Search

Railroads are operating waste transfer stations in their rights of way without any governmental oversight, despite the fact that solid waste management and disposal has long been regulated at the state and local level. This incongruous situation is the result of railroads' aggressive litigation campaign to preempt generally applicable laws under a federal statute designed to deregulate rail economics. This phenomenon illustrates new uses of preemption doctrine by regulated entities, and some agencies, as a shield against state regulation even when there is no effective federal regulation to fill the gap. Restrained preemption jurisprudence is a necessary counterweight to regulatory voids, as Congress cannot anticipate all creative legal arguments that urge preemption based on unclear statutory language, is often imprecise when defining the scope of preemption provisions, and does not readily revise statutes to correct erroneous judicial interpretations. Courts must therefore have a primary role to ensure that preemption is not unintentionally overextended to the detriment of health and safety regulations. However, the courts' declining use of a presumption against preemption of police power laws has upset the delicate balance between federal and state interests. With a view towards restoring the presumption against preemption, this Article criticizes past attempts to ground it upon historical areas of state regulation, and suggests grounding it upon a line of Supreme Court cases that use regulatory gaps to mark the plausible limits of congressional intent to preempt. This proposed revival of the presumption against preemption also draws support from constitutional imitations on Congress's powers to veto state laws. [ABSTRACT FROM AUTHOR]

Simple Summary: Synovial sarcoma is a soft-tissue sarcoma that lacks effective systemic therapy and carries poor prognosis due to frequent late local recurrence and metastases. The cancer is known to be driven in part by increased expression of the pro-survival protein BCL-2. Surprisingly, synovial sarcoma proved resistant to BCL-2 inhibitors in pre-clinical trials. We identified increased activity of a second pro-survival protein, MCL-1, as responsible for this resistance. We showed that co-targeting both BCL-2 and MCL-1 proves to be an effective therapeutic approach both in cell culture and animal models of synovial sarcoma, supporting translation into clinical trials. Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2-expressing hematological cancers, affords an intriguing therapeutic possibility to treat SS. In addition, there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers, attributing to the limited toxicity of venetoclax. However, preclinical studies of venetoclax in SS have demonstrated an unexpected ineffectiveness. In this study, we analyzed the response of SS to venetoclax and the underlying BCL-2 family biology in an effort to understand venetoclax treatment failure and find a therapeutic strategy to sensitize SS to venetoclax. We found remarkably depressed levels of the endogenous MCL-1 inhibitor, NOXA, in SS compared to other sarcomas. Expressing NOXA led to sensitization to venetoclax, as did the addition of the MCL-1 BH3 mimetic, S63845. Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy. [ABSTRACT FROM AUTHOR]

Background: A wide range of household secondary infection rates has been reported, and the role of children in population transmission dynamics for SARS-CoV-2 remains ill-defined. We sought to better understand household infection early in the pandemic., Methodology: A cross-sectional study of 17 households in the Atlanta metropolitan area with at least one child and one case of COVID-19 in the prior 1-4 months were recruited between December 2020 and April 2021. Self-collected saliva samples were tested on a multiplexed platform to detect IgG antibodies that bind to SARS-CoV-2 antigens. Secondary infection rates (SIR) were calculated and compared., Results: We report results on 17 families, including 66 individuals. We found an average SIR of 0.58; children and adults were similarly infected (62% children vs. 75% adults) ( p  = 0.2). Two out of 17 households had a pediatric index per our definition. Number of pediatric infections per household ( p  = 0.18), isolation ( p  = 0.34), and mask wearing ( p  = 0.80) did not differ significantly among households with an SIR above the mean vs. those with SIR below the mean. Households with higher SIR also had a higher number of symptomatic cases ( p  < 0.001)., Discussion: We demonstrated high household SIRs at the early stages of the pandemic in late 2020 to early 2021 with similar impact on children and adults. The ease of collecting saliva and the detection of asymptomatic infections highlight the advantages of this strategy and potential for scale-up., Competing Interests: EJA has consulted for Pfizer, Sanofi Pasteur, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc. and Sanofi Pasteur. His institution has also received funding from NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nowak, Lane, Mbanya, Carter, Binion, Espinoza, Collins, Heaney, Pisanic, Kruczynski, Spicer, Rivera, Glover, Ojo-Akosile, Breiman, Anderson, Lobelo and Fairley.)

Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular disease (CVD) risk. Compared with males, females are twice as likely to develop PTSD after trauma exposure, and cardiovascular reactivity to stress is a known risk factor for CVD. We aimed to examine hemodynamic responses to acute mental stress in trauma-exposed females with and without a clinical diagnosis of PTSD. We hypothesized that females with PTSD would have higher heart rate (HR), blood pressure (BP), and lower blood flow velocity (BFV) responsiveness compared with controls. We enrolled 21 females with PTSD and 21 trauma-exposed controls. We continuously measured HR using a three-lead electrocardiogram, BP using finger plethysmography, and brachial BFV using Doppler ultrasound. All variables were recorded during 10 min of supine rest, 5 min of mental arithmetic, and 5 min of recovery. Females with PTSD were older, and had higher BMI and higher resting diastolic BP. Accordingly, age, BMI, and diastolic BP were covariates for all repeated measures analyses. Females with PTSD had a blunted brachial BFV response to mental stress (time × group, p = 0.005) compared with controls, suggesting greater vasoconstriction. HR and BP responses were comparable. In conclusion, our results suggest early impairment of vascular function in premenopausal females with PTSD., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

