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The increasing descending drive needed to sustain a submaximal isometric torque makes it difficult to isolate fatigue-related changes to neural excitability because evoked electromyographic (EMG) responses are influenced by the relative activation of the motoneuron pool. Hence, it is becoming increasingly common to investigate fatigue using a sustained contraction with maintained output from the motoneuron pool; i.e., matched surface EMG. Although this approach controls motoneuron pool output, it is unknown how cortical contributions to ongoing muscle activity or common modulation between muscles is altered during a matched-EMG contraction. During separate visits, 16 participants performed a sustained 10-min isometric elbow flexion contraction at 20% maximal voluntary contraction (MVC) torque or the level of integrated biceps brachii EMG recorded at 20% MVC torque. Electroencephalographic and surface EMG recordings were obtained from the sensorimotor area and biceps and triceps brachii, respectively. The matched-torque contraction caused increased corticomuscular coherence for biceps brachii (~75%) and intermuscular coherence (~97%), but reduced MVC torque (~33%), voluntary activation (~9%), and torque steadiness (~83%). In contrast, the matched-EMG contraction caused reduced MVC torque (~21%), with no change in coherence, voluntary activation, or EMG steadiness. Further, participants reported higher ratings of perceived effort scores by 6min into the matched-torque compared to matched-EMG contraction. These findings indicate that, during a matched-torque contraction, the nervous system enhances common oscillatory activity to continue the task, but this does not prevent degradation of performance (torque steadiness). In contrast, when motoneuron pool output was clamped, other neural strategies are used to maintain muscle output.

Low fractions of inspired oxygen ([Formula: see text]; i.e., hypoxia) affect aspects of skeletal muscle contractility in humans, but it remains unclear if postactivation potentiation (PAP) and the torque-frequency (T-F) relationship are altered. We investigated the effects of 2 (H2) and 4 (H4) h of normobaric hypoxia ([Formula: see text] = 0.11 ± 0.47) on the magnitude of PAP of the knee extensors and the T-F relationship of the dorsiflexors in 13 and 12 healthy participants, respectively. To assess PAP, a resting twitch was evoked via femoral nerve stimulation before and 2-300 s after a 10-s maximal voluntary contraction (MVC). A T-F relationship was obtained by stimulating the common fibular nerve with a single pulse and 1-s trains between 5 and 100 Hz. During hypoxia, peripheral oxygen saturation decreased by ∼18% from 98.0 ± 0.8% at baseline ( P < 0.001). MVC force and voluntary activation (VA) of the knee extensors were lower than baseline throughout hypoxia (e.g., ∼8% and ∼5%, respectively, at H2; P ≤ 0.027); however, the magnitude of PAP was not altered by hypoxia ( P ≥ 0.711). Surprisingly, PAP did increase with time across the control day ( P ≤ 0.012). MVC torque and VA of the dorsiflexors were unaffected by hypoxia ( P ≥ 0.127), but the estimated frequency required to evoke 50% of 100 Hz torque increased by ∼1.2 Hz at H2 ( P ≤ 0.021). These results imply that 2 h of normobaric hypoxia were sufficient to 1 ) impair neural drive to the knee extensors but not the mechanism(s) responsible for PAP and 2 ) lead to a rightward shift of the T-F relationship for the dorsiflexors. NEW & NOTEWORTHY Postactivation potentiation of the knee extensors was unaffected by 4 h of normobaric hypoxia exposure but may be confounded by hypoxia-related impairments to the conditioning contraction. In the dorsiflexors, contractile rates increased in hypoxia, which led to a rightward shift of the torque-frequency relationship, such that a higher frequency was required to obtain 50% of maximal torque. These results expand our understanding of the acute effects of hypoxia on skeletal muscle function.

Hypoxia increases postural sway compared to normoxia, but the underlying sensorimotor factors remain unclear. An important contributor to balance control is cutaneous feedback arising from the feet, which can be partially characterized by electrically evoking a reflex from a purely cutaneous nerve (i.e., sural) and sampling the subsequent motor activity of a muscle. The purpose of the present study was to determine how normobaric hypoxia influences sural nerve reflex parameters during a standing posture. It was hypothesized that normobaric hypoxia would reduce cutaneous reflex area compared to normoxia. Participants (n = 16; 5 females, 11 males) stood with their feet together while receiving two trials of 50 sural nerve stimulations (200-Hz, 5-pulse train, presented randomly every 3-6 s) at baseline (BL; normoxia), and at 2 (H2) and 4 (H4) h of normobaric hypoxia (~ 0.11 fraction of inspired oxygen in a hypoxic chamber). The sural nerve reflex was recorded using surface electromyography from the left medial gastrocnemius, and characterized by area and duration of the initial positive and negative peaks of the response. When normalized to pre-stimulus electromyography, the area of the peak-to-peak cutaneous reflex was not different than BL (p ≥ 0.14) for up to 4 h of normobaric hypoxia (BL: 0.26 ± 0.22, H2: 0.19 ± 0.19, H4: 0.22 ± 0.20 A.U.). Furthermore, the duration of the response was not different during hypoxia (BL: 73.2 ± 42.4; H2: 75.2 ± 47.0; H4: 77.6 ± 54.6 ms; p ≥ 0.13) than BL. Thus, reflexes arising from cutaneous afferents of the lateral border of the foot are resilient to at least 4 h of normobaric hypoxia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

