Intermittent Exposure Research Articles

Effects of exercise training with intermittent hyperoxic intervention on endurance performance and muscle metabolic properties in male mice.

This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O2 [10 min] and 30% O2 [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.

Persisting neurobehavioral consequences of daily or intermittent paternal cannabis administration in F1 and F2 Rats

Repeated paternal preconception exposure to Δ9-tetrahydrocannabinol (Δ9-THC) alone or together with the other constituents in a cannabis extract has been shown in our earlier studies in rats to cause significant neurobehavioral impairment in their offspring. In the current study, we compared the effects of daily cannabis extract (CE) exposure to cannabis on two consecutive days per week, modeling weekend cannabis use in human. The CE contained Δ9-THC as well as cannabidiol and cannabinol. We also extended the investigation of the study to cross-generational effects of grand-paternal cannabis exposure on the F2 generation and included testing the effects of paternal cannabis exposure on responding for opiate self-administration in F1 and F2 generation offspring. We replicated the findings of neurobehavioral impairment in F1 offspring of male rats exposed to cannabis extract containing 4 mg/kg/day of Δ9-THC daily for four weeks prior to mating with drug naïve females. The 4-week cannabis extract exposure caused a significant decrease in weight gain in the male rats exposed daily. In contrast, their offspring showed significantly greater body weights and anogenital distances (AGD) in the third to fourth weeks after birth. The behavioral effects seen in the F1 generation were increased habituation of locomotor activity in the figure-8 maze in female offspring and increased lever pressing for the opiate drug remifentanil in male offspring. The F2 generation showed significantly impaired negative geotaxis and an elimination of the typical sex-difference in locomotor activity, with effects not seen in the F1 generation. This study shows that daily paternal cannabis exposure for four weeks prior to mating causes significant neurobehavioral impairment in the F1 and F2 offspring. Intermittent exposure on two consecutive days per week for four weeks caused comparable neurobehavioral impairment. In sum, there should be concern about paternal as well as maternal exposure to cannabis concerning neurobehavioral development of their offspring.

Protein kinase C epsilon-mediated modulation of T-type calcium channels underlies alcohol withdrawal hyperexcitability in the midline thalamus.

Millions of people struggle with alcohol use disorder (AUD). Abrupt abstinence after a period of chronic alcohol use can precipitate the alcohol withdrawal syndrome (AWS), which includes hyperexcitability and, potentially, seizures. We have shown that T-type Ca2+ channels are novel, sensitive targets of alcohol, an effect that is dependent upon protein kinase C (PKC). The purpose of this study was to (1) understand midline thalamic neuronal hyperexcitability during alcohol withdrawal and its dependence on PKC; (2) characterize T channel functional changes using both current clamp and voltage clamp methods; and (3) determine which PKC isoform may be responsible for alcohol withdrawal (WD) effects. Whole-cell patch clamp recordings were performed in midline thalamic neurons in brain slices prepared from C57bl/6 mice that underwent chronic intermittent alcohol exposure in a standard vapor chamber model. The recordings were compared to those from air-exposed controls. T-channel inactivation curves and burst responses were acquired through voltage-clamp and current-clamp recordings, respectively. Whole-cell voltage clamp recordings of native T-type current exhibited a depolarizing shift in the voltage-dependency of inactivation during alcohol withdrawal compared to air-exposed controls. A PKCε translocation inhibitor peptide mitigated this change. Current clamp recordings demonstrated more spikes per burst during alcohol withdrawal. Consistent with voltage clamp findings, the PKCɛ translocation inhibitor peptide reduced the number of spikes per burst after WD. We found that alcohol WD produces T channel-mediated hyperexcitability in the midline thalamus, produced in part by a shift in the inactivation curve consistent with greater availability of T current. WD effects on T current inactivation were reduced to control levels by blocking PKCε translocation. Our results demonstrate that PKCε translocation plays an important role in the regulation of alcohol withdrawal-induced hyperexcitability in midline thalamic circuitry.

