Hormonal intrauterine devices and heat exchange during exercise.

Synthetic progestins in oral contraceptives are thought to blunt heat dissipation by reducing skin blood flow and sweating. However, whether progestin-releasing intrauterine devices (IUDs) modulate heat loss during exercise-heat stress is unknown. We used direct calorimetry to measure whole-body total (dry + evaporative) heat loss in young, physically active women (mean (SD); aged 24 (4) years, V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{peak}}}}$ 39.3 (5.3) ml/kg/min) with (IUD; n = 19) and without (Control; n = 17) IUDs in the follicular and luteal phases of the menstrual cycle during light- and moderate-intensity exercise at fixed rates of heat production (∼175 and ∼275 W/m2 ) in 30°C, ∼21% relative humidity. Between-group and -phase differences were evaluated using traditional hypothesis testing and statistical equivalence testing within pre-determined bounds (±11 W/m2 ; difference required to elicit a ±0.3°C difference in core temperature over 1 h) in each exercise bout. Whole-body total heat loss was statistically equivalent between groups within ±11 W m-2 (IUD-Control [90% CIs]; Light: -2 [-8, 5] W/m2 , P = 0.007; Moderate: 0 [-6, 6] W/m2 , P = 0.002), as were dry and evaporative heat loss (P ≤ 0.023), except for evaporative heat loss during moderate-intensity exercise (equivalence: P = 0.063, difference: P = 0.647). Whole-body total and evaporative heat loss were not different between phases (P ≥ 0.267), but dry heat loss was 3 [95% CIs: 1, 5] W/m2 greater in the luteal phase (P ≤ 0.022). Despite this, all whole-body heat loss outcomes were equivalent between phases (P ≤ 0.003). These findings expand our understanding of the factors that modulate heat exchange in women and provide valuable mechanistic insight of the role of endogenous and exogenous female sex hormones in thermoregulation. KEY POINTS: Progestin released by hormonal intrauterine devices (IUDs) may negatively impact heat dissipation during exercise by blunting skin blood flow and sweating. However, the influence of IUDs on thermoregulation has not previously been assessed. We used direct calorimetry to show that IUD users and non-users display statistically equivalent whole-body dry and evaporative heat loss, body heat storage and oesophageal temperature during moderate- and high-intensity exercise in a warm, dry environment, indicating that IUDs do not appear to compromise exercise thermoregulation. However, within IUD users and non-users, dry heat loss was increased and body heat storage and oesophageal temperature were reduced in the luteal compared to the follicular phase of the menstrual cycle, though these effects were small and unlikely to be practically meaningful. Together, these findings expand our understanding of the factors that modulate heat exchange in women and have important practical implications for the design of future studies of exercise thermoregulation.

Physiological responses to 9 hours of heat exposure in young and older adults. Part III: Association with self-reported symptoms and mood state.

Older adults are at greater risk of heat-related morbidity and mortality during heat waves, which is commonly linked to impaired thermoregulation. However, little is known about the influence of increasing age on the relation between thermal strain and perceptual responses during daylong heat exposure. We evaluated thermal and perceptual responses in 20 young (19-31 yr) and 39 older adults (20 with hypertension and/or type 2 diabetes; 61-78 yr) resting in the heat for 9 h (heat index: 37°C). Body core and mean skin temperature areas under the curve (AUC, hours 0-9) were assessed as indicators of cumulative thermal strain. Self-reported symptoms (68-item environmental symptoms questionnaire) and mood disturbance (40-item profile of mood states questionnaire) were assessed at end-heating (adjusted for prescores). Body core temperature AUC was 2.4°C·h [1.0, 3.7] higher in older relative to young adults (P < 0.001), whereas mean skin temperature AUC was not different (-0.5°C·h [-4.1, 3.2] P = 0.799). At end-heating, self-reported symptoms were not different between age groups (0.99-fold [0.80, 1.23], P = 0.923), with or without adjustment for body core or mean skin temperature AUC (both P ≥ 0.824). Mood disturbance was 0.93-fold [0.88, 0.99] lower in older, relative to young adults (P = 0.031). Older adults with and without chronic health conditions experienced similar thermal strain, yet those with these conditions reported lower symptom scores and mood disturbance compared with young adults and their age-matched counterparts (all P ≤ 0.026). Although older adults experienced heightened thermal strain during the 9-h heat exposure, they did not experience greater self-reported symptoms or mood disturbance relative to young adults.NEW & NOTEWORTHY Despite experiencing greater cumulative thermal strain during 9 h of passive heat exposure, older adults reported similar heat-related symptoms and lower mood disturbance than young adults. Furthermore, self-reported symptoms and mood disturbance were lower in older adults with common age-associated health conditions than young adults and healthy age-matched counterparts. Perceptual responses to heat in older adults can underestimate their level of thermal strain compared with young adults, which may contribute to their increased heat vulnerability.