There have been ongoing efforts by federal agencies and scientific communities since the early 1990s to incorporate sex and/or gender in all aspects of cardiovascular research. Scientific journals provide a critical function as change agents to influence transformation by encouraging submissions for topic areas, and by setting standards and expectations for articles submitted to the journal. As part of ongoing efforts to advance sex and gender in cardiovascular physiology research, the American Journal of Physiology-Heart and Circulatory Physiology recently launched a call for papers on Considering Sex as a Biological Variable. This call was an overwhelming success, resulting in 78 articles published in this collection. This review summarizes the major themes of the collection, including Sex as a Biological Variable Within: Endothelial Cell and Vascular Physiology, Cardiovascular Immunity and Inflammation, Metabolism and Mitochondrial Energy, Extracellular Matrix Turnover and Fibrosis, Neurohormonal Signaling, and Cardiovascular Clinical and Epidemiology Assessments. Several articles also focused on establishing rigor and reproducibility of key physiological measurements involved in cardiovascular health and disease, as well as recommendations and considerations for study design. Combined, these articles summarize our current understanding of sex and gender influences on cardiovascular physiology and pathophysiology and provide insight into future directions needed to further expand our knowledge.

Sleep disturbance, one of the most common menopausal symptoms, contributes to autonomic dysfunction and is linked to hypertension and cardiovascular risk. Longitudinal studies suggest that hyperreactivity of blood pressure (BP) to a stressor can predict the future development of hypertension. It remains unknown if postmenopausal females who experience sleep disturbance (SDG) demonstrate greater hemodynamic and sympathetic neural hyperreactivity to a stressor. We hypothesized that postmenopausal females with reported sleep disturbance would exhibit increased hemodynamic and sympathetic reactivity to a stressor compared with postmenopausal females without sleep disturbance (non-SDG). Fifty-five postmenopausal females (age, 62 ± 4 yr old; SDG, n = 36; non-SDG; n = 19) completed two study visits. The Menopause-Specific Quality of Life Questionnaire (MENQOL) was used to assess the presence of sleep disturbance (MENQOL sleep scale, ≥2 units). Beat-to-beat BP (finger plethysmography), heart rate (HR; electrocardiogram), and muscle sympathetic nerve activity (MSNA; microneurography; SDG, n = 25; non-SDG, n = 15) were continuously measured during a 10-min baseline and 2-min stressor (cold pressor test; CPT) in both groups. Menopause age and body mass index were similar between groups ( P > 0.05). There were no differences between resting BP, HR, or MSNA ( P > 0.05). HR and BP reactivity were not different between SDG and non-SDG ( P > 0.05). In contrast, MSNA reactivity had a more rapid increase in the first 30 s of the CPT in the SDG (burst incidence, Δ10.2 ± 14.8 bursts/100 hb) compared with the non-SDG (burst incidence, Δ4.0 ± 14.8 bursts/100 hb, time × group, P = 0.011). Our results demonstrate a more rapid sympathetic neural reactivity to a CPT in postmenopausal females with perceived sleep disturbance, a finding that aligns with and advances recent evidence that sleep disturbance is associated with sympathetic neural hyperactivity in postmenopausal females. NEW & NOTEWORTHY This is the first study to demonstrate that muscle sympathetic nerve activity (MSNA) to a cold pressor test is augmented in postmenopausal females with perceived sleep disturbance. The more rapid increase in MSNA reactivity during the cold pressor test in the sleep disturbance group was present despite similar increases in the perceived pain levels between groups. Baseline MSNA burst incidence and burst frequency, as well as blood pressure and heart rate, were similar between the sleep disturbance and nonsleep disturbance groups.

Recent reports suggest that quantification of signal-averaged sympathetic transduction is influenced by resting muscle sympathetic nerve activity (MSNA) and burst occurrence relative to the average mean arterial pressure (MAP). Herein, we asked how these findings may influence age-related reductions in sympathetic transduction. Beat-to-beat blood pressure and MSNA were recorded during 5 min of rest in 27 younger (13 females: age, 25 ± 5 yr; BMI, 25 ± 4 kg/m 2 ) and 26 older (15 females: age, 59 ± 5 yr; BMI, 26 ± 4 kg/m 2 ) healthy adults. All MSNA bursts were signal averaged together. Beat-to-beat MAP values were then split into low (T1), middle (T2), and high (T3) tertiles, and signal-averaged transduction was calculated within each tertile. Resting MSNA was higher in older adults and MAP was similar between groups. Older adults exhibited blunted overall MAP transduction (younger, Δ1.5 ± 0.6 vs. older, Δ0.9 ± 0.7 mmHg; P = 0.005), which was irrespective of relation to prevailing MAP. A greater proportion of bursts occurred above the average MAP in older adults ( P < 0.001), and a larger proportion of these bursts were associated with depressor responses ( P = 0.005). Nonetheless, assessment of bursts above the average MAP associated with pressor responses revealed similar age-associated reductions in transduction (younger, Δ2.6 ± 1.6 vs. older, Δ1.7 ± 0.8 mmHg; P = 0.016). These findings indicate an age-related increase in burst occurrence above the average resting MAP, which alone does not explain blunted transduction, thereby supporting the physiological underpinnings of age-related decrements in sympathetic transduction to blood pressure. NEW & NOTEWORTHY The current study demonstrated that aging is associated with a greater prevalence of sympathetic bursts occurring above the average blood pressure, which offers both methodologically and physiologically relevant information regarding aging and sympathetic control of blood pressure. These data support age-related reductions in sympathetic transduction via a reduced pressor response to sympathetic bursts irrespective of the prevailing absolute blood pressure value, along with increases in sympathetic outflow necessary to maintain blood pressure.