Anthropogenic noise disrupts early-life development in a fish with paternal care

Anthropogenic noise is a global pollutant but its potential impacts on early life-stages in fishes are largely unknown. Here, using controlled laboratory experiments, we tested for impacts of continuous or intermittent exposure to low-frequency broadband noise on early life-stages of the common goby (Pomatoschistus microps), a marine fish with exclusive paternal care. Neither continuous nor intermittent noise exposure had an effect on filial cannibalism, showing that males were capable and willing to care for their broods. However, broods reared in continuous noise covered a smaller area and contained fewer eggs than control broods. Moreover, although developmental rate was the same in all treatments, larvae reared by males in continuous noise had, on average, a smaller yolk sac at hatching than those reared in the intermittent noise and control treatments, while larvae body length did not differ. Thus, it appears that the increased consumption of the yolk sac reserve was not utilised for increased growth. This suggests that exposure to noise in early life-stages affects fitness-related traits of surviving offspring, given the crucial importance of the yolk sac reserve during the early life of pelagic larvae. More broadly, our findings highlight the wide-ranging impacts of anthropogenic noise on aquatic wildlife living in an increasingly noisy world.

The Potential Interplay Between HIF-1α, Angiogenic, and Autophagic Signaling During Intermittent Hypoxic Exposure and Exercise.

Berkemeier QN, Deyhle MR, McCormick JJ, Escobar KA, Mermier CM. The Potential Interplay between HIF-1α, Angiogenic, and Autophagic Signaling during Intermittent Hypoxic Exposure and Exercise High Alt Med Biol. 00:000-000, 2024.-Berkemeier QN, Deyhle MR, McCormick JJ, Escobar KA, Mermier CM. The Potential Interplay between HIF-1α, Angiogenic, and Autophagic Signaling During Intermittent Hypoxic Exposure and Exercise High Alt Med Biol. 00:000-000, 2024.-Environmental hypoxia as a result of decreased barometric pressure upon ascent to high altitudes (>2,500 m) presents increased physiological demands compared with low altitudes, or normoxic environments. Competitive athletes, mountaineers, wildland firefighters, military personnel, miners, and outdoor enthusiasts commonly participate in, or are exposed to, forms of exercise or physical labor at moderate to high altitudes. However, the majority of research on intermittent hypoxic exposure is centered around hematological markers, and the skeletal muscle cellular responses to exercise in hypoxic environments remain largely unknown. Two processes that may be integral for the maintenance of cellular health in skeletal muscle include angiogenesis, or the formation of new blood vessels from preexisting vasculature and autophagy, a process that removes and recycles damaged and dysfunctional cellular material in the lysosome. The purpose of this review is to is to examine the current body of literature and highlight the potential interplay between low-oxygen-sensing pathways, angiogenesis, and autophagy during acute and prolonged intermittent hypoxic exposure in conjunction with exercise.The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Army, DOD, DOE, ORAU/ORISE or U.S. Government.

Intermittent ethanol vapor exposure enhances ferroptosis following repeated mild traumatic brain injury in the frontal lobe of adolescent rats; potential role of mitochondrial dysregulation