According to current guidelines, when measuring voluntary activation (VA) using transcranial magnetic stimulation (TMS), stimulator output (SO) should not exceed the intensity that, during a maximal voluntary contraction (MVC), elicits a motor evoked potential (MEP) from the antagonist muscle >15%-20% of its maximal M-wave amplitude. However, VA is based on agonist evoked-torque responses [i.e., superimposed twitch (SIT) and estimated resting twitch (ERT)], which means limiting SO based on electromyographic (EMG) responses will often lead to a submaximal SIT and ERT, possibly underestimating VA. Therefore, the purpose of this study was to compare elbow flexor VA calculated using the original method (i.e., intensity based on MEP size; SO MEP ) and a method based solely on eliciting the largest SIT at 50% MVC torque (SO SIT ), regardless of triceps brachii MEP size. Fifteen healthy, young participants performed 10 sets of brief contractions at 100%, 75%, and 50% MVC torque, with TMS delivered at SO MEP (73.0 ± 13.5%) or SO SIT (92.0 ± 10.8%) for five sets each. Although the mean ERT torque was greater using SO SIT (15.2 ± 4.8 Nm) compared with SO MEP (13.0 ± 3.7 Nm; P = 0.031), the SIT amplitude at 100% MVC torque was not different (SO MEP : 0.69 ± 0.49 Nm vs. SO SIT : 0.74 ± 0.52 Nm; P = 0.604). Despite the ERT disparity, VA scores were not different between SO MEP (94.6 ± 3.5%) and SO SIT (95.0 ± 3.3%; P = 0.572). Even though SO SIT did not lead to a higher VA score than the SO MEP method, it has the benefit of yielding the same result without the need to record antagonist EMG or perform MVCs when determining SO, which can induce fatigue before measuring VA. NEW & NOTEWORTHY When using transcranial magnetic stimulation (TMS) to determine voluntary activation (VA) of the elbow flexors, we hypothesized that a stimulator output designed to limit antagonist muscle activity would evoke submaximal agonist superimposed twitch amplitudes, thus underestimating VA. Contrary to our hypothesis, VA was not greater with an output based on maximal superimposed twitch amplitude. Nevertheless, our findings advance methodological practices by simplifying the equipment and minimizing the time required to determine VA using TMS.

A peer-mentoring network, funded by the National Science Foundation ADVANCE program, profoundly impacted the career trajectory of five women chemistry faculty at predominantly undergraduate institutions. By providing each other support, encouragement, information, and accountability, we advanced our careers, became leaders in our own right, and implemented change at our institutions. To extend this benefit to more women STEM faculty, we have developed and implemented a model to support 74 faculty and administrators representing 51 institutions across the country.

Ventilatory acclimatization (VA) is important to maintain adequate oxygenation with ascent to high altitude (HA). Transient hypoxic ventilatory response tests lack feasibility and fail to capture the integrated steady-state responses to chronic hypoxic exposure in HA fieldwork. We recently characterized a novel index of steady-state respiratory chemoreflex drive (SSCD), accounting for integrated contributions from central and peripheral respiratory chemoreceptors during steady-state breathing at prevailing chemostimuli. Acetazolamide is often utilized during ascent for prevention or treatment of altitude-related illnesses, eliciting metabolic acidosis and stimulating respiratory chemoreceptors. To determine if SSCD reflects VA during ascent to HA, we characterized SSCD in 25 lowlanders during incremental ascent to 4240 m over 7 days. We subsequently compared two separate subgroups: no acetazolamide (NAz; n = 14) and those taking an oral prophylactic dose of acetazolamide (Az; 125 mg BID; n = 11). At 1130/1400 m (day zero) and 4240 m (day seven), steady-state measurements of resting ventilation (V̇ I ; L/min), pressure of end-tidal (P ET )CO 2 (Torr), and peripheral oxygen saturation (SpO 2 ; %) were measured. A stimulus index (SI; P ET CO 2 /SpO 2 ) was calculated, and SSCD was calculated by indexing V̇ I against SI. We found that (a) both V̇ I and SSCD increased with ascent to 4240 m (day seven; V̇ I : +39%, p < 0.0001, Hedges' g = 1.52; SSCD: +56.%, p < 0.0001, Hedges' g = 1.65), (b) and these responses were larger in the Az versus NAz subgroup (V̇ I : p = 0.02, Hedges' g = 1.04; SSCD: p = 0.02, Hedges' g = 1.05). The SSCD metric may have utility in assessing VA during prolonged stays at altitude, providing a feasible alternative to transient chemoreflex tests., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Both voluntary rebreathing (RB) of expired air and voluntary apneas (VA) elicit changes in arterial carbon dioxide and oxygen (CO 2 and O 2 ) chemostimuli. These chemostimuli elicit synergistic increases in cerebral blood flow (CBF) and sympathetic nervous system activation, with the latter increasing systemic blood pressure. The extent that simultaneous and inverse changes in arterial CO 2 and O 2 and associated increases in blood pressure affect the CBF responses during RB versus VAs are unclear. We instrumented 21 healthy participants with a finometer (beat-by-beat mean arterial blood pressure; MAP), transcranial Doppler ultrasound (middle and posterior cerebral artery velocity; MCAv, PCAv) and a mouthpiece with sample line attached to a dual gas analyzer to assess pressure of end-tidal (P ET )CO 2 and P ET O 2 . Participants performed two protocols: RB and a maximal end-inspiratory VA. A second-by-second stimulus index (SI) was calculated as P ET CO 2 /P ET O 2 during RB. For VA, where P ET CO 2 and P ET O 2 could not be measured throughout, SI values were calculated using interpolated end-tidal gas values before and at the end of the apneas. MAP reactivity (MAPR) was calculated as the slope of the MAP/SI, and cerebrovascular reactivity (CVR) was calculated as the slope of MCAv or PCAv/SI. We found that compared to RB, VA elicited ~ fourfold increases in MAPR slope (P < 0.001), translating to larger anterior and posterior CVR (P ≤ 0.01). However, cerebrovascular conductance (MCAv or PCAv/MAP) was unchanged between interventions (P ≥ 0.2). MAP responses during VAs are larger than those during RB across similar chemostimuli, and differential CVR may be driven by increases in perfusion pressure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Quantifying prolonged low-frequency force depression (PLFFD) with the gold-standard 1-s trains presents challenges, so paired pulses have been used. Owing to greater impairment of high-frequency doublet than tetanic torque, paired pulses underestimate PLFFD. This study aimed to approximate the minimum number of high-frequency pulses needed to avoid such underestimation and assess the feasibility of modeling PLFFD from a limited number of experimental pulses. In 13 participants, a 1-s 10-Hz train and 100-Hz trains with 2, 4, 7, 12, 15, 25, 50, or 100 pulses were evoked before and after (15 min, 2, 4, and 7 days) eccentric exercise of the dorsiflexors. With ≤12 pulses, impairment of 100-Hz torque was greater than the 1-s train ( P ≤ 0.05; e.g., 12 vs. 100 pulses at 4 days: 97.8 ± 8.5% vs. 100.5 ± 8.2% baseline). Consequently, with ≤12 pulses, PLFFD was underestimated compared with the gold-standard measure ( P ≤ 0.05; e.g., 12 vs. 100 pulse 10:100-Hz torque ratio at 4 days: 86.8 ± 12.8% vs. 84.6 ± 13.5% baseline). Modeling reproduced 10:100-Hz ratios (PLFFD) with 95% limits of agreement of -13.6% to 16.7% of experimental values with ≥12 pulses. Our results indicate that a minimum of 13-25 pulses of 100 Hz are needed to accurately quantify PLFFD in the dorsiflexors. Although this may not be the minimum range for other muscles, a similar relationship with pulse number likely exists. Modeling may eventually provide an option to estimate PLFFD from experimental trains with relatively few pulses; however, further development is imperative to reduce variability. NEW & NOTEWORTHY Ideally, prolonged low-frequency force depression (PLFFD) is measured with 1-s trains of supramaximal stimuli; however, this induces considerable discomfort. We tested briefer trains to approximate the minimum number of high-frequency pulses needed to accurately determine PLFFD and the feasibility of modeling 1-s tetani with relatively few pulses. After eccentric exercise, 13-25 high-frequency pulses were needed to accurately measure PLFFD. Modeling reproduced mean experimental values but had considerable variability.

