature review is to 1) provide readers with foundational information and terminology, 2) explore relevant health and healthcare disparities, and 3) identify the role of the AT within an interprofessional care team treating TGD patients.

Sports Medicine Physicians Comfort and Competence in Caring for Transgender and Gender Nonconforming Patients and Athletes.

OBJECTIVE: The purpose of this study was to explore primary care sports medicine physicians' comfort, competence, education, and scope of training in caring for transgender and gender nonconforming (TGNC) patients/athletes. DESIGN: Mixed-methods, cross-sectional survey. SETTING: Online. PATIENTS OR PARTICIPANTS: In total, 4300 e-mails were successfully sent with 252 eligible responses received from the American Medical Society for Sports Medicine members. INDEPENDENT VARIABLES: Previous relationships with TGNC persons; previous relationships with TGNC patients/athletes; frequency of care for TGNC patients/athletes. MAIN OUTCOME MEASURES: The participants completed a 38-item tool used to assess perceived comfort and competence treating TGNC patients/athletes. Physicians defined "transgender" and described their thoughts on unfair competitive advantage of transgender athletes. RESULTS: Most participants had worked with a TGNC patient (70.2%, n = 177), but far fewer worked with a TGNC athlete (n = 26.6%, n = 67). Among the participants who provided a definition of transgender (n = 183), only 28.4% (n = 52) of participants were able to correctly define the term, whereas most were able to partially (57.9%, n = 106) characterize the term. The most common mechanisms identified for learning about TGNC patients were reading peer-reviewed journal articles (44.8%, n = 113) and CME (41.3%, n = 104). Those with previous TGNC friend/family, patient, and athlete relationships had a significantly different level of comfort and competence treating TGNC patients/athletes. CONCLUSIONS: Previous care relationships with TGNC strongly influences comfort and perceived competence of primary care sports medicine physicians. Training, from unbiased peer-reviewed sources of data, is critical to improve care for TGNC patients/athletes.

Environment and genotype predict the genomic nature of domestication of salmonids as revealed by gene expression.

Billions of salmonids are produced annually by artificial reproduction for harvest and conservation. Morphologically, behaviourally and physiologically these fish differ from wild-born fish, including in ways consistent with domestication. Unlike most studied domesticates, which diverged from wild ancestors millennia ago, salmonids offer a tractable model for early-stage domestication. Here, we review a fundamental mechanism for domestication-driven differences in early-stage domestication, differentially expressed genes (DEGs), in salmonids. We found 34 publications examining DEGs under domestication driven by environment and genotype, covering six species, over a range of life-history stages and tissues. Three trends emerged. First, domesticated genotypes have increased expression of growth hormone and related metabolic genes, with differences magnified under artificial environments with increased food. Regulatory consequences of these DEGs potentially drive overall DEG patterns. Second, immune genes are often DEGs under domestication and not simply owing to release from growth-immune trade-offs under increased food. Third, domesticated genotypes exhibit reduced gene expression plasticity, with plasticity further reduced in low-complexity environments typical of production systems. Recommendations for experimental design improvements, coupled with tissue-specific expression and emerging analytical approaches for DEGs present tractable avenues to understand the evolution of domestication in salmonids and other species.

Triglyceride lipolysis triggers liquid crystalline phases in lipid droplets and alters the LD proteome.

Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs), but how these lipids are organized within LDs and influence their proteome remain unclear. Using in situ cryo-electron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid crystalline lattices inside them. Mechanistically this requires TG lipolysis, which decreases the LD's TG:SE ratio, promoting SE transition to a liquid crystalline phase. Molecular dynamics simulations reveal TG depletion promotes spontaneous TG and SE demixing in LDs, additionally altering the lipid packing of the PL monolayer surface. Fluorescence imaging and proteomics further reveal that liquid crystalline phases are associated with selective remodeling of the LD proteome. Some canonical LD proteins, including Erg6, relocalize to the ER network, whereas others remain LD-associated. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid crystalline phases influence ER-LD interorganelle transport. Our data suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.