Adolescents involved in sports have increased risk of traumatic brain injuries (TBI), and frequently participate in binge alcohol consumption in comparison to non-athletic peers. Recovery from a TBI requires substantial energy, and effcient metabolic activity, which depend on intact mitochondria structure and function. Alcohol impairs mitochondrial function, including mitochondrial dynamics and metabolism); that may ultimately lead to cell death. Among cell death pathways, the iron-dependent programmed cell death known as ferroptosis; which has been shown to be predominant in TBI is especially sensitive to changes in mitochondrial energy production. Whether alcohol affects TBI-associated alterations in mitochondrial function and promotes ferroptosis is not known. The aim of this study was to determine how alcohol contributes to repeated-mild TBI (rmTBI)-induced alterations in mitochondrial function (dynamics & metabolism) and ferroptosis signaling in the prefrontal cortex of adolescent male rats. Adolescent male Wistar rats were randomly assigned to i) Sham + Air (control), ii) Sham + ethanol (EtOH), iii) rmTBI + Air, or iv) rmTBI + EtOH. Starting on postnatal day 45, the animals received 3 days of intermittent EtOH vapor exposure (14 hrs on/10 hrs off). Twenty-four hours after the final EtOH exposure, animals were given an mTBI or sham procedure. This sequence was repeated for four cycles. Seven days after the final rmTBI, animals were euthanized, and brains excised for analysis, specifically the frontal lobe. Our preliminary results demonstrate that mitochondrial fusion protein, OPA1, expression was not altered in the PFC by either rmTBI or by EtOH exposure alone. However, rmTBI+EtOH resulted in a significant increase in OPA1 expression. EtOH exposure produced a significant increase in COX-IV (a subunit of ETC complex IV) expression. However, COX-IV expression was not significantly different between rmTBI or rmTBI + EtOH and controls. Mitochondrial complex I activity was not altered by rmTBI, EtOH, or rmTBI + EtOH. Expression of transferrin receptor (TfR1), a specific marker of ferroptosis was significantly increased by rmTBI and EtOH this effect was further exacerbated in the rmTBI + EtOH group. Overall, our study shows that the combination of rmTBI with EtOH exposure affects OPA1-mediated mitochondrial fusion. Additionally, exposure to EtOH increases complex IV expression. Moreover, both rmTBI and EtOH exposure independently triggered signaling pathways associated with ferroptosis, and this effect was synergistically increased when with rmTBI+ EtOH. These findings underscore the intricate interplay between EtOH exposure and rmTBI, influencing crucial mitochondrial proteins and markers of ferroptosis in the frontal lobe of the adolescent rat brain. Further research is needed to fully comprehend the underlying mechanisms and implications of these observations. This research was supported by NIH/NIAAA R01 AA025792 (PEM, NWG) & T32 AA007577 (PEM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ACUTE INTERMITTENT HEAT EXPOSURE WITH MORE FREQUENT AND SHORTER COOLING BREAKS ENHANCES PERFORMANCE AND ELICITS COMPARABLE PHYSIOLOGICAL RESPONSES TO CONTINUOUS HEAT EXPOSURE

INTRODUCTION & AIMS Heat acclimation (HA) is critical to mitigate the adverse effects of heat on exercise performance. While these methods yield physiological adaptations to heat, it also results in greater internal training load. This can potentially compromise training quality and lead to overreaching. Therefore, there is a need for HA protocols that address situations where training quality is crucial, yet the heat stimulus is necessary. The aim of this study was to investigate the influence of shorter, more frequent rest breaks with per-cooling (PerC) as an alternative HA session on physiological, perceptual, and self-paced maximal cycling performance, compared to continuous heat exposure. METHODS Thirteen participants completed one continuous and three intermittent heat exposure (IHE) maximal self-paced cycling protocols matched for total exercise and rest duration, in a random order in heat (36°C, 80% relative humidity): 1 x 60-min exercise (CON), 3 x 20-min exercise with 7.5-min rest between sets (IHE-20), 4 x 15-min exercise with 5-min rest between sets (IHE-15), 6 x 10-min exercise with 3-min rest between sets (IHE-10). Mixed-method PerC (crushed-ice ingestion and cooling vest) was applied during rest periods of all IHE protocols. RESULTS Total distance completed was greater in IHE-10, IHE-15, and IHE-20 compared to CON (+11%, +9%, and +8%, respectively), with no difference observed between IHE protocols. Total time spent above 38.5°C core temperature (Tc) was longer in CON compared to IHE-15 and IHE-20 (+62% and +78%, respectively), but similar to IHE-10 (+5%). Furthermore, a longer time above 38.5°C Tc occurred in IHE-10 versus IHE-15 and IHE-20 (+54% and +69%, respectively). Sweat loss did not differ between conditions. CONCLUSION Intermittent heat exposure with PerC may be a viable alternative HA protocol in situations where training quality takes precedence over thermal stimulus, or when both factors hold equal priority.