Unaccustomed eccentric (ECC) exercise induces muscle fatigue as well as damage and initiates a protective response to minimize impairments from a subsequent bout (i.e., repeated bout effect; RBE). It is uncertain if the sexes differ for neuromuscular responses to ECC exercise and the ensuing RBE. Twenty-six young adults (13 females) performed 2 bouts (4 weeks apart) of 200 ECC maximal voluntary contractions (MVCs) of the dorsiflexors. Isometric (ISO) MVC torque and the ratio of ISO torque in response to low- versus high-frequency stimulation (10:100 Hz) were compared before and after (2-10 min and 2, 4, and 7 days) exercise. The decline in ECC and ISO MVC torque and the 10:100 Hz ratio following bout 1 did not differ between sexes ( P > 0.05), with reductions from baseline of 31.5% ± 12.3%, 24.1% ± 15.4%, and 51.3% ± 12.2%, respectively. After bout 2, the 10:100 Hz ratio declined less (45.0% ± 12.4% from baseline) and ISO MVC torque recovered sooner compared with bout 1 but no differences between sexes were evident for the magnitude of the RBE ( P > 0.05). These data suggest that fatigability with ECC exercise does not differ for the sexes and adaptations that mitigate impairments to calcium handling are independent of sex. Novelty: One bout of 200 maximal eccentric dorsiflexor contractions caused equivalent muscle fatigue and damage for females and males. The repeated bout effect observed after a second bout 4 weeks later also had no sex-related differences. Prolonged low-frequency force depression is promoted as an indirect measure of muscle damage in humans.