Repetitive paired-pulse TMS increases motor cortex excitability and visuomotor skill acquisition in young and older adults.

Transcranial magnetic stimulation (TMS) over primary motor cortex (M1) recruits indirect (I) waves that can be modulated by repetitive paired-pulse TMS (rppTMS). The purpose of this study was to examine the effect of rppTMS on M1 excitability and visuomotor skill acquisition in young and older adults. A total of 37 healthy adults (22 young, 18-32 yr; 15 older, 60-79 yr) participated in a study that involved rppTMS at early (1.4 ms) and late (4.5 ms) interstimulus intervals (ISIs), followed by the performance of a visuomotor training task. M1 excitability was examined with motor-evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. We found that rppTMS increased M1 excitability in young and old adults, with the greatest effects for PA TMS at the late ISI (4.5 ms). Motor skill acquisition was improved by rppTMS at an early (1.4 ms) but not late (4.5 ms) ISI in young and older adults. An additional study using a non-I-wave interval (3.5 ms) also showed increased M1 excitability and visuomotor skill acquisition. These findings show that rppTMS at both I-wave and non-I-wave intervals can alter M1 excitability and improve visuomotor skill acquisition in young and older adults.

Combining RNAscope and immunohistochemistry to visualize inflammatory gene products in neurons and microglia.

A challenge for central nervous system (CNS) tissue analysis in neuroscience research has been the difficulty to codetect and colocalize gene and protein expression in the same tissue. Given the importance of identifying gene expression relative to proteins of interest, for example, cell-type specific markers, we aimed to develop a protocol to optimize their codetection. RNAscope fluorescent in situ hybridization (FISH) combined with immunohistochemistry (IHC) in fixed (CNS) tissue sections allows for reliable quantification of gene transcripts of interest within IHC-labeled cells. This paper describes a new method for simultaneous visualization of FISH and IHC in thicker (14-µm), fixed tissue samples, using spinal cord sections. This method's effectiveness is shown by the cell-type-specific quantification of two genes, namely the proinflammatory cytokine interleukin-1beta (IL-1b) and the inflammasome NLR family pyrin domain containing 3 (NLRP3). These genes are challenging to measure accurately using immunohistochemistry (IHC) due to the nonspecificity of available antibodies and the hard-to-distinguish, dot-like visualizations of the labeled proteins within the tissue. These measurements were carried out in spinal cord sections after unilateral chronic constriction injury of the sciatic nerve to induce neuroinflammation in the spinal cord. RNAscope is used to label transcripts of genes of interest and IHC is used to label cell-type specific antigens (IBA1 for microglia, NeuN for neurons). This combination allowed for labeled RNA transcripts to be quantified within cell-type specific boundaries using confocal microscopy and standard image analysis methods. This method makes it easy to answer empirical questions that are intractable with standard IHC or in situ hybridization alone. The method, which has been optimized for spinal cord tissue and to minimize tissue preparation time and costs, is described in detail from tissue collection to image analysis. Further, the relative expression changes in inflammatory genes NLRP3 and IL-1b in spinal cord microglia vs. neurons of somatotopically relevant laminae are described for the first time.

Physiological responses to 9 hours of heat exposure in young and older adults. Part II: Autophagy and the acute cellular stress response.