Ethanol pre-exposure attenuates the hypoxic ventilatory response and may attenuate expression of long term facilitation following intermittent hypoxia treatment in adult rats

Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder in which airway collapse or obstruction during sleep leads to periodic bouts of inadequate (hypopneic) or absent (apneic) ventilation despite neurorespiratory effort. Repetitive apneic and hypopneic exposures during sleep can induce intermittent hypoxemia, sympathetic activation, and sleep fragmentation which can lead to a host of maladaptive behavioral and physiological outcomes. Intermittent hypoxia, which consists of alternating exposure to hypoxia and normal oxygen levels (normoxia), can induce a long-lasting increase in breathing motor output called long term facilitation (LTF) and is currently being investigated as a therapeutic treatment. Interestingly, experts in the field of LTF have noted how IH models some key aspects of OSA. It has been well established through clinical studies that ethanol consumption prior to sleep exacerbates existing OSA, increasing the apnea/hypopnea index and worsening arterial blood oxygen desaturations during the night. However, it is unknown whether ethanol affects expression of LTF following IH treatment. If LTF might serve as a means of increasing ventilatory output to compensate for periods of apnea and hypopnea during OSA, ethanol might not only worsen the severity of OSA, but impede individuals’ compensatory response. Thus, for this study we hypothesized that ethanol treatment would attenuate LTF expression and the magnitude of the hypoxic ventilatory response during IH treatment. Using adult female Sprague-Dawley rats, we administered either low-dose (0.8 g/kg) or high-dose (3 g/kg) ethanol through intraperitoneal injection to model a 2-drink nightcap or binge drinking-type ethanol exposure, respectively. Immediately afterwards, we measured subjects’ ventilatory output during baseline, then during a 5 by 3-minute moderate IH protocol, and for one hour following the end of IH using whole-body plethysmography. Finally, we took venous blood samples to assay serum ethanol concentration at the end of the approximately 2.5 hour plethysmography measurement. Results from the high-dose ethanol group indicate that ethanol pre-exposure might attenuate respiratory rate and minute volume LTF in comparison to saline-treated control. Furthermore, high-dose ethanol attenuated the hypoxic ventilatory response with respect to respiratory rate and minute volume. Low dosage of ethanol attenuated subjects’ HVR of respiratory rate and minute volume, but conflictingly trends towards increasing LTF of tidal volume while diminishing LTF of respiratory rate when compared to saline control. Overall, our findings indicate that high levels of ethanol exposure dramatically diminish the acute ventilatory response to hypoxic exposure and may impede long-term increases in ventilatory output following IH treatment. On the other hand, lower doses of ethanol have a subtler effect on the ventilatory response to hypoxia. Future directions will include analysis of additional parameters of ventilatory function to gain a more detailed understanding of how ethanol effects respiratory plasticity in the context of intermittent hypoxic exposure. NIH 5T32 AA027488 to ALSUniversity of Kentucky Endowment to WJA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of pituitary adenylate cyclase-activating polypeptide neurons in the hypothalamic ventromedial nucleus and the cognate PAC1 receptor in the regulation of hedonic feeding

We explored the role of pituitary adenylate cyclase-activating polypeptide (PACAP) neurons in the hypothalamic ventromedial nucleus (VMN) in regulating hedonic feeding. We hypothesized that VMN PACAP neurons would inhibit reward-encoding mesolimbic (A10) dopamine neurons and thereby suppress impulsive consumption brought on by intermittent exposure to highly palatable food. Visualized whole-cell patch clamp recordings coupled with in vivo behavioral experiments were utilized in wildtype, PACAP- cre, TH- cre and TH- cre/PAC1 receptor-floxed mice. We found that optogenetic stimulation of VMN PACAP neurons inhibited postsynaptic targets in the ventral tegmental area (VTA), an effect replicated by bath application of exogenous PACAP during recordings from preidentified A10 dopamine neurons. These inhibitory actions were abrogated by the PAC1/VPAC2 receptor antagonist PACAP6-38, the KATP channel blocker tolbutamide, and by selective knockdown of the PAC1 receptor in A10 dopamine neurons. PACAP delivered directly into the VTA decreases binge feeding accompanied by reduced meal size and duration. These effects are negated by PACAP6-38, PAC1 receptor knockdown in A10 dopamine neurons, and apoptotic ablation of VMN PACAP neurons. These findings demonstrate that VMN PACAP neurons blunt impulsive, binge feeding behavior by activating PAC1 receptors and KATP channels to inhibit A10 dopamine neurons. As such, they impart impactful insight into potential treatment strategies for conditions such as obesity and food addiction. Work funded by PHS grant DA024314. Work funded by PHS grant DA024314. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstinence and Fear Experienced during This Period Produce Distinct Cortical and Hippocampal Adaptations in Alcohol-Dependent Rats.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer's Disease Treatment.