Central and peripheral respiratory chemoreceptors are stimulated during voluntary breath holding due to chemostimuli (i.e., hypoxia and hypercapnia) accumulating at the metabolic rate. We hypothesized that voluntary breath-hold duration (BHD) would be (a) positively related to the initial pressure of inspired oxygen prior to breath holding, and (b) negatively correlated with respiratory chemoreflex responsiveness. In 16 healthy participants, voluntary breath holds were performed under three conditions: hyperoxia (following five normal tidal breaths of 100% O 2 ), normoxia (breathing room air), and hypoxia (following ~30-min of 13.5%-14% inspired O 2 ). In addition, the hypoxic ventilatory response (HVR) was tested and steady-state chemoreflex drive (SS-CD) was calculated in room air and during steady-state hypoxia. We found that (a) voluntary BHD was positively related to initial oxygen status in a dose-dependent fashion, (b) the HVR was not correlated with BHD in any oxygen condition, and (c) SS-CD magnitude was not correlated with BHD in normoxia or hypoxia. Although chemoreceptors are likely stimulated during breath holding, they appear to contribute less to BHD compared to other factors such as volitional drive or lung volume., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Prolonged low-frequency force depression (PLFFD) after damaging eccentric exercise may last for several days. Historically, PLFFD has been calculated from the tetanic force responses to trains of supramaximal stimuli. More recently, for methodological reasons, stimulation has been reduced to two pulses. However, it is unknown whether doublet responses provide a valid measure of PLFFD in the days after eccentric exercise. In 12 participants, doublets and tetani were elicited at 10 and 100 Hz before and after (2, 3, 5 min, 48 and 96 h) 200 eccentric maximal voluntary contractions of the dorsiflexors. Doublet and tetanic torque responses at 10 Hz were similarly depressed throughout recovery ( P > 0.05; e.g., 2 min: 58.9 ± 12.8% vs. 57.1 ± 14.5% baseline; 96 h: 85.6 ± 11.04% vs. 85.1 ± 10.8% baseline). At 100 Hz, doublet torque was impaired more than tetanic torque at all time points ( P < 0.05; e.g., 2 min: 70.5 ± 14.2% vs. 88.1 ± 11.7% baseline; 96 h: 83.0 ± 14.2% vs. 98.7 ± 9.5% baseline). As a result, the postfatigue reduction of the 10 Hz-to-100 Hz ratio (PLFFD) was markedly greater for tetani than for doublets ( P < 0.05; e.g., 2 min: 64.3 ± 15.1% vs. 83.0 ± 5.8% baseline). In addition, the doublet ratio recovered by 48 h (99.2 ± 5.0% baseline), whereas the tetanic ratio was still impaired at 96 h (88.2 ± 9.7% baseline). Our results indicate that doublets are not a valid measure of PLFFD in the minutes and days after eccentric exercise. If study design favors the use of paired stimuli, it should be acknowledged that the true magnitude and duration of PLFFD are likely underestimated. NEW & NOTEWORTHY Prolonged low-frequency force depression (PLFFD) will result from damaging exercise and may last for several days. After 200 eccentric maximal dorsiflexor contractions, we compared the gold-standard measure of PLFFD (calculated using trains of supramaximal stimulation) to the value obtained from an alternative technique that is becoming increasingly common (paired supramaximal stimuli). Doublets underestimated the magnitude and duration of PLFFD compared with tetani, so caution must be used when reporting PLFFD derived from paired stimuli.

Volitional Apnea produces a robust peak sympathetic response through several interacting mechanisms. However, the specific contribution of each mechanism has not been elucidated. Muscle sympathetic activity was collected in participants (n = 10; 24 ± 3 years) that performed four maximal volitional apneas aimed at isolating lung-stretch (mechanical) and chemoreflex drive: (Ainslie and Duffin ) end-expiratory breath-hold, (Ainslie et al. ) end-inspiratory breath-hold, (Alpher et al. ) prehyperventilation breath-hold, and (Andersson and Schagatay ) prehyperoxia breath-hold. A final repeated rebreathe breath-hold protocol was performed to measure the peak sympathetic response during successive breath-holds at increasing chemoreflex stress. Finally, the influence of dynamic ventilation was assessed through asphyxic rebreathe. Muscle sympathetic activity was calculated as the change in burst frequency (burst/min), burst incidence (burst/100 heart-beats), and amplitude (au) between baseline and prevolitional breakpoint. Rebreathe was analyzed at similar chemoreflex stress as inspiratory breath-hold. All maneuvers increased muscle sympathetic activity compared to baseline (P < 0.01). However, prehyperoxia exhibited a smaller increase (+22.18 ± 9.13 burst/min; +25.52 ± 11.7 burst/100 heart-beats) compared to inspiratory, expiratory, and prehyperventilation breath-holds. At similar chemoreflex strain, rebreathe sympathetic activity was blunted compared to inspiratory breath-hold (P < 0.01). Finally, muscle sympathetic activity was not different between the repeated rebreathe trials, despite elevated chemoreflex stress and lower breath-hold duration with each subsequent breath-hold. We have demonstrated an obligatory role of the peripheral, but not central, chemoreflex (prehyperventilation vs. prehyperoxia) in producing peak sympathetic responses. At similar chemoreflex stresses the act of dynamic ventilation, but not static lung stretch per se, blunts muscle sympathetic activity. Finally, similar peak sympathetic responses during successive repeated breath-holds suggest a sympathetic ceiling may exist., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP-II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the binding mechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two β-sheets of the β-barrel common to iLBPs and the α-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed.

For undergraduate students, involvement in authentic research represents scholarship that is consistent with disciplinary quality standards and provides an integrative learning experience. In conjunction with performing research, the communication of the results via presentations or publications is a measure of the level of scientific engagement. The empirical study presented here uses generalized linear mixed models with hierarchical bootstrapping to examine the factors that impact the means of dissemination of undergraduate research results. Focusing on the research experiences in physics and chemistry of undergraduates at four Primarily Undergraduate Institutions (PUIs) from 2004-2013, statistical analysis indicates that the gender of the student does not impact the number and type of research products. However, in chemistry, the rank of the faculty advisor and the venue of the presentation do impact the number of research products by undergraduate student, whereas in physics, gender match between student and advisor has an effect on the number of undergraduate research products. This study provides a baseline for future studies of discipline-based bibliometrics and factors that affect the number of research products of undergraduate students.