With rising global temperatures, heat-related mortality is increasing, particularly among older adults. Although this is often attributed to declines in thermoregulatory function, little is known regarding the effect of age on the cellular processes associated with mitigating heat-induced cytotoxicity. We compared key components of the cellular stress response in 19 young (19-31 yr; 10 female) and 37 older adults (61-78 yr; 10 female) during 9 h of heat exposure (40°C, 9% relative humidity). Mean body temperature (Tbody) was calculated from core and skin temperatures. Changes in proteins associated with autophagy, apoptotic signaling, acute inflammation, and the heat shock response were assessed via Western blot in peripheral blood mononuclear cells harvested before and after exposure. Tbody increased by 1.5 (SD 0.3)°C and 1.7 (0.3)°C in the young and older adults, respectively. We observed similar elevations in autophagy-related proteins (LC3-II and LC3-II/I) in young and older adults (both P ≥ 0.121). However, the older adults displayed signs of autophagic dysfunction, evidenced by a 3.7-fold [95% CI: 2.4, 5.6] greater elevation in the selective autophagy receptor p62 (P < 0.001). This was paired with elevations in apoptotic responses, with a 1.7-fold [1.3, 2.3] increase in cleaved caspase-3 in the older relative to young adults (P < 0.001). Older adults also exhibited diminished heat shock protein 90 responses (0.7-fold [0.5, 0.9] vs. young, P = 0.011) and, at any given level of thermal strain (Tbody area under the curve), elevated tumor necrosis factor-α (1.5-fold [1.0, 2.5] vs. young, P = 0.008). Attenuated autophagic responses may underlie greater vulnerability to heat-induced cellular injury in older adults.NEW & NOTEWORTHY We demonstrate for the first time that peripheral blood mononuclear cells from older adults exhibit signs of autophagic impairments during daylong (9 h) heat exposure relative to their younger counterparts. This was paired with greater apoptotic signaling and inflammatory responses, and an inability to stimulate components of the heat shock response. Thus, autophagic dysregulation during prolonged heat exposure may contribute to age-related heat vulnerability during hot weather and heat waves.

ebony underpins Batesian mimicry in melanic stoneflies.

The evolution of Batesian mimicry - whereby harmless species avoid predation through their resemblance to harmful species - has long intrigued biologists. In rare cases, Batesian mimicry is linked to intraspecific colour variation, in which only some individuals within a population resemble a noxious 'model'. Here, we assess intraspecific colour variation within a widespread New Zealand stonefly, wherein highly melanized individuals of Zelandoperla closely resemble a chemically defended aposematic stonefly, Austroperla cyrene. We assess convergence in the colour pattern of these two species, compare their relative palatability to predators, and use genome-wide association mapping to assess the genetic basis of this resemblance. Our analysis reveals that melanized Zelandoperla overlap significantly with Austroperla in colour space but are significantly more palatable to predators, implying that they are indeed Batesian mimics. Analysis of 194,773 genome-wide SNPs reveals an outlier locus (ebony) strongly differentiating melanic versus non-melanic Zelandoperla. Genotyping of 338 specimens from a single Zelandoperla population indicates that ebony explains nearly 70% of the observed variance in melanism. As ebony has a well-documented role in insect melanin biosynthesis, our findings indicate this locus has a conserved function across deeply divergent hexapod lineages. Distributional records suggest a link between the occurrence of melanic Zelandoperla and the forested ecosystems where the model Austroperla is abundant, suggesting the potential for adaptive shifts in this system underpinned by environmental change.

Physiological responses to 9 hours of heat exposure in young and older adults. Part I: Body temperature and hemodynamic regulation.