The Power of Access in Parkinson's Disease Care: A Retrospective Review of Telehealth Uptake During the COVID-19 Pandemic.

Objective: The onset of the COVID-19 pandemic in March of 2020 forced a rapid pivot to telehealth and compelled a use-case experiment in specialty telehealth neurology movement disorders care. The aims of this study were to quantify the potential benefit of telehealth as an option to the Parkinson's disease community as shown by the first 9 months of the COVID-19 pandemic, and to quantify the potential impact of the absence of a deep brain stimulation (DBS) telehealth option on DBS patient follow-up. Methods: New patient visits to the Inova Parkinson's and Movement Disorder's Center from April to December 2020 (9 months) were retrospectively reviewed for telehealth vs. in-person, demographics (age, gender, race, primary insurance), chief complaint, prior movement disorders specialist (MDS) consultation, imaging tests ordered, and distance/travel time from primary zip code to clinic. Additionally, DBS programming visit volume from April to December 2020 was compared to DBS programming visit volume from April to December 2019. Results: Of the 1,097 new patients seen, 85% were via telehealth (N = 932) and 15% in person (N = 165). In the telehealth cohort, 97.75% had not consulted with an MDS before (N = 911), vs. 87.9% of in-person (N = 145). Age range was 61.8 +/- 17.9 years (telehealth), 68.8 +/- 16.0 years (in-person). Racial breakdown for telehealth was 60.7% White (N = 566), 10.4% Black (N = 97), 7.4% Asian (N = 69) and 4.5% Hispanic (N = 42); in-person was 70.9% White (N = 117), 5.5% Black (N = 9), 7.9% Asian (N = 13) and 5.5% Hispanic (N = 9). Top 5 consultation reasons, top 10 primary insurance providers and imaging studies ordered between the two cohorts were similar. Distance/travel time between primary zip code and clinic were 33.8 +/- 104.8 miles and 42.2 +/- 93.4 min (telehealth) vs. 38.1 +/- 114.7 miles and 44.1 +/- 97.6 min (in-person). DBS programming visits dropped 24.8% compared to the same period the year before (254 visits to 191 visits). Conclusion: Telehealth-based new patient visits to a Movement Disorders Center appeared successful at increasing access to specialty care. The minimal difference in supporting data highlights the potential parity to in-person visits. With no telehealth option for DBS visits, a significant drop-off was seen in routine DBS management.

Neutral and adaptive drivers of genomic change in introduced brook trout (Salvelinus fontinalis) populations revealed by pooled sequencing.

Understanding the drivers of successful species invasions is important for conserving native biodiversity and for mitigating the economic impacts of introduced species. However, whole-genome resolution investigations of the underlying contributions of neutral and adaptive genetic variation in successful introductions are rare. Increased propagule pressure should result in greater neutral genetic variation, while environmental differences should elicit selective pressures on introduced populations, leading to adaptive differentiation. We investigated neutral and adaptive variation among nine introduced brook trout (Salvelinus fontinalis) populations using whole-genome pooled sequencing. The populations inhabit isolated alpine lakes in western Canada and descend from a common source, with an average of ~19 (range of 7-41) generations since introduction. We found some evidence of bottlenecks without recovery, no strong evidence of purifying selection, and little support that varying propagule pressure or differences in local environments shaped observed neutral genetic variation differences. Putative adaptive loci analysis revealed nonconvergent patterns of adaptive differentiation among lakes with minimal putatively adaptive loci (0.001%-0.15%) that did not correspond with tested environmental variables. Our results suggest that (i) introduction success is not always strongly influenced by genetic load; (ii) observed differentiation among introduced populations can be idiosyncratic, population-specific, or stochastic; and (iii) conservatively, in some introduced species, colonization barriers may be overcome by support through one aspect of propagule pressure or benign environmental conditions.

Evolution of thermal physiology alters the projected range of threespine stickleback under climate change.