Measurements of central and peripheral respiratory chemoreflexes are important in the context of high altitude as indices of ventilatory acclimatization. However, respiratory chemoreflex tests have many caveats in the field, including considerations of safety, portability and consistency. This overview will (a) outline commonly utilized tests of the hypoxic ventilatory response (HVR) in humans, (b) outline the caveats associated with a variety of peak response HVR tests in the laboratory and in high altitude fieldwork contexts, and (c) advance a novel index of steady-state chemoreflex drive (SS-CD) that addresses the many limitations of other chemoreflex tests. The SS-CD takes into account the contribution of central and peripheral respiratory chemoreceptors, and eliminates the need for complex equipment and transient respiratory gas perturbation tests. To quantify the SS-CD, steady-state measurements of the pressure of end-tidal (P ET )CO 2 (Torr) and peripheral oxygen saturation (SpO 2 ; %) are used to quantify a stimulus index (SI; P ET CO 2 /SpO 2 ). The SS-CD is then calculated by indexing resting ventilation (L/min) against the SI. SS-CD data are subsequently reported from 13 participants during incremental ascent to high altitude (5160 m) in the Nepal Himalaya. The mean SS-CD magnitude increased approximately 96% over 10 days of incremental exposure to hypobaric hypoxia, suggesting that the SS-CD tracks ventilatory acclimatization. This novel SS-CD may have future utility in fieldwork studies assessing ventilatory acclimatization during incremental or prolonged stays at altitude, and may replace the use of complex and potentially confounded transient peak response tests of the HVR in humans.

Carotid chemoreceptors detect changes in PO 2 and elicit a peripheral respiratory chemoreflex (PCR). The PCR can be tested through a transient hypoxic ventilatory response test (TT-HVR), which may not be safe nor feasible at altitude. We characterized a transient hyperoxic ventilatory withdrawal test in the setting of steady-state normobaric hypoxia (13.5-14% F I O 2 ) and compared it to a TT-HVR and a steady-state poikilocapnic hypoxia test, within-individuals. No PCR test magnitude was correlated with any other test, nor was any test magnitude correlated with oxygenation while in steady-state hypoxia. Due to the heterogeneity between the different PCR test procedures and magnitudes, and the confounding effects of alterations in CO 2 acting on both central and peripheral chemoreceptors, we developed a novel method to assess prevailing steady-state chemoreflex drive in the context of hypoxia. Quantifying peak hypoxic/hyperoxic responses at low altitude may have minimal utility in predicting oxygenation during ascent to altitude, and here we advance a novel index of chemoreflex drive., (Copyright © 2017 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? We developed and validated a 'stimulus index' (SI; ratio of end-tidal partial pressures of CO 2 and O 2 ) method to quantify cerebrovascular reactivity (CVR) in anterior and posterior cerebral circulations during breath holding. We aimed to determine whether the magnitude of CVR is correlated with breath-hold duration. What is the main finding and its importance? Using the SI method and transcranial Doppler ultrasound, we found that the magnitude of CVR of the anterior and posterior cerebral circulations is not positively correlated with physiological or psychological break-point during end-inspiratory breath holding. Our study expands the ability to quantify CVR during breath holding and elucidates factors that affect break-point. The central respiratory chemoreflex contributes to blood gas homeostasis, particularly in response to accumulation of brainstem CO 2 . Cerebrovascular reactivity (CVR) affects chemoreceptor stimulation inversely through CO 2 washout from brainstem tissue. Voluntary breath holding imposes alterations in blood gases, eliciting respiratory chemoreflexes, potentially contributing to breath-hold duration (i.e. break-point). However, the effects of cerebrovascular reactivity on break-point have yet to be determined. We tested the hypothesis that the magnitude of CVR contributes directly to breath-hold duration in 23 healthy human participants. We developed and validated a cerebrovascular stimulus index methodology [SI; ratio of end-tidal partial pressures of CO 2 and O 2 (P ET ,CO2/P ET ,O2)] to quantify CVR by correlating measured and interpolated values of P ET ,CO2 (r = 0.95, P < 0.0001), P ET ,O2 (r = 0.98, P < 0.0001) and SI (r = 0.94, P < 0.0001) during rebreathing. Using transcranial Doppler ultrasound, we then quantified the CVR of the middle (MCAv) and posterior (PCAv) cerebral arteries by plotting cerebral blood velocity against interpolated SI during a maximal end-inspiratory breath hold. The MCAv CVR magnitude was larger than PCAv (P = 0.001; +70%) during breath holding. We then correlated MCAv and PCAv CVR with the physiological (involuntary diaphragmatic contractions) and psychological (end-point) break-point, within individuals. There were significant inverse but modest relationships between both MCAv and PCAv CVR and both physiological and psychological break-points (r < -0.53, P < 0.03). However, these relationships were absent when MCAv and PCAv cerebrovascular conductance reactivity was correlated with both physiological and psychological break-points (r > -0.42; P > 0.06). Although central chemoreceptor activation is likely to be contributing to break-point, our data suggest that CVR-mediated CO 2 washout from central chemoreceptors plays no role in determining break-point, probably because of a reduced arterial-to-tissue CO 2 gradient during breath holding., (© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.)