Despite National Institute of Health (NIH) mandates requiring sex as a biological variable (SABV), female underrepresentation persists in research, driving the American Journal of Physiology-Heart and Circulatory Physiology (Am J Physiol-Heart Circ) to publish SABV expectations in 2021. To determine progress within the Am J Physiol-Heart Circ , this mini-review evaluated SABV during the first 6 mo of each decade from 1980 to 2020, and 2019, to mitigate pandemic influence. Of the 1,205 articles published, 1,087 articles were included in this review (articles without original research subjects were excluded), of which 72.9% identified subjects. There were consistently fewer female human participants than males, except within 2019 (1980: females n = 3, males n = 5; 1990: females n = 70, males n = 199; 2000: females n = 305, males n = 355; 2010: females n = 186, males n = 472; 2019: females n = 1,695, males n = 1,550; 2020: females n = 1,157, males n = 1,222) and fewer female animals than males (1980: females n = 58, males n = 1,291; 1990: females n = 447, males n = 2,628; 2000: females n = 590, males n = 3,083; 2010: females n = 663, males n = 4,517; 2019: females n = 338, males n = 1,340; 2020: females n = 1,372, males n = 1,973). Only 16 (12.3%) articles including humans discussed SABV from 1980 to 2020. There are persistent SABV disparities within Am J Physiol-Heart Circ with some improvements in recent years. It is imperative that organizations such as the American Physiological Society and NIH foster an expectation of SABV as the norm, not the exception.

Core body temperature (CBT) reductions occur before and during the sleep period, with the extent of presleep reductions corresponding to sleep onset and quality. Presleep reductions in CBT coincide with increased cardiac parasympathetic activity measured via heart rate variability (HRV), and while this appears to persist into the sleep period, individual differences in presleep CBT decline and nocturnal HRV remain unexplored. The purpose of the current study was to assess the relationship between individual differences in presleep CBT reductions and nocturnal heart rate (HR) and HRV in a population of 15 objectively poor sleeping adults [10 males, 5 females; age, 33 ± 4 yr; body mass index (BMI) 27 ± 1 kg/m 2 ] with the hypothesis that blunted CBT rate of decline would be associated with elevated HR and reduced nocturnal HRV. Following an adaptation night, all participants underwent an overnight, in-laboratory sleep study with simultaneous recording of polysomnographic sleep including electrocardiography (ECG) and CBT recording. Correlations between CBT rate of change before sleep and nocturnal HRV were assessed. Blunted rate of CBT decline was significantly associated with increased heart rate (HR) in stage 2 ( N2 ; R = 0.754, P = 0.001), stage 3 ( N3 ; R = 0.748, P = 0.001), and rapid-eye movement (REM; R = 0.735, P = 0.002). Similarly, blunted rate of CBT decline before sleep was associated with reduced HRV across sleep stages. These findings indicate a relationship between individual differences in presleep thermoregulatory processes and nocturnal cardiac autonomic function in poor sleeping adults. NEW & NOTEWORTHY Core body temperature (CBT) reductions before sleep onset coincide with increases in heart rate variability (HRV) that persist throughout the sleep period. However, the relationship between individual differences in the efficiency of presleep core temperature regulation and nocturnal heart rate variability remains equivocal. The present study reports an association between the magnitude of presleep core body temperature changes and nocturnal parasympathetic activity, highlighting overlap between thermoregulatory processes before sleep and nocturnal cardiac autonomic function.

Chronic anxiety is prevalent and associated with an increased risk of cardiovascular disease. Prior studies that have reported a relationship between muscle sympathetic nerve activity (MSNA) and anxiety have focused on participants with anxiety disorders and/or metabolic syndrome. The present study leverages a large cohort of healthy adults devoid of cardiometabolic disorders to examine the hypothesis that trait anxiety severity is positively associated with resting MSNA and blood pressure. Resting blood pressure (BP) (sphygmomanometer and finger plethysmography), MSNA (microneurography), and heart rate (HR; electrocardiogram) were collected in 88 healthy participants (52 males, 36 females, 25 ± 1 yr, 25 ± 1 kg/m 2 ). Multiple linear regression was performed to assess the independent relationship between trait anxiety, MSNA, resting BP, and HR while controlling for age and sex. Trait anxiety was significantly correlated with systolic arterial pressure (SAP; r = 0.251, P = 0.018), diastolic arterial pressure (DAP; r = 0.291, P = 0.006), mean arterial pressure (MAP; r = 0.328, P = 0.002), MSNA burst frequency (BF; r = 0.237, P = 0.026), and MSNA burst incidence (BI; r = 0.225, P = 0.035). When controlling for the effects of age and sex, trait anxiety was independently associated with SAP (β = 0.206, P = 0.028), DAP (β = 0.317, P = 0.002), MAP (β = 0.325, P = 0.001), MSNA BF (β = 0.227, P = 0.030), and MSNA BI (β = 0.214, P = 0.038). Trait anxiety is associated with increased blood pressure and MSNA, demonstrating an important relationship between anxiety and autonomic blood pressure regulation. NEW & NOTEWORTHY Anxiety is associated with development of cardiovascular disease. Although the sympathetic nervous system is a likely mediator of this relationship, populations with chronic anxiety have shown little, if any, alteration in resting levels of directly recorded muscle sympathetic nerve activity (MSNA). The present study is the first to reveal an independent relationship between trait anxiety, resting blood pressure, and MSNA in a large cohort of healthy males and females devoid of cardiometabolic comorbidities.

Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans.

Cardiovascular disease (CVD), the leading cause of death among US adults, is more prevalent in menopausal females compared with age-matched males. Vasomotor symptoms of menopause (VMS; hot flashes/flushes and night sweats) are common among females undergoing menopausal transition and have been associated with elevated blood pressure (BP) and increased CVD risk. Autonomic dysregulation of BP has been posited as a contributing factor to the elevated CVD risk in menopausal females with VMS. This review includes 1 ) a brief overview of the relationship between VMS and CVD, 2 ) mechanisms of hot flushes and their potential impact on short- and long-term BP regulation, and 3 ) how the disruption of autonomic function associated with VMS might provide a mechanistic pathway to CVD development. Finally, this review will highlight knowledge gaps and future directions toward better understanding of hot flush physiology and VMS contributions to CVD.

Sympathetic responsiveness to laboratory mental stress is highly variable, making interpretations of its role in stress reactivity challenging. The present study assessed muscle sympathetic nerve activity (MSNA, microneurography) responsiveness to the Trier social stress test (TSST), which employs an anticipatory stress phase, followed by a public speaking and mental arithmetic task. We hypothesized that sympathetic reactivity to the anticipatory phase would offer a more uniform response between individuals due to elimination of confounds (i.e. respiratory changes, muscle movement, etc.) observed during more common stress tasks. Participants included 26 healthy adults (11 men, 15 women, age: 25 ± 6 years, body mass index: 24 ± 3 kg/m 2 ). Continuous heart rate (electrocardiogram) and beat-to-beat blood pressure (finger plethysmography) were recorded from all participants, while MSNA recordings were obtained in 20 participants. MSNA burst frequency was significantly reduced during anticipatory stress. During the speech, although burst frequency was unchanged, total MSNA was significantly increased. Changes in diastolic arterial pressure were predictive of changes in MSNA during anticipatory (β = -0.680, P = 0.001), but not the speech (P = 0.318) or mental maths (P = 0.051) phases. Lastly, sympathetic reactivity to anticipatory stress was predictive of subsequent reactivity to both speech (β = 0.740, P = 0.0002) and maths (β = 0.663, P = 0.001). In conclusion, anticipatory social stress may offer a more versatile means of assessing sympathetic reactivity to mental stress in the absence of confounds and appears to predict reactivity to subsequent mental stress paradigms. KEY POINTS: Cardiovascular reactivity to laboratory mental stress is predictive of future health outcomes. However, reactivity of the sympathetic nervous system to mental stress is highly variable. The current study assessed peripheral muscle sympathetic nerve activity in response to the Trier social stress test, a psychosocial stressor that includes anticipatory stress, public speaking and mental arithmetic. Our findings demonstrate that sympathetic neural activity is consistently reduced during anticipatory stress. Conversely, the classically observed inter-individual variability of sympathetic responsiveness was observed during speech and maths tasks. Additionally, sympathetic reactivity to the anticipatory period accurately predicted how an individual would respond to both speech and maths tasks, outlining the utility of anticipatory stress in future research surrounding stress reactivity. Utilization of the Trier social stress test in autonomic physiology may offer an alternative assessment of sympathetic responsiveness to stress with more consistent inter-individual responsiveness and may be a useful tool for further investigation of stress reactivity., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Heart rate variability (HRV) is commonly used within sleep and cardiovascular research, yet HRV reliability across various sleep stages remains equivocal. The present study examined the reliability of frequency- and time-domain HRV within stage-2 (N2), slow-wave (SWS), and rapid-eye-movement (REM) sleep during both stable and disrupted sleep. We hypothesized that high-frequency (HF) HRV would be reliable in all three sleep stages, low-frequency (LF) HRV would be reliable during N2 and SWS, and that disrupted sleep via spontaneous cortical arousals would decrease HRV reliability. Twenty-seven participants (11 men, 16 women, 26 ± 1 yr) were equipped with laboratory polysomnography for 1 night. Both frequency- and time-domain HRV were analyzed in two 5- to 10-min blocks during multiple stable and disrupted sleep cycles across N2, SWS, and REM sleep. HF HRV was highly correlated across stable N2 ( r = 0.839, P < 0.001), SWS ( r = 0.765, P < 0.001), and REM ( r = 0.881, P < 0.001). LF HRV was moderate-to-highly correlated during stable cycles of N2 sleep ( r = 0.694, P < 0.001), SWS, ( r = 0.765, P < 0.001), and REM ( r = 0.699, P < 0.001) sleep. When stable sleep was compared with disrupted sleep, both time- and frequency-domain HRV were reliable (α > 0.90, P < 0.05) in N2, SWS, and REM, except for LF HRV during SWS (α = 0.62, P = 0.089). In conclusion, time- and frequency-domain HRV demonstrated reliability across stable N2, SWS, and REM sleep, and remained reliable during disrupted sleep. These findings support the use of HRV during sleep as a tool for assessing cardiovascular health and risk stratification. NEW & NOTEWORTHY Heart rate variability (HRV) is a commonly employed indirect estimate of cardiac autonomic activity during sleep with limited reliability studies. Nocturnal frequency-domain HRV was reliable across differing stable sleep cycles of stage-2 (N2), slow-wave (SWS), and rapid-eye-movement (REM) sleep. Moreover, frequency- and time-domain HRV were reliable during stable and disturbed sleep, except SWS low-frequency HRV. Our finding supports nocturnal HRV as a potential tool for cardiovascular risk stratification.

