This study examined cardiovascular, perceptual and neuromuscular fatigue characteristics during and after cycling intervals with and without blood flow restriction (BFR). Fourteen endurance ...cyclists/triathletes completed four 4-minute self-paced aerobic cycling intervals at the highest sustainable intensity, with and without intermittent BFR (60% of arterial occlusion pressure). Rest interval durations were six, four and four minutes, respectively. Power output, cardiovascular demands and ratings of perceived exertion (RPE) were averaged over each interval. Knee extension torque and
electromyography responses following electrical stimulation of the femoral nerve were recorded pre-exercise, post-interval one (+1, 2 and 4-minutes) and post-interval four (+1, 2, 4, 6 and 8-minutes). Power output during BFR intervals was lower than non-BFR (233 ± 54 vs 282 ± 60 W,
< 0.001). Oxygen uptake and heart rate during BFR intervals were lower compared to non-BFR (38.7 ± 4.5 vs 44.7 ± 6.44 mL
kg
min
,
< 0.001; 160 ± 14 vs 166 ± 10 bpm,
< 0.001), while RPE was not different between conditions. Compared to pre-exercise, maximal voluntary contraction torque and peak twitch torque were reduced after the first interval with further reductions following the fourth interval (
< 0.001) independent of condition (
= 0.992). Voluntary activation (twitch interpolation) did not change between timepoints (
= 0.375). Overall, intermittent BFR reduced the mechanical and cardiovascular demands of self-paced intervals without modifying RPE or knee-extensor neuromuscular characteristics. Therefore, BFR reduced the cardiovascular demands while maintaining the muscular demands associated with self-paced intervals. Self-paced BFR intervals could be used to prevent cardiovascular and perceptual demands being the limiting factor of exercise intensity, thus allowing greater physiological muscular demands compared to intervals without BFR.
The use of blood flow restriction (BFR) during self-paced intervals (at the highest perceived sustainable intensity) causes a reduction in power output, pulmonary oxygen uptake and heart rate compared with non-restricted self-paced intervals.Despite lower mechanical and physiological demands during BFR cycling, the magnitude and aetiology of neuromuscular fatigue were not different to intervals without BFR, indicating the internal muscular load during BFR was elevated and potentially equivalent compared to without BFR.Self-paced intervals could be a suitable model to prescribe aerobic BFR exercise as an adjunct training stimulus for endurance cyclists.
Astrocytes are highly dynamic cells that modulate synaptic transmission within a temporal domain of seconds to minutes in physiological contexts such as Long-Term Potentiation (LTP) and ...Heterosynaptic Depression (HSD). Recent studies have revealed that astrocytes also modulate a faster form of synaptic activity (milliseconds to seconds) known as Transient Heterosynaptic Depression (tHSD). However, the mechanism underlying astrocytic modulation of tHSD is not fully understood. Are the traditional gliotransmitters ATP or glutamate released via hemichannels/vesicles or are other, yet, unexplored pathways involved? Using various approaches to manipulate astrocytes, including the Krebs cycle inhibitor fluoroacetate, connexin 43/30 double knockout mice (hemichannels), and inositol triphosphate type-2 receptor knockout mice, we confirmed early reports demonstrating that astrocytes are critical for tHSD. We also confirmed the importance of group II metabotropic glutamate receptors (mGluRs) in astrocytic modulation of tHSD using a group II agonist. Using dominant negative SNARE mice, which have disrupted glial vesicle function, we also found that vesicular release of gliotransmitters and activation of adenosine A1 receptors are not required for tHSD. As astrocytes can release lipids upon receptor stimulation, we asked if astrocyte-derived endocannabinoids are involved in tHSD. Interestingly, a cannabinoid receptor 1 (CB1R) antagonist blocked and an inhibitor of the endogenous endocannabinoid 2-arachidonyl glycerol (2-AG) degradation potentiates tHSD in hippocampal slices. Taken together, this study provides the first evidence for group II mGluR-mediated astrocytic endocannabinoids in transiently suppressing presynaptic neurotransmitter release associated with the phenomenon of tHSD.
Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A ...(PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.
Condensation and sublimation of ices at the surface of the planet is a key part of both the Martian H2O and CO2 cycles, either from a seasonal or diurnal aspect. While most of the ice is located ...within the polar caps, surface frost is known to be formed during nighttime down to equatorial latitudes. Here, we use data from the Emirates Mars Infrared Spectrometer onboard the Emirates Mars Mission to monitor the diurnal and seasonal evolution of the ices at the surface of Mars over almost one Martian year. The unique local time coverage provided by the instrument allows us to observe the apparition of equatorial CO2 frost in the second half of the Martian night around the equinoxes, to its sublimation at sunrise.
Plain Language Summary
The H2O and CO2 ices that form at the surface on Mars play an important role in the exchange between the atmosphere and the surface of the planet. While most of the ice is located within the two polar caps that grew and shrink seasonally, ice is also known to condensate as surface frost during the night and sublimate during the day. This nighttime surface frost deposition can be observed even at equatorial latitudes. In this paper we use data from the Emirates Mars Infrared Spectrometer onboard the Emirates Mars Mission to detect the H2O and CO2 ices at the surface of the planet at all local times over almost one Martian Year, which allows us to monitor both the seasonal and diurnal evolution of the distribution of ices at the surface of Mars. We observe that nighttime CO2 frost forms at equatorial latitudes in the second half of the night to disappear at sunrise around the Martian equinoxes.