Despite decades of rigorous research and numerous clinical trials, Alzheimer's disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.

Identification of the subaerial unconformity, genesis, and distribution in Lower Triassic Baikouquan Formation, Mahu Sag, Junggar Basin, Western China

The genesis of unconformities involves multiple influences on basin formation and evolution, which affects the favorable reservoir and hydrocarbon distribution. Within the Early Triassic Baikouquan Formation in the Mahu Sag of the Junggar Basin, we identified subaerial unconformities (SU), namely SU1 and SU2. SU1 is characterized by regional, irregular valleys, whereas SU2 displays extensive lateral extent with comparatively lower relief. These distinctions stem from detailed analyses involving cores, well data, seismic profiles, and spatial distributions, enriching our understanding of SUs in the Junggar Basin. Key findings from our study include: (1) SU occurrences within the Baikouquan Formation span the falling-stage systems tract (FSST) and expanding system tract (EST), corresponding to relative lake level changes. SU1 emerges during descending lake levels, whereas SU2 develops during rising levels. (2) The extensive uplift of the Junggar Basin's perimeter, driven by the late Hercynian movement, heightened topographic gradient shapes a steeper lake shoreline profile, fostering SU development. Arid paleoclimatic conditions during the Permian-Triassic interval accelerate SU formation in the FSST. (3) SU typically comprises regional compound scour surfaces (RCS) and river intermittent exposure surfaces (IES). Continuous winnowing at RCS led to relatively high primary porosities, IES can develop better secondary porosity with superposed freshwater leaching. The investigation into the subaerial unconformity in the study area holds broader implications for comprehending depositional processes, reservoir distribution, and petroleum prospects, both locally and within a global lake basin context.

Effects of various living-low and training-high modes with distinct training prescriptions on sea-level performance: A network meta-analysis.

This study aimed to separately compare and rank the effect of various living-low and training-high (LLTH) modes on aerobic and anaerobic performances in athletes, focusing on training intensity, modality, and volume, through network meta-analysis. We systematically searched PubMed, Web of Science, Embase, EBSCO, and Cochrane from their inception date to June 30, 2023. Based on the hypoxic training modality and the intensity and duration of work intervals, LLTH was divided into intermittent hypoxic exposure, continuous hypoxic training, repeated sprint training in hypoxia (RSH; work interval: 5-10 s and rest interval: approximately 30 s), interval sprint training in hypoxia (ISH; work interval: 15-30 s), short-duration high-intensity interval training (s-IHT; short work interval: 1-2 min), long-duration high-intensity interval training (l-IHT; long work interval: > 5 min), and continuous and interval training under hypoxia. A meta-analysis was conducted to determine the standardized mean differences (SMDs) among the effects of various hypoxic interventions on aerobic and anaerobic performances. From 2,072 originally identified titles, 56 studies were included in the analysis. The pooled data from 53 studies showed that only l-IHT (SMDs: 0.78 [95% credible interval; CrI, 0.52-1.05]) and RSH (SMDs: 0.30 [95% CrI, 0.10-0.50]) compared with normoxic training effectively improved athletes' aerobic performance. Furthermore, the pooled data from 29 studies revealed that active intermittent hypoxic training compared with normoxic training can effectively improve anaerobic performance, with SMDs ranging from 0.97 (95% CrI, 0.12-1.81) for l-IHT to 0.32 (95% CrI, 0.05-0.59) for RSH. When adopting a program for LLTH, sufficient duration and work intensity intervals are key to achieving optimal improvements in athletes' overall performance, regardless of the potential improvement in aerobic or anaerobic performance. Nevertheless, it is essential to acknowledge that this study incorporated merely one study on the improvement of anaerobic performance by l-IHT, undermining the credibility of the results. Accordingly, more related studies are needed in the future to provide evidence-based support. It seems difficult to achieve beneficial adaptive changes in performance with intermittent passive hypoxic exposure and continuous low-intensity hypoxic training.