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation, e.g., plasma norepinephrine and muscle sympathetic nerve activity, but include heart rate variability (HRV) when direct assessments are lacking. The review also highlights sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support several epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia and has also been confirmed with direct, regionally specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between ticks/mosquitoes and small mammals and reptiles and non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continues to be reported. In addition to in humans, viral persistence has been shown to establish in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines. Although a considerable amount of research has centered on the potential roles of defective virus particles, autophagy and/or apoptosis-induced evasion of the immune response, and the precise mechanism of these features in flavivirus persistence have yet to be elucidated. In this review, we present findings that aid in understanding how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in flaviviral persistence, the advancement of animal models of viral persistence, and studying host factors that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral-host relationships in wildlife animals and could be used to elucidate the underlying mechanisms responsible for the establishment of viral persistence in these animals.

Chronic insufficient sleep is a common occurrence around the world and results in numerous physiological detriments and consequences, including cardiovascular complications. The purpose of the present study was to assess the relationship between habitual total sleep time (TST) measured objectively via at-home actigraphy and heart rate (HR) reactivity to nocturnal cortical arousals. We hypothesized that short habitual TST would be associated with exaggerated cardiac reactivity to nocturnal cortical arousals. Participants included 35 healthy individuals [20 men, 15 women, age: 24 ± 1 yr, body mass index (BMI): 27 ± 1 kg/m 2 ], and were split using a median analysis into short-sleeping (SS; n = 17) and normal-sleeping (NS; n = 18) adults based on a minimum of 7 days of at-home actigraphy testing. All participants underwent a full overnight laboratory polysomnography (PSG) testing session, including continuous HR (electrocardiogram, ECG) sampling. HR reactivities to all spontaneous cortical arousals were assessed for 30 cardiac cycles following the onset of the arousal in all participants. Baseline HR was not significantly different between groups ( P > 0.05). Spontaneous nocturnal arousal elicited an augmented HR response in the SS group, specifically during the recovery period [ F (5.261,163.08) = 3.058, P = 0.01, η p 2 = 0.09]. There were no significant differences in HR reactivity between sexes [ F (3.818,118.368) = 1.191, P = 0.318]. These findings offer evidence of nocturnal cardiovascular dysregulation in habitual short sleepers, independent from any diagnosed sleep disorders. NEW & NOTEWORTHY Short habitual sleep is associated with poor cardiovascular outcomes, but mechanisms remain equivocal. The present study used objectively measured habitual sleep via wrist actigraphy, and reports that habitual short sleepers have augmented heart rate recovery responses to spontaneous arousals as determined by gold-standard polysomnography. There were no reported sex differences. The augmented heart rate recovery to spontaneous cortical arousals may be an important mechanism contributing to the associations between insufficient sleep and cardiovascular risk.

The use of spontaneous bursts of muscle sympathetic nerve activity (MSNA) to assess arterial baroreflex control of sympathetic nerve activity has seen increased utility in studies of both health and disease. However, methods used for analyzing spontaneous MSNA baroreflex sensitivity are highly variable across published studies. Therefore, we sought to comprehensively examine methods of producing linear regression slopes to quantify spontaneous MSNA baroreflex sensitivity in a large cohort of subjects ( n = 150) to support a standardized procedure for analysis that would allow for consistent and comparable results across laboratories. The primary results demonstrated that 1 ) consistency of linear regression slopes was considerably improved when the correlation coefficient was above -0.70, which is more stringent compared with commonly reported criterion of -0.50, 2 ) longer recording durations increased the percentage of linear regressions producing correlation coefficients above -0.70 (1 min = 15%, 2 min = 28%, 5 min = 53%, 10 min = 67%, P < 0.001) and reaching statistical significance (1 min = 40%, 2 min = 69%, 5 min = 78%, 10 min = 89%, P < 0.001), 3 ) correlation coefficients were improved with 3-mmHg versus 1-mmHg and 2-mmHg diastolic blood pressure (BP) bin size, and 4 ) linear regression slopes were reduced when the acquired BP signal was not properly aligned with the cardiac cycle triggering the burst of MSNA. In summary, these results support the use of baseline recording durations of 10 min, a correlation coefficient above -0.70 for reliable linear regressions, 3-mmHg bin size, and importance of properly time-aligning MSNA and diastolic BP. Together, these findings provide best practices for determining spontaneous MSNA baroreflex sensitivity under resting conditions for improved rigor and reproducibility of results.