Species distribution models (SDMs) are widely used to predict range shifts but could be unreliable under climate change scenarios because they do not account for evolution. The thermal physiology of a species is a key determinant of its range and thus incorporating thermal trait evolution into SDMs might be expected to alter projected ranges. We identified a genetic basis for physiological and behavioural traits that evolve in response to temperature change in natural populations of threespine stickleback (Gasterosteus aculeatus). Using these data, we created geographical range projections using a mechanistic niche area approach under two climate change scenarios. Under both scenarios, trait data were either static ("no evolution" models), allowed to evolve at observed evolutionary rates ("evolution" models) or allowed to evolve at a rate of evolution scaled by the trait variance that is explained by quantitative trait loci (QTL; "scaled evolution" models). We show that incorporating these traits and their evolution substantially altered the projected ranges for a widespread panmictic marine population, with over 7-fold increases in area under climate change projections when traits are allowed to evolve. Evolution-informed SDMs should improve the precision of forecasting range dynamics under climate change, and aid in their application to management and the protection of biodiversity.

Altered Spatiotemporal Gaze Dynamics During Unexpected Obstacle Negotiation in a Fatigued State.

Humans use their peripheral vision during locomotion to perceive an approaching obstacle in their path, while also focusing central gaze on steps ahead of them. However, certain physiological and psychological factors may change this strategy, such as when a walker is physically fatigued. In this study, 21 healthy participants walked through a dark room while wearing eye tracking glasses before and following intense exercise. Obstacles were placed in random locations along their path and became illuminated when participants approached them. Results indicate that, when fatigued, participants had altered spatial gaze strategies, including more frequent use of central gaze to perceive obstacles and an increased gaze angular displacement. However, there were no changes in temporal gaze strategies following exercise. These findings reveal how physical fatigue alters one's visual perception of their environment during locomotion, and may partially explain why people are at greater risk of trips and falls while fatigued.

Gait Adaptations to Physical Fatigue During the Negotiation of Variable and Unexpected Obstacles.

OBJECTIVE: The purpose of this study was to investigate how physical fatigue impacts one's ability to negotiate unexpected and randomly located obstacles during locomotion. BACKGROUND: Physically demanding occupations place workers at risk of trips and falls-a major health and financial burden. How worker physical fatigue and fitness impacts their ability to navigate through unpredictable environments is not thoroughly explored in current literature. In this exploratory study, we further examine these relationships. METHODS: Twenty-one young, physically fit participants completed a series of obstacle negotiation trials in the dark, where an obstacle would suddenly be illuminated as they reached it. Participants then engaged in a fatigue protocol, before repeating a series of the same negotiation trials. RESULTS: When fatigued, participants exhibited a significant decrease in leading toe and trailing toe clearance, as well as a significant increase in leading heel clearance. Moreover, participants stepped closer to the obstacle with their both feet on the step prior to negotiation. Participants also walked at a faster velocity. Regression analyses revealed that participants' VO2max and height were significant predictors of foot placement metrics. CONCLUSION: Results indicate that physical fatigue negatively impacts crossing mechanics of young, healthy individuals, and that a higher level of VO2 capacity may reduce the occurrences of altered crossing behavior that coincide with physical fatigue. APPLICATION: These results highlight the effect of fatigue on worker safety during performance of job-related duties and are of interest to professionals seeking to reduce the incidence of slips, trips, and falls in the workplace.

Prevalence of Pseudobulbar Affect (PBA) in Parkinson's Disease: An Underrecognized Patient Burden.