Aging is associated with an elevated risk of heat-related mortality and morbidity, attributed, in part, to declines in thermoregulation. However, comparisons between young and older adults have been limited to brief exposures (1-4 h), which may not adequately reflect the duration or severity of the heat stress experienced during heat waves. We therefore evaluated physiological responses in 20 young (19-31 yr; 10 females) and 39 older (61-78 yr; 11 females) adults during 9 h of rest at 40°C and 9% relative humidity. Whole body heat exchange and storage were measured with direct calorimetry during the first 3 h and final 3 h. Core temperature (rectal) was monitored continuously. The older adults stored 88 kJ [95% confidence interval (CI): 29, 147] more heat over the first 3 h of exposure (P = 0.006). Although no between-group differences were observed after 3 h [young: 37.6°C (SD 0.2°C) vs. older: 37.7°C (0.3°C); P = 0.216], core temperature was elevated by 0.3°C [0.1, 0.4] (adjusted for baseline) in the older group at hour 6 [37.6°C (0.2°C) vs. 37.9°C (0.2°C); P < 0.001] and by 0.2°C [0.0, 0.3] at hour 9 [37.7°C (0.3°C) vs. 37.8°C (0.3°C)], although the latter comparison was not significant after multiplicity correction (P = 0.061). Our findings indicate that older adults sustain greater increases in heat storage and core temperature during daylong exposure to hot dry conditions compared with their younger counterparts. This study represents an important step in the use of ecologically relevant, prolonged exposures for translational research aimed at quantifying the physiological and health impacts of hot weather and heat waves on heat-vulnerable populations.NEW & NOTEWORTHY We found greater increases in body heat storage and core temperature in older adults than in their younger counterparts during 9 h of resting exposure to hot dry conditions. Furthermore, the age-related increase in core temperature was exacerbated in older adults with common heat-vulnerability-linked health conditions (type 2 diabetes and hypertension). Impairments in thermoregulatory function likely contribute to the increased risk of heat-related illness and injury seen in older adults during hot weather and heat waves.

CBD hydroxyquinone photo-isomerises to a highly reactive intermediate.

The legalisation of hemp has led to wide commercial availability of cannabidiol (CBD)-containing products. Here we show that the CBD-hydroxyquinone (HU-331), a readily formed oxidation product and common impurity in CBD isolates, undergoes a previously unknown photo-isomerisation to produce a highly reactive intermediate in solution. Studies supported by calculations indicate that this intermediate rapidly reacts with oxygen to form a multitude of cannabinoid products. The purple colour observed in light-aged CBD-containing solutions is largely due to the anions of these by-products and is not significantly due to the HU-331 anion. Our findings suggest that these uncharacterized cannabinoid derivatives can be present in CBD-containing e-liquids and solutions that have been stored under ambient light conditions, calling for quality control processes that manage HU-331 contamination.

Sulfur(iv) reagents for the SuFEx-based synthesis of substituted sulfamate esters.

Sulfur(vi) fluoride exchange chemistry has been reported to be effective at synthesizing valuable sulfur(vi) functionalities through sequential nucleophilic additions, yet oxygen-based nucleophiles are limited in this approach to phenolic derivatives. Herein, we report a new sulfur(iv) fluoride exchange strategy to access synthetically challenging substituted sulfamate esters from alkyl alcohols and amines. We also report the development of a non-gaseous, sulfur(iv) fluoride exchange reagent, N-methylimidazolium sulfinyl fluoride hexafluorophosphate (MISF). By leveraging the reactivity of the sulfur(iv) center of this novel reagent, the sequential addition of alcohols and amines to MISF followed by oxidation afforded the desired substituted sulfamates in 40-83% yields after two steps. This new strategy expands the scope of SuFEx chemistry by increasing the accessibility of underdeveloped -S(O)F intermediates for future explorations.

Facile synthesis of sulfonyl fluorides from sulfonic acids.

Herein, we demonstrate two complementary strategies for the syntheses of sulfonyl fluorides using sulfonic acids and their salts. One strategy involves the conversion of sulfonic acid sodium salts to sulfonyl fluorides using thionyl fluoride in 90-99% yields in one hour. Lessons learned from the mechanism of this reaction also have enabled a complementary deoxyfluorination of sulfonic acids using Xtalfluor-E® - a bench stable solid - allowing for the conversion of both aryl and alkyl sulfonic acids and salts to sulfonyl fluorides in 41-94% yields. Notably, using Xtalfluor-E® enabled milder conditions and the use of both sulfonic acids and their sodium salts.

Modulation of I-Wave Generating Pathways With Repetitive Paired-Pulse Transcranial Magnetic Stimulation: A Transcranial Magnetic Stimulation-Electroencephalography Study.

