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.

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.

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.

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.

Lipid droplet biogenesis is spatially coordinated at ER-vacuole contacts under nutritional stress.

Eukaryotic cells store lipids in cytosolic organelles known as lipid droplets (LDs). Lipid droplet bud from the endoplasmic reticulum (ER), and may be harvested by the vacuole for energy during prolonged periods of starvation. How cells spatially coordinate LD production is poorly understood. Here, we demonstrate that yeast ER-vacuole contact sites (NVJs) physically expand in response to metabolic stress, and serve as sites for LD production. NVJ tether Mdm1 demarcates sites of LD budding, and interacts with fatty acyl-CoA synthases at the NVJ periphery. Artificially expanding the NVJ through over-expressing Mdm1 is sufficient to drive NVJ-associated LD production, whereas ablating the NVJ induces defects in fatty acid-to-triglyceride production. Collectively, our data suggest a tight metabolic link between nutritional stress and LD biogenesis that is spatially coordinated at ER-vacuole contact sites.

Predicting the fate of eDNA in the environment and implications for studying biodiversity.

Environmental DNA (eDNA) applications are transforming the standard of characterizing aquatic biodiversity via the presence, location and abundance of DNA collected from environmental samples. As eDNA studies use DNA fragments as a proxy for the presence of organisms, the ecological properties of the complex and dynamic environments from which eDNA is sampled need to be considered for accurate biological interpretation. In this review, we discuss the role that differing environments play on the major processes that eDNA undergoes between organism and collection, including shedding, decay and transport. We focus on a mechanistic understanding of these processes and highlight how decay and transport models are being developed towards more accurate and robust predictions of the fate of eDNA. We conclude with five recommendations for eDNA researchers and practitioners, to advance current best practices, as well as to support a future model of eDNA spatio-temporal persistence.

Contemporary ancestor? Adaptive divergence from standing genetic variation in Pacific marine threespine stickleback.

BACKGROUND: Populations that have repeatedly colonized novel environments are useful for studying the role of ecology in adaptive divergence - particularly if some individuals persist in the ancestral habitat. Such "contemporary ancestors" can be used to demonstrate the effects of selection by comparing phenotypic and genetic divergence between the derived population and their extant ancestors. However, evolution and demography in these "contemporary ancestors" can complicate inferences about the source (standing genetic variation, de novo mutation) and pace of adaptive divergence. Marine threespine stickleback (Gasterosteus aculeatus) have colonized freshwater environments along the Pacific coast of North America, but have also persisted in the marine environment. To what extent are marine stickleback good proxies of the ancestral condition? RESULTS: We sequenced > 5800 variant loci in over 250 marine stickleback from eight locations extending from Alaska to California, and phenotyped them for platedness and body shape. Pairwise FST varied from 0.02 to 0.18. Stickleback were divided into five genetic clusters, with a single cluster comprising stickleback from Washington to Alaska. Plate number, Eda, body shape, and candidate loci showed evidence of being under selection in the marine environment. Comparisons to a freshwater population demonstrated that candidate loci for freshwater adaptation varied depending on the choice of marine populations. CONCLUSIONS: Marine stickleback are structured into phenotypically and genetically distinct populations that have been evolving as freshwater stickleback evolved. This variation complicates their usefulness as proxies of the ancestors of freshwater populations. Lessons from stickleback may be applied to other "contemporary ancestor"-derived population studies.

R(NA)-tistic expression: The art of matching unknown mRNA and proteins to environmental response in ecological genomics.