Key Points
We monitor the seasonal growth and retreat of both polar caps over MY 36
We monitor the presence of CO2 ice on the surface of Mars over MY 36, through the season and through all times of day
CO2 ice appears at the surface at equatorial latitudes during the second half of the night around the equinoxes
Electrochemical deposition of Sr and Ba into liquid Bi metal was investigated in LiCl-KCl-SrCl2-BaCl2 electrolytes at 500 °C as a means to separate stable alkaline-earth ions from the molten salts ...(eutectic LiCl-KCl) utilized for recycling used nuclear fuel, by leveraging the strong chemical interactions between alkaline-earth metals and liquid Bi. The liquid Bi electrodes were subjected to cathodic discharge up to 270 C g–1 at a constant current density of 50 mA cm−2 in eutectic LiCl-KCl with the addition of 5 mol% total of SrCl2 and/or BaCl2. The use of Bi resulted in complex electrode reactions, leading to co-deposition of Sr (2.0–6.5 mol%), Ba (4.1–12.8 mol%), and Li (5.9–16.2 mol%), and coulombic efficiencies of 63–67% were achieved. The observed co-deposition was also supported via thermodynamic analyses of electrode potentials by incorporating the experimentally determined activity values of each alkali/alkaline-earth metal in Bi. The results of this work suggest that alkaline-earth fission products accumulated in molten salts (Sr2+ and Ba2+) can be recovered into liquid Bi by electrochemical separation, which could be employed as a critical step for recycling the process salt (LiCl-KCl) in order to minimize the generation of additional nuclear wastes.
A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one ...(HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.
DNA repair has long been considered impossible in human spermatozoa due to the high level of DNA compaction observed in these cells. However, detailed examination of the base excision repair pathway ...in human spermatozoa has revealed the presence of an enzyme critical to this pathway, 8-oxoguanine DNA glycosylase 1 (OGG1). This glycosylase was associated with the sperm nucleus and mitochondria and could actively excise 8-hydroxy-2'-deoxyguanosine (8OHdG), releasing this adduct into the extracellular space. This activity was significantly reduced in the presence of cadmium (II), a recognized inhibitor of OGG1, in a time- and dose-dependent manner (P<0.001). Remarkably, spermatozoa do not possess the downstream components of the base excision repair pathway, apurinic endonuclease 1 (APE1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1). The absence of these proteins was particularly significant, as APE1 is required to create a 3'-hydroxyl (3'-OH) terminus at the apurinic site created by OGG1, which would be recognized by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. As a result, TUNEL was unable to detect oxidatively induced DNA damage in spermatozoa following exposure to hydrogen peroxide. In the same cells, intracellular and extracellular 8OHdG could be clearly detected in a manner that was highly correlated with the outcome of the sperm chromatin structure assay (SCSA). However, incubation of these cells for 48 hours revealed a time-dependent increase in TUNEL positivity, suggesting the perimortem activation of a nuclease. These results emphasize the limited capacity of mature spermatozoa to mount a DNA repair response to oxidative stress, and highlight the importance of such mechanisms in the oocyte in order to protect the embryo from paternally mediated genetic damage.
•Recent literature demonstrates that vancomycin powder significantly reduces risk of Gram positive infections following fixation of high-risk tibia fractures, while tobramycin powder reduces risk of ...post-operative infection in an animal model.•Product costs of 1 gram vancomycin powder and 1.2 grams tobramycin powder are $20.64 and $75.80 at our institution, respectively.•Initial infection rates would need to be reduced by less than 0.1% for vancomycin powder or tobramycin powder to be economically justified.•Preventing 1 post-operative infection among 1000 surgeries with use of vancomycin and/or tobramycin powder results in break-even cost.
There is increasing interest regarding the risks and benefits of intrawound antibiotics applied directly to surgical wounds for the prevention of infection following orthopaedic trauma surgery. The purpose of this study was to investigate the economic justifiability of vancomycin and tobramycin powders for infection prophylaxis in orthopaedic trauma surgery.
The cost of vancomycin and tobramycin powders, infection rates and costs of treating surgical site infections were obtained from our institution's records and existing literature. A break-even analysis was then performed using vancomycin powder only, tobramycin powder only and combined vancomycin and tobramycin powders to determine the respective absolute risk reduction (ARR) in infection rate needed to make the prophylactic application of each therapy type break-even.
At our institutional pricing of $20.64 and $75.80 for 1g vancomycin and 1.2g tobramycin, respectively, use of each individually would be economically justified if it reduced an average infection rate of 4.3% by an ARR of 0.02% and 0.07%, respectively. Used in combination for $90.66, the ARR was 0.09%. Varying cost of treating infection from $5,000-$200,000 while maintaining cost of antibiotic powder at $90.66 demonstrated a range in ARR from 1.93% to 0.05%, respectively. At the same cost of $90.66 but varying infection rate from 1% to 25% did not affect ARR, which was constant at 0.09%.
Considering the cost of vancomycin and tobramycin powder at our institution, the application of these powders, whether independently or in combination, appear to be economically justifiable for infection prevention in orthopaedic trauma surgery.
Despite significant advances in treatment and prevention of HIV-1 infection, poor adherence to daily combination antiretroviral therapy (ART) regimens remains a major obstacle toward achieving ...sustained viral suppression and prevention. Adherence to ART could also be compromised by adverse drug reactions and societal factors that limit access to therapy. Therefore, medicines that aim to improve adherence by limiting ART side effects, frequency of dosing and socially acceptable regimens are becoming more attractive.
This review highlights recent advances and challenges in the development of long-acting drug delivery strategies for HIV prevention and treatment. Approaches for extended oral and transdermal deliveries, microbicides, broadly neutralizing antibodies, and long-acting implantable and injectable deliveries are reviewed.
Emerging approaches on long-acting antiretroviral therapies and broadly neutralizing antibody technologies are currently at various stages of development. Such efforts, if successful and become broadly accepted by clinicians and users, will provide newer and simpler options for prevention and treatment of HIV infection.
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