K-complexes are a key marker of nonrapid eye movement sleep, specifically during stages II sleep. Recent evidence suggests the heart rate responses to a K-complexes may differ between men and women. The purpose of this study was to compare beat-to-beat blood pressure responses to K-complexes in men and women. We hypothesized that the pressor response following a spontaneous K-complex would be augmented in men compared with women. Ten men [age: 23 ± 2 yr, body mass index (BMI): 28 ± 4 kg/m 2 ] and ten women (age: 23 ± 5 yr, BMI: 25 ± 4 kg/m 2 ) were equipped with overnight finger plethysmography and standard 10-lead polysomnography. Hemodynamic responses to a spontaneous K-complex during stable stage II sleep were quantified for 10 consecutive cardiac cycles, and measurements included systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and heart rate. K-complex elicited greater pressor responses in men when blood pressures were expressed as SAP (cardiac cycle × sex: P = 0.007) and DAP (cardiac cycle × sex: P = 0.004). Heart rate trended to be different between men and women (cardiac cycle × sex: P = 0.078). These findings suggest a divergent pressor response between men and women following a spontaneous K-complex during normal stage II sleep. These findings could contribute to sex-specific differences in cardiovascular risk that exist between men and women. NEW & NOTEWORTHY K-complexes during stage II sleep have been shown to elicit acute increases in blood pressure and heart rate, but the role of sex (i.e., male vs. female) in this response is unclear. In the present study, we demonstrate that the pressor response following spontaneous K-complexes were augmented in men compared to age-matched women. The augmented blood pressure reactivity to spontaneous K-complexes during stage II sleep in men advance the field of cardiovascular sex differences, with implications for nocturnal blood pressure control.

Binge alcohol consumption elicits acute and robust increases of muscle sympathetic nerve activity (MSNA), yet the impact of evening binge drinking on morning-after MSNA is unknown. The present study examined the effects of evening binge alcohol consumption on polysomnographic sleep and morning-after MSNA. We hypothesized that evening binge drinking (i.e. 4-5 drink equivalent in <2 h) would reduce sleep quality and increase morning-after blood pressure (BP) and MSNA. Following a familiarization night within the sleep laboratory, 22 participants (12 men, 10 women; 25 ± 1 yr) were examined after simulated binge drinking or fluid control (randomized, crossover design). Morning MSNA was successfully recorded across both conditions in 16 participants (8 men, 8 women) during a 10-min baseline and three Valsalva's maneuvers (VM). Binge drinking reduced rapid eye movement (REM) sleep (15 ± 1 vs. 20 ± 1%, P = 0.003), increased stage II sleep (54 ± 1 vs. 51 ± 1%, P = 0.002), and increased total urine output (2.9 ± 0.2 vs. 2.1 ± 0.1 liters, P < 0.001) but did not alter morning-after urine specific gravity. Binge drinking increased morning-after heart rate [65 (54-72) vs. 58 (51-67) beats/min, P = 0.013] but not resting BP or MSNA. Binge drinking elicited greater sympathoexcitation during VM (38 ± 3 vs. 43 ± 3 bursts/min, P = 0.036). Binge drinking augmented heart rate ( P = 0.002), systolic BP ( P = 0.022), and diastolic BP ( P = 0.037) reactivity to VM phase IV and blunted cardiovagal baroreflex sensitivity during VM phases II ( P = 0.028) and IV ( P = 0.043). In conclusion, evening binge alcohol consumption disrupted REM sleep and morning-after autonomic function. These findings provide new mechanistic insight into the potential role of binge drinking on cardiovascular risk. NEW & NOTEWORTHY Chronic binge alcohol consumption is associated with future cardiovascular disease (CVD) risk in both men and women. In addition, binge alcohol consumption is known to disrupt normal sleep quality during the early morning hours, coinciding with the morning sympathetic surge. In the present study, an evening of binge alcohol consumption increased baseline morning heart rate and cardiovascular reactivity during the Valsalva maneuver (VM) strain. Specifically, muscle sympathetic nerve activity and phase IV hemodynamic responses increased during VM the morning after binge alcohol consumption. The autonomic dysfunction and increased cardiovascular reactivity during VM suggests a contributing mechanism to CVD risk present in individuals who binge drink.