A challenge of modern ecological genomics is reducing uncertainty surrounding the biological inferences from gene expression. For example, approximately 40% of proteins in eukaryotic model organisms do not contain characterized domains (Gollery et al., 2006). Even proteins of "known function" are typically only characterized in the sense that they have a domain function, but provide no information on their biological role within the cell (e.g., activation, pathways or targets). Yet, as molecular ecologists, a common objective is to elucidate how organisms respond to environmental variation through changes in gene expression, including homoeostatic, acclimatory, and adaptive responses to environmental stressors, a challenge increased by poor protein ecological annotation. Now, in this issue of Molecular Ecology, Orsini et al. (2017) use the quintessential Daphnia system to characterize the differences in stress response in three genotypic backgrounds to common biotic and abiotic stressors found in nature. Using an optimized weighted gene co-expression network analysis, they link genes of unknown function to genes that they co-activate with and enrich for gene ontology. Determining the functional networks of genes that behave in genotype- and treatment-specific responses gives insight into possible pathways and respective ecological roles, helping pave the way for the next generation of transcriptomic studies in molecular ecology.

Angling-induced injuries have a negative impact on suction feeding performance and hydrodynamics in marine shiner perch, Cymatogaster aggregata.

Fishing is a popular and lucrative sport around the world and, in some cases, may contribute to declining fish stocks. To mediate this problem and maintain fish biomass in aquatic ecosystems, catch-and-release fishing, whereby a fish is caught and immediately released, has been implemented in many countries. It is unclear whether the injuries to the mouth that are caused by the hook have an impact on feeding performance of fishes. Using high-speed video and computational fluid dynamics (CFD), we asked whether injuries around the mouth caused by fishing hooks have a negative impact on suction feeding performance (measured as maximum prey velocity) of the commonly angled marine shiner perch (Cymatogaster aggregata). We hypothesized that fish with mouth injuries would exhibit decreased feeding performance compared with controls. Ten shiner perch were caught using scientific angling and 10 were caught using a seine net. Feeding events were then recorded at 500 frames per second using a high-speed camera. Compared with the control group, maximum prey velocity was significantly lower in the injured group (P<0.01). Maximum gape, time to peak gape, maximum jaw protrusion and predator-prey distance were comparable between the control and injured groups, leading us to conclude that the injury-induced hole in the buccal cavity wall reduced the pressure gradient during mouth expansion, thereby reducing the velocity of water entering the fish's mouth. This was confirmed with our CFD modelling. Fishing injuries in nature are likely to depress feeding performance of fish after they have been released, although it is currently unclear whether this has a significant impact on survival.

Adaptive genomic divergence under high gene flow between freshwater and brackish-water ecotypes of prickly sculpin (Cottus asper) revealed by Pool-Seq.

Understanding the genomic basis of adaptive divergence in the presence of gene flow remains a major challenge in evolutionary biology. In prickly sculpin (Cottus asper), an abundant euryhaline fish in northwestern North America, high genetic connectivity among brackish-water (estuarine) and freshwater (tributary) habitats of coastal rivers does not preclude the build-up of neutral genetic differentiation and emergence of different life history strategies. Because these two habitats present different osmotic niches, we predicted high genetic differentiation at known teleost candidate genes underlying salinity tolerance and osmoregulation. We applied whole-genome sequencing of pooled DNA samples (Pool-Seq) to explore adaptive divergence between two estuarine and two tributary habitats. Paired-end sequence reads were mapped against genomic contigs of European Cottus, and the gene content of candidate regions was explored based on comparisons with the threespine stickleback genome. Genes showing signals of repeated differentiation among brackish-water and freshwater habitats included functions such as ion transport and structural permeability in freshwater gills, which suggests that local adaptation to different osmotic niches might contribute to genomic divergence among habitats. Overall, the presence of both repeated and unique signatures of differentiation across many loci scattered throughout the genome is consistent with polygenic adaptation from standing genetic variation and locally variable selection pressures in the early stages of life history divergence.

Speciation through the lens of biomechanics: locomotion, prey capture and reproductive isolation.