Objective Pseudobulbar affect (PBA) is a neurological condition characterized by emotional lability and a discrepancy between the patient's emotional expression and emotional experience. These uncontrollable episodes cause distress in social situations resulting in embarrassment and social withdrawal. The most comprehensive study to date estimated that 26% of Parkinson's disease (PD) patients screened positive for PBA symptoms via the validated Center for Neurologic Study-Lability Scale (CNS-LS) screening tool. We hypothesize that the prevalence of this disabling syndrome is higher than reported, often being labeled as depression. Methods One hundred patients were enrolled in the study and screened with a CNS-LS tool, all of whom were diagnosed with PD by a fellowship-trained movement disorder specialist. Patients were also asked about previous diagnosis of depression, current antidepressant medication use, and history of PBA diagnosis and treatment. Results The percentage of PD patients (n = 100) with PBA symptoms as defined by a CNS-LS score ≥13 was 41% (n = 41) and by a CNS-LS score ≥17 was 21.0% (n = 21). In our sample, 38.0% of patients (n = 38) had a previous clinical diagnosis of depression and 25.0% (n = 25) were currently undergoing treatment for their depression. There was a significant association between previous depression diagnosis, current antidepressant use, and higher CNS-LS scores (p < 0.001). Conclusion Using either of the CNS-LS score cutoffs, a significant proportion of the PD population in our sample displayed symptoms of PBA. We also found an association between previous diagnosis of depression and higher CNS-LS scores as well as between antidepressant use and higher CNS-LS scores. This suggests both a higher prevalence than prior studies showed as well as frequent misdiagnosis or co-diagnosis with depression.

Glucose restriction drives spatial reorganization of mevalonate metabolism.

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high-molecular-weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively, we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.

Mitochondrial volume density and evidence for its role in adaptive divergence in response to thermal tolerance in threespine stickleback.

Phenotypic plasticity is predicted to permit persistence in new environments, and may subsequently evolve to enhance fitness. Colonizing environments with lower winter temperatures can lead to the evolution of lower critical thermal minima; the corresponding physiological traits associated with temperature tolerance are predicted to involve mitochondrial function. Threespine stickleback (Gasterosteus aculeatus) have colonized freshwater lakes along the Pacific Northwest. These freshwater populations are known to exhibit cold-induced increases in mitochondrial volume density in pectoral muscle, but whether such plasticity evolved before or after colonization is uncertain. Here, we measure critical thermal minima (CTmin) in one marine and one freshwater population of threespine stickleback, and mitochondrial volume density in pectoral and cardiac tissue of both populations acclimated to different temperature treatments (6.2, 14.5 and 20.6 â„ƒ). Mitochondrial volume density increased with cold acclimation in pectoral muscle; cardiac muscle was non-plastic but had elevated mitochondrial volume densities compared to pectoral muscle across all temperature treatments. There were no differences in the levels of plasticity between marine and freshwater stickleback, but neither were there differences in CTmin. Importantly, marine stickleback exhibited plasticity under low-salinity conditions, suggesting that marine stickleback had at least one necessary phenotype for persistence in freshwater environments before colonization occurred.

Heritability of DNA methylation in threespine stickleback (Gasterosteus aculeatus).

Epigenetic mechanisms underlying phenotypic change are hypothesized to contribute to population persistence and adaptation in the face of environmental change. To date, few studies have explored the heritability of intergenerationally stable methylation levels in natural populations, and little is known about the relative contribution of cis- and trans-regulatory changes to methylation variation. Here, we explore the heritability of DNA methylation, and conduct methylation quantitative trait loci (meQTLs) analysis to investigate the genetic architecture underlying methylation variation between marine and freshwater ecotypes of threespine stickleback (Gasterosteus aculeatus). We quantitatively measured genome-wide DNA methylation in fin tissue using reduced representation bisulfite sequencing of F1 and F2 crosses, and their marine and freshwater source populations. We identified cytosines (CpG sites) that exhibited stable methylation levels across generations. We found that additive genetic variance explained an average of 24-35% of the methylation variance, with a number of CpG sites possibly autonomous from genetic control. We also detected both cis- and trans-meQTLs, with only trans-meQTLs overlapping with previously identified genomic regions of high differentiation between marine and freshwater ecotypes. Finally, we identified the genetic architecture underlying two key CpG sites that were differentially methylated between ecotypes. These findings demonstrate a potential role for DNA methylation in facilitating adaptation to divergent environments and improve our understanding of the heritable basis of population epigenomic variation.