OBJECTIVES: Repetitive paired-pulse transcranial magnetic stimulation (iTMS) at indirect (I) wave intervals increases motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation (TMS) to primary motor cortex (M1). However, the effects of iTMS at early and late intervals on the plasticity of specific I-wave circuits remain unclear. This study therefore aimed to assess how the timing of iTMS influences intracortical excitability within early and late I-wave circuits. To investigate the cortical effects of iTMS more directly, changes due to the intervention were also assessed using combined TMS-electroencephalography (EEG). MATERIAL AND METHODS: Eighteen young adults (aged 24.6 ± 4.2 years) participated in four sessions in which iTMS targeting early (1.5-millisecond interval; iTMS1.5) or late (4.0-millisecond interval; iTMS4.0) I-waves was applied over M1. Neuroplasticity was assessed using both posterior-to-anterior (PA) and anterior-to-posterior (AP) stimulus directions to record MEPs and TMS-evoked EEG potentials (TEPs) before and after iTMS. Short-interval intracortical facilitation (SICF) at interstimulus intervals of 1.5 and 4.0 milliseconds was also used to index I-wave activity. RESULTS: MEP amplitude was increased after iTMS (p < 0.01), and this was greater for PA responses (p < 0.01) but not different between iTMS intervals (p = 0.9). Irrespective of iTMS interval and coil current, SICF was facilitated after the intervention (p < 0.01). Although the N45 produced by AP stimulation was decreased by iTMS1.5 (p = 0.04), no other changes in TEP amplitude were observed. CONCLUSIONS: The timing of iTMS failed to influence which I-wave circuits were potentiated by the intervention. In contrast, decreases in the N45 suggest that the neuroplastic effects of iTMS may include disinhibition of intracortical inhibitory processes.

Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. Using Nrf2 knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2α. Co-treatment of MGO (1 µM) with monomethyl fumarate (MMF, 10, 20, 50 µM), the active metabolite of DRF, reduced p-eIF2α levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.

Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with pain testing. In this study, we characterize a novel low-dose myelin-oligodendrocyte-glycoprotein (MOG)-induced Sprague-Dawley (SD) model of EAE-related pain in male rats, optimized to minimize motor impairments/disabilities. Adult male SD rats were treated with increasing doses of intradermal myelin-oligodendrocyte-glycoprotein (MOG1-125) (0, 4, 8, and 16 µg) in incomplete Freund's adjuvant (IFA) vehicle to induce mild EAE. Von Frey testing and motor assessments were conducted prior to EAE induction and then weekly thereafter to assess EAE-induced pain and motor impairment. Results from these studies demonstrated that doses of 8 and 16 µg MOG1-125 were sufficient to produce stable mechanical allodynia for up to 1 month in the absence of hindpaw motor impairments/disabilities. In the follow-up studies, these doses of MOG1-125, were administered to create allodynia in the absence of confounded motor impairments. Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2-TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days. We found that (+)-NTX also reverses EAE-induced mechanical allodynia in the MOG-induced SD rat model of EAE, supporting parallels between models, but now allowing a protracted timecourse to be examined completely free of motor confounds. Exploring further mechanisms, we demonstrated that both spinal NOD-like receptor protein 3 (NLRP3) and interleukin-17 (IL-17) are necessary for EAE-induced pain, as intrathecal injections of NLRP3 antagonist MCC950 and IL-17 neutralizing antibody both acutely reversed EAE-induced pain. Finally, we show that spinal glial immunoreactivity induced by EAE is reversed by (+)-NTX, and that spinal demyelination correlates with the severity of motor impairments/disabilities. These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2-TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

Motor cortex plasticity is greater in endurance-trained cyclists following acute exercise.