Background: Accurate calculation of medication dosages can be challenging for nursing students. Specific interventions related to types of errors made by nursing students may improve the learning of this important skill., Objective: The objective of this study was to determine areas of challenge for students in performing medication dosage calculations in order to design interventions to improve this skill., Design: Strengths and weaknesses in the teaching and learning of medication dosage calculations were assessed. These data were used to create online interventions which were then measured for the impact on student ability to perform medication dosage calculations., Setting: The setting of the study is one university in Canada., Participants: The qualitative research participants were 8 nursing students from years 1-3 and 8 faculty members. Quantitative results are based on test data from the same second year clinical course during the academic years 2012 and 2013., Methods: Students and faculty participated in one-to-one interviews; responses were recorded and coded for themes. Tests were implemented and scored, then data were assessed to classify the types and number of errors., Results: Students identified conceptual understanding deficits, anxiety, low self-efficacy, and numeracy skills as primary challenges in medication dosage calculations. Faculty identified long division as a particular content challenge, and a lack of online resources for students to practice calculations. Lessons and online resources designed as an intervention to target mathematical and concepts and skills led to improved results and increases in overall pass rates for second year students for medication dosage calculation tests., Conclusion: This study suggests that with concerted effort and a multi-modal approach to supporting nursing students, their abilities to calculate dosages can be improved. The positive results in this study also point to the promise of cross-discipline collaborations between nursing and education., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

New Findings: What is the central question of this study? We aimed to characterize the cardiorespiratory and cerebrovascular responses to transient and steady-state tests of the peripheral chemoreflex and to compare the hypoxic ventilatory responses (HVRs) between these tests. What is the main finding and its importance? The cardiovascular and cerebrovascular responses to transient tests were small in magnitude and short in duration. The steady-state isocapnic hypoxia test elicited a larger HVR than the transient 100% N(2) test, but the response magnitudes were correlated within individuals. The transient test of the HVR elicits fewer systemic effects than steady-state techniques and may have greater experimental utility than previously appreciated. Carotid chemoreceptors detect changes in arterial PO(2) and PCO(2), eliciting a peripheral chemoreflex (PCR). Steady-state (SS) hypoxia tests using dynamic end-tidal forcing (DEF) have been used to assess the hypoxic ventilatory response (HVR) but may be confounded by concomitant systemic effects. Transient tests of the PCR have also been developed but are not widely used, nor have the cardiovascular and cerebrovascular responses been characterized. We characterized the cardiorespiratory and cerebrovascular responses to transient tests of the PCR and compared the HVR between transient and SS-DEF tests. We hypothesized that the cardiovascular and cerebrovascular responses to the transient tests would be minimal and that the respiratory responses elicited from the transient and SS-DEF tests would be different in magnitude and not well correlated within individuals. Participants underwent five consecutive trials of two transient tests [three-breath 100% N(2) (TT-N(2)) and a single-breath 13% CO(2), in air] and two 10 min SS-DEF tests [isocapnic (SS-ISO) and poikilocapnic (SS-POI) hypoxia]. In response to the transient tests, heart rate, mean arterial pressure and the middle and posterior cerebral artery blood velocity increased (all P < 0.01), but responses were small (all <10%) and transient. Although the TT-N(2) and SS-POI tests elicited similar HVR magnitudes, they were not well correlated within individuals (r = 0.064, P = 0.79). The TT-N(2) test elicited a smaller HVR than the SS-ISO test, but they were correlated within individuals (r = 0.57, P = 0.008). Given that the transient tests exploit the temporal domain of the peripheral chemoreceptors and have minimal cardiovascular and cerebrovascular confounders, we suggest that they may have broader utility than previously appreciated., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazole-pyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza-benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G·C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, ΔT(M), and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K(eq) 4.0±0.2×10(7) M(-1))., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The physiology of breath holding is complex, and voluntary breath-hold duration is affected by many factors, including practice, psychology, respiratory chemoreflexes, and lung stretch. In this activity, we outline a number of simple laboratory activities or classroom demonstrations that illustrate the complexity of the integrative physiology behind breath-hold duration. These activities require minimal equipment and are easily adapted to small-group demonstrations or a larger-group inquiry format where students can design a protocol and collect and analyze data from their classmates. Specifically, breath-hold duration is measured during a number of maneuvers, including after end expiration, end inspiration, voluntary prior hyperventilation, and inspired hyperoxia. Further activities illustrate the potential contribution of chemoreflexes through rebreathing and repeated rebreathing after a maximum breath hold. The outcome measures resulting from each intervention are easily visualized and plotted and can comprise a comprehensive data set to illustrate and discuss complex and integrated cardiorespiratory physiology., (Copyright © 2015 The American Physiological Society.)

Molecular dynamics simulations of the DNA 10-mer 5'-CCACGCGTGG-3' alone and complexed with the formamido-imidazole-pyrrole-imidazole (f-ImPyIm) polyamide minor groove binder in a 2:1 fashion were conducted for 50 ns using the pbsc0 parameters within the AMBER 12 software package. The change in DNA structure upon binding of f-ImPyIm was evaluated via minor groove width and depth, base pair parameters of Slide, Twist, Roll, Stretch, Stagger, Opening, Propeller, and x-displacement, dihedral angle distributions of ζ, ε, α, and γ determined using the Curves+ software program, and hydrogen bond formation. The dynamic hydrogen bonding between the f-ImPyIm and its cognate DNA sequence was compared to the static image used to predict sequence recognition by polyamide minor groove binders. Many of the predicted hydrogen bonds were present in less than 50% of the simulation; however, persistent hydrogen bonds between G5/15 and the formamido group of f-ImPyIm were observed. It was determined that the DNA is wider in the Complex than without the polyamide binder; however, there is flexibility in this particular sequence, even in the presence of the f-ImPyIm as evidenced by the range of minor groove widths the DNA exhibits and the dynamics of the hydrogen bonding that binds the two f-ImPyIm ions to the minor groove. The Complex consisting of the DNA and the 2 f-ImPyIm binders shows slight fraying of the 5' end of the 10-mer at the end of the simulation, but the portion of the oligomer responsible for recognition and binding is stable throughout the simulation. Several structural changes in the Complex indicate that minor groove binders may have a more active role in inhibiting transcription than just preventing binding of important transcription factors., (Copyright © 2015 John Wiley & Sons, Ltd.)