Speciation is a multifaceted process that involves numerous aspects of the biological sciences and occurs for multiple reasons. Ecology plays a major role, including both abiotic and biotic factors. Whether populations experience similar or divergent ecological environments, they often adapt to local conditions through divergence in biomechanical traits. We investigate the role of biomechanics in speciation using fish predator-prey interactions, a primary driver of fitness for both predators and prey. We highlight specific groups of fishes, or specific species, that have been particularly valuable for understanding these dynamic interactions and offer the best opportunities for future studies that link genetic architecture to biomechanics and reproductive isolation (RI). In addition to emphasizing the key biomechanical techniques that will be instrumental, we also propose that the movement towards linking biomechanics and speciation will include (i) establishing the genetic basis of biomechanical traits, (ii) testing whether similar and divergent selection lead to biomechanical divergence, and (iii) testing whether/how biomechanical traits affect RI. Future investigations that examine speciation through the lens of biomechanics will propel our understanding of this key process.

Receptors rather than signals change in expression in four physiological regulatory networks during evolutionary divergence in threespine stickleback.

The molecular mechanisms underlying behavioural evolution following colonization of novel environments are largely unknown. Molecules that interact to control equilibrium within an organism form physiological regulatory networks. It is essential to determine whether particular components of physiological regulatory networks evolve or if the network as a whole is affected in populations diverging in behavioural responses, as this may affect the nature, amplitude and number of impacted traits. We studied the regulation of four physiological regulatory networks in freshwater and marine populations of threespine stickleback raised in a common environment, which were previously characterized as showing evolutionary divergence in behaviour and stress reactivity. We measured nineteen components of these networks (ligands and receptors) using mRNA and monoamine levels in the brain, pituitary and interrenal gland, as well as hormone levels. Freshwater fish showed higher expression in the brain of adrenergic (adrb2a), serotonergic (htr2a) and dopaminergic (DRD2) receptors, but lower expression of the htr2b receptor. Freshwater fish also showed higher expression of the mc2r receptor of the glucocorticoid axis in the interrenals. Collectively, our results suggest that the inheritance of the regulation of these networks may be implicated in the evolution of behaviour and stress reactivity in association with population divergence. Our results also suggest that evolutionary change in freshwater threespine stickleback may be more associated with the expression of specific receptors rather than with global changes of all the measured constituents of the physiological regulatory networks.

HIV associated Lymphocytic Interstitial Pneumonia: a clinical, histological and radiographic study from an HIV endemic resource-poor setting.

BACKGROUND: There is a paucity of clinical and histopathological data about HIV-associated lymphocytic interstitial pneumonitis (LIP) in adults from HIV endemic settings. The role of Ebstein-Barr virus (EBV) in the pathogenesis remains unclear. METHODS: We reviewed the clinical, radiographic and histopathological features of suspected adult LIP cases at the Groote Schuur Hospital, Cape Town South Africa, over a 6 year period. Archived tissue sections were stained for CD3, CD4, CD8, CD20 and LMP-1 antigen (an EBV marker). RESULTS: 42 cases of suspected LIP(100% HIV-infected) were identified. 75% of patients were empirically treated for TB prior to being referred to the chest service for further investigation. Tissue samples were obtained using trans-bronchial biopsy. 13/42 were classified as definite LIP (lymphocytic infiltrate with no alternative diagnosis), 19/42 probable LIP (lymphocytic infiltrate but evidence of anthracosis or fibrosis) and 10 as non-LIP (alternative histological diagnosis). Those with definite LIP were predominantly young females (85%) with a median CD4 count of 194 (IQR 119-359). Clinical or radiological features had poor predictive value for LIP. Histologically, the lymphocytic infiltrate comprised mainly B cells and CD8 T cells. The frequency of positive EBV LMP-1 antigen staining was similar in definite and non- LIP patients [(2/13 (15%) vs. 3/10 (30%); p = 0.52]. CONCLUSIONS: In a HIV endemic setting adult HIV-associated LIP occurs predominantly in young women. The diagnosis can often be made on transbronchial biopsy and is characterized by a predominant CD8 T cell infiltrate. No association with EBV antigen was found.

The shape of things to come in the study of the origin of species?