Previous research using transcranial magnetic stimulation (TMS) has shown that plasticity within primary motor cortex (M1) is greater in people who undertake regular exercise, and a single session of aerobic exercise can increase M1 plasticity in untrained participants. This study aimed to examine the effect of an acute bout of exercise on M1 plasticity in endurance-trained (cyclists) and untrained individuals. Fourteen endurance-trained cyclists (mean ± SD; 23 ± 3.8 yr) and 14 untrained individuals (22 ± 1.8 yr) performed two experimental sessions. One session included an acute bout of high-intensity interval training (HIIT) exercise involving stationary cycling, whereas another session involved no-exercise (control). Following exercise (or control), I-wave periodicity repetitive TMS (iTMS) was used (1.5-ms interval, 180 pairs) to induce plasticity within M1. Motor evoked potentials (MEPs) induced by single and paired-pulse TMS over M1 were recorded from a hand muscle at baseline, after HIIT (or control) exercise and after iTMS. Corticospinal and intracortical excitability was not influenced by HIIT exercise in either group (all P > 0.05). There was an increase in MEP amplitude after iTMS, and this was greater after HIIT exercise (compared with control) for all subjects (P < 0.001). However, the magnitude of this response was larger in endurance cyclists compared with the untrained group (P = 0.049). These findings indicate that M1 plasticity induced by iTMS was greater in endurance-trained cyclists following HIIT. Prior history of exercise training is, therefore, an important consideration for understanding factors that contribute to exercise-induced plasticity.NEW & NOTEWORTHY We use a novel form of repetitive transcranial magnetic stimulation to show that motor cortex plasticity is increased after acute exercise and that this effect is bolstered in endurance-trained cyclists. These findings indicate that participation in regular endurance exercise (involving lower limb muscles) has widespread effects on cortical plasticity (assessed in unexercised upper limb muscles) following acute lower-limb cycling exercise. It also highlights that exercise history is an important factor in exercise-induced cortical plasticity.

Reduced olfactory acuity in recently flightless insects suggests rapid regressive evolution.

BACKGROUND: Insects have exceptionally fast smelling capabilities, and some can track the temporal structure of odour plumes at rates above 100 Hz. It has been hypothesized that this fast smelling capability is an adaptation for flying. We test this hypothesis by comparing the olfactory acuity of sympatric flighted versus flightless lineages within a wing-polymorphic stonefly species. RESULTS: Our analyses of olfactory receptor neuron responses reveal that recently-evolved flightless lineages have reduced olfactory acuity. By comparing flighted versus flightless ecotypes with similar genetic backgrounds, we eliminate other confounding factors that might have affected the evolution of their olfactory reception mechanisms. Our detection of different patterns of reduced olfactory response strength and speed in independently wing-reduced lineages suggests parallel evolution of reduced olfactory acuity. CONCLUSIONS: These reductions in olfactory acuity echo the rapid reduction of wings themselves, and represent an olfactory parallel to the convergent phenotypic shifts seen under selective gradients in other sensory systems (e.g. parallel loss of vision in cave fauna). Our study provides evidence for the hypothesis that flight poses a selective pressure on the speed and strength of olfactory receptor neuron responses and emphasizes the energetic costs of rapid olfaction.

Colonoscopy skills improvement training improves patient comfort during colonoscopy.

INTRODUCTION: We aimed to assess the effect of Colonoscopy Skills Improvement (CSI) training on patient comfort and sedation-related complications during colonoscopy. METHODS: This retrospective cohort study was performed on 19 endoscopists practicing in a Canadian tertiary care center who completed CSI training between October 2014 and May 2016. Data from 50 procedures immediately prior to, immediately after, and eight months following CSI training were included for each endoscopist. The primary outcome variable was intraprocedural comfort, and secondary outcomes included intraprocedural hypotension and hypoxia. Data were extracted from an electronic medical record and analyzed using SPSS version 20.0. Univariate analysis and stepwise multivariable logistic regression were performed to determine if there was an association between patient comfort and CSI training. Predictors of these outcomes including patient age, gender, sedation use and dosing, procedure completion, quality of bowel preparation, endoscopist experience, and specialty were included in the analysis. RESULTS: 2533 colonoscopies were included in the study. The mean dose of sedatives was reduced immediately following CSI training and at 8 months for both Fentanyl (75.4 mcg v. 67.8 mcg v. 65.9 mcg, p < 0.001) and Midazolam (2.57 mg v. 2.27 mg v. 2.19 mg, p < 0.001). The percentage of patients deemed to have a comfortable exam improved following endoscopist participation in CSI training and remained improved at 8 months (55.1% v. 70.2% v. 69.8%, p < 0.001). No significant change in rates of intraprocedural hypoxia or hypotension were noted following CSI training. CONCLUSION: CSI training is associated with improved patient comfort and reduced sedation requirements during colonoscopy.

Motor cortex plasticity and visuomotor skill learning in upper and lower limbs of endurance-trained cyclists.