The arrangement of water and chloride ions around a model peptide (glycyl-L-prolyl-glycine-NH2) was investigated using Molecular Dynamics (MD) simulations and complementary Empirical Potential Structure Refinement (EPSR) simulations which adapt the modelled structure to reproduce experimentally measured neutron diffraction data. The results are in good qualitative agreement and show a common picture for all hydrogen-containing amine and amide groups: namely that there are two common chloride interactions observed - a direct contact between Cl(-) and peptide backbone and a water-mediated interaction. The geometry of this mediation depends on the distance between chloride and nitrogen and hints towards two distinct modes of interaction between water and the ion, either along one of the O-H bonds or along the water dipole.

Water-mediated bond formation: The structure of the peptide GPG-NH2 has been investigated in aqueous solution to understand the role of water in the formation of a β-turn. Using a combination of neutron diffraction enhanced by isotopic substitution, NMR spectroscopy, and computer simulations, it was found that water is an essential component to initiate folding in solution., (© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

With the aim of incorporating a recognition element that acts as a fluorescent probe upon binding to DNA, three novel pyrrole (P) and imidazole (I)-containing polyamides were synthesized. The compounds contain a p-anisylbenzimidazolecarboxamido (Hx) moiety attached to a PP, IP, or PI unit, giving compounds HxPP (2), HxIP (3), and HxPI (4), respectively. These fluorescent hybrids were tested against their complementary nonfluorescent, non-formamido tetraamide counterparts, namely, PPPP (5), PPIP (6), and PPPI (7) (cognate sequences 5'-AAATTT-3', 5'-ATCGAT-3', and 5'-ACATGT-3', respectively). The binding affinities for both series of polyamides for their cognate and noncognate sequences were ascertained by surface plasmon resonance (SPR) studies, which revealed that the Hx-containing polyamides gave binding constants in the 10(6) M(-1) range while little binding was observed for the noncognates. The binding data were further compared to the corresponding and previously reported formamido-triamides f-PPP (8), f-PIP (9), and f-PPI (10). DNase I footprinting studies provided additional evidence that the Hx moiety behaved similarly to two consecutive pyrroles (PP found in 5-7), which also behaved like a formamido-pyrrole (f-P) unit found in distamycin and many formamido-triamides, including 8-10. The biophysical characterization of polyamides 2-7 on their binding to the abovementioned DNA sequences was determined using thermal melts (ΔT(M)), circular dichroism (CD), and isothermal titration calorimetry (ITC) studies. Density functional calculations (B3LYP) provided a theoretical framework that explains the similarity between PP and Hx on the basis of molecular electrostatic surfaces and dipole moments. Furthermore, emission studies on polyamides 2 and 3 showed that upon excitation at 322 nm binding to their respective cognate sequences resulted in an increase in fluorescence at 370 nm. These low molecular weight polyamides show promise for use as probes for monitoring DNA recognition processes in cells.

The objective of this study was to investigate the influence of talc and humidity conditions during storage on the crystal growth of guaifenesin on the surface of melt-extruded matrix tablets. Tablets consisted of the model drug guaifenesin in a matrix of either Acryl-EZE(R) or Eudragit(R) L10055 and either no talc, 25% or 50% talc. After processing, the hot-melt-extruded matrix tablets were supersaturated with amorphous guaifenesin, which resulted in the development of guaifenesin drug crystals on exposed surfaces of the tablet during storage (all tablets were stored at 24 degrees C). A previously developed, quantitative test was used to assay for surface guaifenesin. In tablets with a drug-to-polymer ratio of 19:81, talc-containing tablets exhibited an earlier onset of crystal growth (storage at 17% relative humidity). The presence of talc also increased the amount of surface crystallization and was independent of the talc concentration, since the talc levels used in this study exceeded the critical nucleant concentration. Additional non-melting components did not have an additive effect on surface crystal growth. High humidity during storage (78%) increased guaifenesin crystallization, but moisture uptake of tablets did not correlate with increased drug recrystallization. When storage at 17% relative humidity was interrupted for 3days by storage at 78% relative humidity before the tablets were returned to their previous low RH storage conditions, crystal growth quickly increased during the high RH interval and remained at an elevated level throughout the remaining storage period. A similar intermediate period of low, 17% relative humidity in tablets stored before and after that time at 78% RH did not affect surface crystallization levels. The effects of humidity and talc on the crystallization of guaifenesin from melt-extruded dosage forms supersaturated with amorphous drug were ascribed to heterogeneous nucleation.

Objectives: This study investigated the effect of aqueous film coating on the recrystallization of guaifenesin from acrylic, hot-melt extruded matrix tablets., Methods: After hot-melt extrusion, matrix tablets were film-coated with either hypromellose or ethylcellulose. The effects of the coating polymer, curing and storage conditions, polymer weight gain, and core guaifenesin concentration on guaifenesin recrystallization were investigated., Results: The presence of either film coating on the guaifenesin-containing tablets was found to prolong the onset time of drug crystallization. The coating polymer was the most important factor determining the delay in the onset of crystallization, with the more hydrophilic polymer, hypromellose, having a higher solubilization potential for the guaifenesin and delaying crystallization for longer period (3 or 6 months in tablets stored at 40 degrees C or 25 degrees C, respectively) than the more hydrophobic ethylcellulose, which displayed a lower solubilization potential for guaifenesin (crystal growth on tablets cured for 2 hours at 60 degrees C occurred within 3 weeks, whereas uncoated tablets displayed surface crystal growth after 30 minutes). Crystal morphology was also affected by the film coating. Elevated temperatures during both curing and storage, incomplete film coalescence, and high core drug concentrations all contributed to an earlier onset of crystal growth.

Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH. Tablets with either constant polymer levels or constant drug-to-polymer ratios and containing different drug particle size fractions and increasing amounts of CA MH were manufactured by melt extrusion and characterized by dissolution testing, powder X-ray diffraction and scanning electron microscopy. The addition of CA MH to the formulation promoted the thermal processibility and matrix integrity by plasticization of the polymer. The drug release from systems with constant drug-to-polymer ratio was significantly increased when CA MH was added as a result of enhanced pore formation. Particle size effects were eliminated when large amounts of CA MH were used due to the loss of drug crystallinity. Matrix tablets with CA MH furthermore showed a faster and more complete drug release compared to systems with drug only or alternative pore formers (sucrose, NaCl, or PEG 3350). The enhanced drug release was attributed to the amorphous character of the soluble components, improved drug dispersion in the plasticized polymer along with increased polymer permeability. In summary, CA MH promoted the miscibility between the drug and Eudragit RS PO during hot-melt extrusion, resulting in the extrusion of an amorphous system with improved dissolution characteristics.

The polyamide f-ImPyIm has a higher affinity for its cognate DNA than either the parent analogue, distamycin A (10-fold), or the structural isomer, f-PyImIm (250-fold), has for its respective cognate DNA sequence. These findings have led to the formulation of a two-letter polyamide "language" in which the -ImPy- central pairings associate more strongly with Watson-Crick DNA than -PyPy-, -PyIm-, and -ImIm-. Herein, we further characterize f-ImPyIm and f-PyImIm, and we report thermodynamic and structural differences between -ImPy- (f-ImPyIm) and -PyIm- (f-PyImIm) central pairings. DNase I footprinting studies confirmed that f-ImPyIm is a stronger binder than distamycin A and f-PyImIm and that f-ImPyIm preferentially binds CGCG over multiple competing sequences. The difference in the binding of f-ImPyIm and f-PyImIm to their cognate sequences was supported by the Na(+)-dependent nature of DNA melting studies, in which significantly higher Na(+) concentrations were needed to match the ability of f-ImPyIm to stabilize CGCG with that of f-PyImIm stabilizing CCGG. The selectivity of f-ImPyIm beyond the four-base CGCG recognition site was tested by circular dichroism and isothermal titration microcalorimetry, which shows that f-ImPyIm has marginal selectivity for (A.T)CGCG(A.T) over (G.C)CGCG(G.C). In addition, changes adjacent to this 6 bp binding site do not affect f-ImPyIm affinity. Calorimetric studies revealed that binding of f-ImPyIm, f-PyImIm, and distamycin A to their respective hairpin cognate sequences is exothermic; however, changes in enthalpy, entropy, and heat capacity (DeltaC(p)) contribute differently to formation of the 2:1 complexes for each triamide. Experimental and theoretical determinations of DeltaC(p) for binding of f-ImPyIm to CGCG were in good agreement (-142 and -177 cal mol(-)(1) K(-)(1), respectively). (1)H NMR of f-ImPyIm and f-PyImIm complexed with their respective cognate DNAs confirmed positively cooperative formation of distinct 2:1 complexes. The NMR results also showed that these triamides bind in the DNA minor groove and that the oligonucleotide retains the B-form conformation. Using minimal distance restraints from the NMR experiments, molecular modeling and dynamics were used to illustrate the structural complementarity between f-ImPyIm and CGCG. Collectively, the NMR and ITC experiments show that formation of the 2:1 f-ImPyIm-CGCG complex achieves a structure more ordered and more thermodynamically favored than the structure of the 2:1 f-PyImIm-CCGG complex.

Second gas-solid virial coefficients for propane, butane, pentane, and hexane were found for Carbopack C and Carbopack C-HT (Supelco Inc.) within the temperature range of 323 to 471 K using gas-solid chromatography in the Henry's law region of adsorption. Carbopack C and Carbopack C-HT are both graphitized carbon black powders. Treatment of Carbopack C with hydrogen at 1273 K converts it to Carbopack C-HT and is believed to remove certain high energy sites or "hot spots" from the carbon surface. These two surfaces provide appropriate model systems to test a two-surface virial analysis. Surface areas for both powders were calculated using a uniform single-surface model and a two-surface model. Only the two-surface virial model which is based on gas-solid interaction parameters determined by an iterative process and numerical integration gave reasonable areas for the two surfaces: 13.2 and 13.9 m2/g for Carbopack C and Carbopack C-HT, respectively. The percentage of high energy sites on the Carbopack C was found to be 2.6% and for Carbopack C-HT was found to be 1.5%. The gas-solid interaction energy for the high energy sites was found to be 1.80 times greater than the corresponding value for the low energy portion of the surface. In addition, the gas-solid adsorption energies for the four alkane adsorbates were found to have a linear correlation with their boiling points and with the ratio of their critical temperatures divided by the square root of their critical pressures. Copyright 1997 Academic Press. Copyright 1997Academic Press