Hypercapnic hypoxia as a rehabilitation method for patients after ischemic stroke

ABSTRACT Introduction Experimental studies on animals have demonstrated a higher neuroprotective efficacy of hypercapnic hypoxia compared to normocapnic hypoxia. Respiratory training with hypercapnic hypoxia has shown a positive impact on the functional state of the nervous system in children with cerebral palsy (CP). It can be presumed that the combined effect of moderate hypercapnia and hypoxia will be promising for clinical application within the context of early rehabilitation after ischemic stroke. Methods A randomized triple-blind placebo-controlled study was conducted on 102 patients with ischemic stroke, aged 63.07 ± 12.1 years. All patients were diagnosed with ischemic stroke based on neuroimaging criteria and/or clinical criteria within the 48–72 hour timeframe. The experimental group (n = 50) underwent daily respiratory training with hypercapnic hypoxia (FetCO2 5–6%, FetO2 15–16%) using the ‘Carbonic’ device for 7–11 sessions of 20 minutes each day during the treatment process. The control group (placebo, n = 52) underwent training on a similar device modified for breathing atmospheric air. Neurological examinations were conducted on all patients before the study and on the day after completing the training course. Results The standard treatment demonstrated effectiveness in terms of neurological status scales in both groups. Intermittent exposure to hypercapnic hypoxia proved more effective in improving neurological function indicators in patients compared to the placebo group: NIHSS scale scores were 40% lower than in the placebo group (p < 0.001); mRS scale scores were 35% lower (p < 0.001); B-ADL-I and RMI indices were higher by 26% (p < 0.01) and 36% (p < 0.001), respectively; MoCA scale results were 13% higher (p < 0.05); HADS and BDI-II scale scores were lower by 35% (p < 0.05) and 25% (p < 0.05), respectively. The increase in MMSE scale scores in the intervention group was 54% higher (p < 0.001), and MoCA scale scores increased by 25% (p < 0.001). Conclusion Respiratory training with hypercapnic hypoxia improves the functional state of the nervous system in patients with ischemic stroke. After conducting further clarifying studies, hypercapnic hypoxia can be considered as an effective method of neurorehabilitation, which can be used as early as 48–72 hours after the onset of stroke.

Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation.

Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.

An Intermittent Exposure Regime Did Not Alter the Crop Yield and Biomass Responses to an Elevated Ozone Concentration

The intermittent ozone (O3) exposure of crops to alternating high and low concentrations is common in fields, but its impact on crop production has not been thoroughly investigated. In this study, two widely planted and O3-sensitive crops, winter wheat and soybean, were intermittently exposed to elevated O3 concentrations in open-top chambers. The results showed that the winter wheat and soybean yields significantly decreased with O3 exposure (AOT40, cumulative hourly O3 concentration above 40 ppb) (p &lt; 0.001). The relative yield losses were 0.99% per AOT40 for winter wheat and 1.2% per AOT40 for soybean, respectively. The responses of the crop biomasses to elevated O3 concentrations were lower than that of crop yield. Although the O3-induced crop yield and biomass losses under continuous O3 exposure were greater than those under intermittent O3 exposure, the differences were not statistically significant. Therefore, we can conclude that the effects of elevated O3 concentrations on crops are closely related to the exposure dose but not significantly related to the temporal distribution of elevated O3 concentrations. This study improves our understanding of how crop production responds to intermittent O3 exposure.

Effects of Highly Palatable Diet on motivation for food and resistance to punishment in rats: Role of sex and age of exposure

Exposure to highly palatable food is believed to induce behavioral and neurobiological changes that may produce addiction-like behavior and increase the risks of obesity and overweight. Studies in rodents have led to conflicting results suggesting that several factors such as sex and age of exposure contribute to the development of maladaptive behaviors towards food. In addition, it is not clear whether effects of exposure to highly palatable diets (HPD) persist after their discontinuation, which would indicate long-term risks to develop addiction-like behavior. In this study, we investigated the persistent effects of an intermittent 8-week exposure to HPD in male and female rats as a function of age of exposure (adult and adolescent). We found that intermittent exposure to HPD did not alter body weight, but it affected consumption of standard food during the time of exposure in all groups. In addition, in adults, HPD produced a decrease in the initial baseline responding in FR1 schedules, an effect that persisted for 4 weeks in males but not in female rats. However, we found that exposure to HPD did not affect resistance to punishment measured by progressive shock strength break points or motivation for food as measured by progressive-ratio break points regardless of sex or age of exposure. Altogether, these results do not provide support for the hypothesis that intermittent exposure to HPD produce persistent increases in the vulnerability to develop addiction-like behaviors towards palatable food.