Premise: With digitization and data sharing initiatives underway over the last 15 years, an important need has been prioritizing specimens to digitize. Because duplicate specimens are shared among herbaria in exchange and gift programs, we investigated the extent to which unique biogeographic data are held in small herbaria vs. these data being redundant with those held by larger institutions. We evaluated the unique specimen contributions that small herbaria make to biogeographic understanding at county, locality, and temporal scales., Methods: We sampled herbarium specimens of 40 plant taxa from each of eight states of the United States of America in four broad status categories: extremely rare, very rare, common native, and introduced. We gathered geographic information from specimens held by large (≥100,000 specimens) and small (<100,000 specimens) herbaria. We built generalized linear mixed models to assess which features of the collections may best predict unique contributions of herbaria and used an Akaike information criterion-based information-theoretic approach for our model selection to choose the best model for each scale., Results: Small herbaria contributed unique specimens at all scales in proportion with their contribution of specimens to our data set. The best models for all scales were the full models that included the factors of species status and herbarium size when accounting for state as a random variable., Conclusions: We demonstrated that small herbaria contribute unique information for research. It is clear that unique contributions cannot be predicted based on herbarium size alone. We must prioritize digitization and data sharing from herbaria of all sizes., (© 2020 The Authors. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Background: COVID-19 and home isolation has impacted quality of life, but the perceived impact on anxiety and sleep remains equivocal. The purpose of this study was to assess the impact of COVID-19 and stay-at-home orders on self-report anxiety and sleep quality, with a focus on sex differences. We hypothesized that the COVID-19 pandemic would be associated with increased anxiety and decreased sleep quality, with stronger associations in women., Methods: One hundred three participants (61 female, 38 ± 1 years) reported perceived changes in anxiety and sleep quality due to stay-at-home orders during the COVID-19 pandemic and were administered the Spielberger State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI). Chi-square and T test analyses were utilized to assess sex differences in reported anxiety and sleep. Analysis of covariance was used to compare the associations between reported impact of COVID-19 and anxiety/sleep parameters., Results: Women (80.3%) reported higher prevalence of increased general anxiety due to COVID-19 when compared to men (50%; p = 0.001) and elevated STAI state anxiety compared to men (43 ± 1 vs. 38 ± 1 a.u., p = 0.007). Despite these differences in anxiety, the perceived impact of COVID-19 on PSQI was not different between sexes. However, when stratified by perceived changes in anxiety due to COVID-19, participants with higher anxiety responses to COVID-19 had higher ISI compared to those with no perceived changes in anxiety (9 ± 1 vs. 5 ± 1 a.u., p = 0.003). Additionally, participants who reported reduced sleep quality due to COVID-19 reported higher state anxiety (45 ± 1 a.u.) compared to those that perceived no change (36 ± 2 a.u., p = 0.002) or increased (36 ± 2 a.u., p < 0.001) sleep quality., Conclusion: COVID-19 and state-ordered home isolation was associated with higher anxiety and reduced sleep quality, with a stronger association in women with respect to anxiety.

Prior longitudinal work suggests that blood pressure (BP) reactivity to the cold pressor test (CPT) helps predict hypertension; yet the impact of age and sex on hemodynamic and neural responsiveness to CPT remains equivocal. Forty-three young (21 ± 1yr, means ± SE) men (YM, n = 20) and women (YW, n = 23) and 16 older (60 ± 1yr) men (OM, n = 9) and women (OW, n = 7) participated in an experimental visit where continuous BP (finger plethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded during a 3- to 5-min baseline and 2-min CPT. Baseline mean arterial pressure (MAP) was greater in OM than in YM (92 ± 4 vs. 77 ± 1 mmHg, P < 0.01), but similar in women ( P = 0.12). Baseline MSNA incidence was greater in OM [69 ± 6 bursts/100 heartbeats (hb)] than in OW (44 ± 7 bursts/100 hb, P = 0.02) and lower in young adults (YM: 17 ± 3 vs. YW: 16 ± 2 bursts/100 hb, P < 0.01), but similar across the sexes ( P = 0.83). However, when exposed to the CPT, MSNA increased more rapidly in OW (Δ43 ± 6 bursts/100 hb; group × time, P = 0.01) compared with OM (Δ15 ± 3 bursts/100 hb) but was not different between YW (Δ30 ± 3 bursts/100 hb) and YM (Δ33 ± 4 bursts/100 hb, P = 1.0). There were no differences in MAP with CPT between groups (group × time, P = 0.33). These findings suggest that OW demonstrate a more rapid initial rise in MSNA responsiveness to a CPT compared with OM. This greater sympathetic reactivity in OW may be a contributing mechanism to the increased hypertension risk in postmenopausal women.

Inadequate nutrient intake leads to oxidative stress disrupting homeostasis, activating signaling, and altering metabolism. Oxidative stress serves as a hallmark in developing prostate lesions, and an aggressive cancer phenotype activating mechanisms allowing cancer cells to adapt and survive. It is unclear how adaptation and survival are facilitated; however, literature across several organisms demonstrates that a reversible cellular growth arrest and the transcription factor, nuclear factor-kappaB (NF-κB), contribute to cancer cell survival and therapeutic resistance under oxidative stress. We examined adaptability and survival to oxidative stress following nutrient deprivation in three prostate cancer models displaying varying degrees of tumorigenicity. We observed that reducing serum (starved) induced reactive oxygen species which provided an early oxidative stress environment and allowed cells to confer adaptability to increased oxidative stress (H 2 O 2 ). Measurement of cell viability demonstrated a low death profile in stressed cells (starved + H 2 O 2 ), while cell proliferation was stagnant. Quantitative measurement of apoptosis showed no significant cell death in stressed cells suggesting an adaptive mechanism to tolerate oxidative stress. Stressed cells also presented a quiescent phenotype, correlating with NF-κB nuclear translocation, suggesting a mechanism of tolerance. Our data suggests that nutrient deprivation primes prostate cancer cells for adaptability to oxidative stress and/or a general survival mechanism to anti-tumorigenic agents.