Perhaps Darwin would agree that speciation is no longer the mystery of mysteries that it used to be. It is now generally accepted that evolution by natural selection can contribute to ecological adaptation, resulting in the evolution of reproductive barriers and, hence, to the evolution of new species (Schluter & Conte 2009; Meyer 2011; Nosil 2012). From genes that encode silencing proteins that cause infertility in hybrid mice (Mihola et al. 2009), to segregation distorters linked to speciation in fruit flies (Phadnis & Orr 2009), or pollinator-mediated selection on flower colour alleles driving reinforcement in Texan wildflowers (Hopkins & Rausher 2012), characterization of the genes that drive speciation is providing clues to the origin of species (Nosil & Schluter 2011). It is becoming apparent that, while recent work continues to overturn historical ideas about sympatric speciation (e.g. Barluenga et al. 2006), ecological circumstances strongly influence patterns of genomic divergence, and ultimately the establishment of reproductive isolation when gene flow is present (Elmer & Meyer 2011). Less clear, however, are the genetic mechanisms that cause speciation, particularly when ongoing gene flow is occurring. Now, in this issue, Franchini et al. (2014) employ a classic genetic mapping approach augmented with new genomic tools to elucidate the genomic architecture of ecologically divergent body shapes in a pair of sympatric crater lake cichlid fishes. From over 450 segregating SNPs in an F2 cross, 72 SNPs were linked to 11 QTL associated with external morphology measured by means of traditional and geometric morphometrics. Annotation of two highly supported QTL further pointed to genes that might contribute to ecological divergence in body shape in Midas cichlids, overall supporting the hypothesis that genomic regions of large phenotypic effect may be contributing to early-stage divergence in Midas cichlids.

Gene expression plasticity evolves in response to colonization of freshwater lakes in threespine stickleback.

Phenotypic plasticity is predicted to facilitate individual survival and/or evolve in response to novel environments. Plasticity that facilitates survival should both permit colonization and act as a buffer against further evolution, with contemporary and derived forms predicted to be similarly plastic for a suite of traits. On the other hand, given the importance of plasticity in maintaining internal homeostasis, derived populations that encounter greater environmental heterogeneity should evolve greater plasticity. We tested the evolutionary significance of phenotypic plasticity in coastal British Columbian postglacial populations of threespine stickleback (Gasterosteus aculeatus) that evolved under greater seasonal extremes in temperature after invading freshwater lakes from the sea. Two ancestral (contemporary marine) and two derived (contemporary freshwater) populations of stickleback were raised near their thermal tolerance extremes, 7 and 22 °C. Gene expression plasticity was estimated for more than 14,000 genes. Over five thousand genes were similarly plastic in marine and freshwater stickleback, but freshwater populations exhibited significantly more genes with plastic expression than marine populations. Furthermore, several of the loci shown to exhibit gene expression plasticity have been previously implicated in the adaptive evolution of freshwater populations, including a gene involved in mitochondrial regulation (PPARAa). Collectively, these data provide molecular evidence that highlights the importance of plasticity in colonization and adaptation to new environments.

Integrating phenotypic plasticity within an Ecological Genomics framework: recent insights from the genomics, evolution, ecology, and fitness of plasticity.

E.B. Ford's 1964 book Ecological Genetics was a call for biologists to engage in multidisciplinary work in order to elucidate the link between genotype, phenotype, and fitness for ecologically relevant traits. In this review, we argue that the integration of an ecological genomics framework in studies of phenotypic plasticity is a promising approach to elucidate the causal links between genes and the environment, particularly during colonization of novel environments, environmental change, and speciation. This review highlights some of the questions and hypotheses generated from a mechanistic, evolutionary, and ecological perspective, in order to direct the continued and future use of genomic tools in the study of phenotypic plasticity.

A road map for molecular ecology.

The discipline of molecular ecology has undergone enormous changes since the journal bearing its name was launched approximately two decades ago. The field has seen great strides in analytical methods development, made groundbreaking discoveries and experienced a revolution in genotyping technology. Here, we provide brief perspectives on the main subdisciplines of molecular ecology, describe key questions and goals, discuss common challenges, predict future research directions and suggest research priorities for the next 20 years.