Hypoxic preacclimatization combining intermittent hypoxia exposure with physical exercise significantly promotes the tolerance to acute hypoxia.

Background: Both hypoxia exposure and physical exercise before ascending have been proved to promote high altitude acclimatization, whether the combination of these two methods can bring about a better effect remains uncertain. Therefore, we designed this study to evaluate the effect of hypoxic preacclimatization combining intermittent hypoxia exposure (IHE) and physical exercise on the tolerance to acute hypoxia and screen the optimal preacclimatization scheme among the lowlanders. Methods: A total of 120 Han Chinese young men were enrolled and randomly assigned into four groups, including the control group and three experimental groups with hypoxic preacclimatization of 5-day rest, 5-day exercise, and 3-day exercise in a hypobaric chamber, respectively. Main physical parameters for hypoxia acclimatization, AMS incidence, physical and mental capacity were measured for each participant in the hypobaric chamber simulated to the altitude of 4500m in the effect evaluation stage. The effect was compared between different schemes. Results: During the effect evaluation stage, SpO2 of the 5-day rest group and 5-day exercise group was significantly higher than that of the control group (p = 0.001 and p = 0.006, respectively). The participants with 5-day rest had significantly lower HR than the controls (p = 0.018). No significant differences of AMS incidence were found among the four groups, while the proportion of AMS headache symptom (moderate and severe vs. mild) was significantly lower in the 3-day exercise group than that in the control group (p = 0.002). The 5-day exercise group had significantly higher VO2max, than the other three groups (p = 0.033, p < 0.001, and p = 0.023, respectively). The 5-day exercise group also had significantly higher digital symbol and pursuit aiming test scores, while shorter color selection reaction time than the control group (p = 0.005, p = 0.005, and p = 0.004, respectively). Conclusion: Hypoxic preacclimatization combining IHE with physical exercise appears to be efficient in promoting the tolerance to acute hypoxia. Hypoxia duration and physical exercise of moderate intensity are helpful for improvement of SpO2 and HR, relief of AMS headache symptoms, and enhancement of mental and physical operation capacity.

Hypobaric hypoxia exposure regulates tissue distribution of nanomedicine for enhanced cancer therapy

BackgroundEffective drug delivery of nanomedicines to targeted sites remains challenging. Given that hypobaric hypoxia and hyperbaric oxygen exposure can significantly change pharmacokinetics of drugs, it is interesting to determine whether they can regulate tissue distribution of nanomedicine, especially in tumor, for enhanced cancer therapy.ResultsHypobaric hypoxia exposure improved the pharmacokinetics of paclitaxel-loaded liposomes and facilitated their distribution in the heart and liver, whereas hyperbaric oxygen exposure did not benefit and even impaired the pharmacokinetics and distribution. Particularly, both hypobaric hypoxia and hyperbaric oxygen exposure could not improve the distribution in subcutaneous tumor. Thus, we constructed orthotopic liver tumor model and discussed whether high distribution of the liposomal nanomedicine in the liver, facilitated by hypobaric hypoxia exposure, could ensure their effective accumulation in liver tumor for enhanced cancer therapy.ConclusionsThe liposomal nanomedicine with adjuvant hypobaric hypoxia exposure significantly inhibited the growth of orthotopic liver tumor for prolonged survival time, achieved by hypobaric hypoxia-promoted accumulation at tumor sites of the liver. It might be the first example of the application of adjuvant intermittent hypobaric hypoxia exposure in treating liver cancer.

TRAF6-mediated ubiquitination of AKT in the nucleus is a critical event underlying the desensitization of G protein-coupled receptors

BackgroundDesensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D2-like receptors (D2R, D3R, D4R), have suggested the existence of other desensitization mechanisms. The present study employed D2R/D3R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT.ResultsAKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D3R, ubiquitination of AKT is also involved in the desensitization of β2 adrenoceptors.ConclusionOur study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.