PURPOSE: Studies with transcranial magnetic stimulation (TMS) show that both acute and long-term exercise can influence TMS-induced plasticity within primary motor cortex (M1). However, it remains unclear how regular exercise influences skill training-induced M1 plasticity and motor skill acquisition. This study aimed to investigate whether skill training-induced plasticity and motor skill learning is modified in endurance-trained cyclists. METHODS: In 16 endurance-trained cyclists (24.4 yrs; 4 female) and 17 sedentary individuals (23.9 yrs; 4 female), TMS was applied in 2 separate sessions: one targeting a hand muscle not directly involved in habitual exercise and one targeting a leg muscle that was regularly trained. Single- and paired-pulse TMS was used to assess M1 and intracortical excitability in both groups before and after learning a sequential visuomotor isometric task performed with the upper (pinch task) and lower (ankle dorsiflexion) limb. RESULTS: Endurance-trained cyclists displayed greater movement times (slower movement) compared with the sedentary group for both upper and lower limbs (all P < 0.05), but there was no difference in visuomotor skill acquisition between groups (P > 0.05). Furthermore, endurance-trained cyclists demonstrated a greater increase in M1 excitability and reduced modulation of intracortical facilitation in resting muscles of upper and lower limbs after visuomotor skill learning (all P < 0.005). CONCLUSION: Under the present experimental conditions, these results indicate that a history of regular cycling exercise heightens skill training-induced M1 plasticity in upper and lower limb muscles, but it does not facilitate visuomotor skill acquisition.

Genomic signatures of inbreeding in a critically endangered parrot, the kakapo.

Events of inbreeding are inevitable in critically endangered species. Reduced population sizes and unique life-history traits can increase the severity of inbreeding, leading to declines in fitness and increased risk of extinction. Here, we investigate levels of inbreeding in a critically endangered flightless parrot, the kakapo (Strigops habroptilus), wherein a highly inbred island population and one individual from the mainland of New Zealand founded the entire extant population. Genotyping-by-sequencing (GBS), and a genotype calling approach using a chromosome-level genome assembly, identified a filtered set of 12,241 single-nucleotide polymorphisms (SNPs) among 161 kakapo, which together encompass the total genetic potential of the extant population. Multiple molecular-based estimates of inbreeding were compared, including genome-wide estimates of heterozygosity (FH), the diagonal elements of a genomic-relatedness matrix (FGRM), and runs of homozygosity (RoH, FRoH). In addition, we compared levels of inbreeding in chicks from a recent breeding season to examine if inbreeding is associated with offspring survival. The density of SNPs generated with GBS was sufficient to identify chromosomes that were largely homozygous with RoH distributed in similar patterns to other inbred species. Measures of inbreeding were largely correlated and differed significantly between descendants of the two founding populations. However, neither inbreeding nor ancestry was found to be associated with reduced survivorship in chicks, owing to unexpected mortality in chicks exhibiting low levels of inbreeding. Our study highlights important considerations for estimating inbreeding in critically endangered species, such as the impacts of small population sizes and admixture between diverse lineages.

Anthropogenic evolution in an insect wing polymorphism following widespread deforestation.

Anthropogenic environmental change can underpin major shifts in natural selective regimes, and can thus alter the evolutionary trajectories of wild populations. However, little is known about the evolutionary impacts of deforestation-one of the most pervasive human-driven changes to terrestrial ecosystems globally. Absence of forest cover (i.e. exposure) has been suggested to play a role in selecting for insect flightlessness in montane ecosystems. Here, we capitalize on human-driven variation in alpine treeline elevation in New Zealand to test whether anthropogenic deforestation has caused shifts in the distributions of flight-capable and flightless phenotypes in a wing-polymorphic lineage of stoneflies from the Zelandoperla fenestrata species complex. Transect sampling revealed sharp transitions from flight-capable to flightless populations with increasing elevation. However, these phenotypic transitions were consistently delineated by the elevation of local treelines, rather than by absolute elevation, providing a novel example of human-driven evolution in response to recent deforestation. The inferred rapid shifts to flightlessness in newly deforested regions have implications for the evolution and conservation of invertebrate biodiversity.