Our laboratory has previously reported that total sleep deprivation (TSD) modifies muscle sympathetic neural activity (MSNA) differently in young men and women. Because postmenopausal women are among the highest risk for hypertension, this study compares MSNA responses with TSD in older men and women. We hypothesized that TSD would alter MSNA in older adults, with greater sympathoexcitation in postmenopausal women. Twenty-seven participants (14 men and 13 women) between the ages of 55 and 75 yr were tested twice, once after 24-h TSD and once after normal sleep (randomized, crossover design). Our primary outcome measure of MSNA (microneurography) was successful across both conditions in 20 participants (10 men and 10 women). Secondary outcome measures included seated blood pressure, heart rate, and fasting plasma testosterone, estradiol, and progesterone. Age (60 ± 1 vs. 61 ± 2 yr) and BMI (27 ± 1 vs. 26 ± 1 kg/m 2 ) were not different between groups. TSD increased systolic blood pressure in both men (124 ± 5 to 130 ± 4 mmHg) and women (107 ± 5 to 116 ± 4 mmHg), but the increases were not different between groups (condition, P = 0.014; condition × sex, P > 0.05). In contrast, TSD elicited divergent MSNA responses in older men and women. Specifically, MSNA burst frequency increased in postmenopausal women (28 ± 3 to 34 ± 3 burst/min), but not older men (38 ± 3 to 35 ± 3 bursts/min; condition × sex, P = 0.032). In conclusion, TSD elicited sympathoexcitation in postmenopausal women but not age-matched men. These findings provide new mechanistic insight into reported links between sleep deprivation and hypertension. NEW & NOTEWORTHY Epidemiological studies report that sleep deprivation is more strongly associated with hypertension in women than in men. In the present study, 24-h total sleep deprivation (TSD) increased blood pressure in postmenopausal women and age-matched men. In contrast, only women demonstrated increases in muscle sympathetic nerve activity after TSD. The sympathoexcitation observed in postmenopausal women suggests a potential contributing mechanism for epidemiological observations and advances our understanding of the complex relations between sleep, sex, and hypertension.

Purpose: A growing body of literature has established that food and alcohol disturbance (FAD: decreasing one's caloric intake in preparation for alcohol consumption) is a specific health risk that endangers health and wellbeing. Recent research on trends in FAD has revealed ethno-racial disparities. A sociological analysis is helpful to center race and examine the role of ethnic identity in reproducing health disparities. The current study is guided by theories of socialization into ideal body types by race., Methods: Study uses data from a cross-sectional survey conducted among college students. The sample includes White and Black American college students, ages 18-25, and uses ordinal logistic regression to test for the impact of race and ethnic identity on engagement in FAD using the Compensatory Eating and Behaviors in Response to Alcohol Consumption Scale (CEBRACS)., Results: FAD prevalence was lower among Black Americans than among White Americans in the sample. Results from ordered logistic regression models indicate that stronger ethnic ties reduce likelihood of FAD among Black Americans but have the opposite effect among White Americans. This modification effect provides evidence that ethnic identity belonging protects against FAD for Black Americans but acts as a risk factor for FAD among White Americans., Conclusions: Findings shed light on the documented racial disparities in FAD and weight control behavior more broadly. Ethnic identity modifies the relationship between race and FAD in our sample., Level of Evidence: Level V, cross-sectional descriptive study.

The technique of microneurography has advanced the field of neuroscience for the past 50 years. While there have been a number of reviews on microneurography, this paper takes an objective approach to exploring the impact of microneurography studies. Briefly, Web of Science (Thomson Reuters) was used to identify the highest citation articles over the past 50 years, and key findings are presented in a decade-by-decade highlight. This includes the establishment of microneurography in the 1960s, the acceleration of the technique by Gunnar Wallin in the 1970s, the international collaborations of the 1980s and 1990s, and finally the highest impact studies from 2000 to present. This journey through 50 years of microneurographic research related to peripheral sympathetic nerve activity includes a historical context for several of the laboratory interventions commonly used today (e.g., cold pressor test, mental stress, lower body negative pressure, isometric handgrip, etc.) and how these interventions and experimental approaches have advanced our knowledge of cardiovascular, cardiometabolic, and other human diseases and conditions.

Legionaminic acid is a member of the nonulosonic acids, which are a class of sugars considered to be a virulence factor within a wide variety of pathogenic bacteria. We have developed a synthetic pathway towards C-7 analogues of legionaminic acid starting from Neu5Ac, resulting in the complete synthesis of both legionaminic acid, and its C-7 epimer, from a common precurser. Our approach involves the late-stage introduction of the requisite C-7 nitrogen functionality, thus making our strategy amenable to the introduction of a range of different amide groups at C-7 of legionaminic acid., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

G-protein-coupled receptor (GPCR) heterodimerization has emerged as a means by which alternative signaling entities can be created; yet, how receptor heterodimers affect receptor pharmacology remains unknown. Previous observations suggested a biochemical antagonism between GPCRs, CXCR4 and CB2 (CNR2), where agonist-bound CXCR4 and agonist-bound CB2 formed a physiologically nonfunctional heterodimer on the membrane of cancer cells, inhibiting their metastatic potential in vitro However, the reduced signaling entities responsible for the observed functional outputs remain elusive. This study now delineates the signaling mechanism whereby heterodimeric association between CXCR4 and CB2, induced by simultaneous agonist treatment, results in decreased CXCR4-mediated cell migration, invasion, and adhesion through inhibition of the Gα13/RhoA signaling axis. Activation of CXCR4 by its cognate ligand, CXCL12, stimulates Gα13 (GNA13), and subsequently, the small GTPase RhoA, which is required for directional cell migration and the metastatic potential of cancer cells. These studies in prostate cancer cells demonstrate decreased protein expression levels of Gα13 and RhoA upon simultaneous CXCR4/CB2 agonist stimulation. Furthermore, the agonist-induced heterodimer abrogated RhoA-mediated cytoskeletal rearrangement resulting in the attenuation of cell migration and invasion of an endothelial cell barrier. Finally, a reduction was observed in the expression of integrin α5 (ITGA5) upon heterodimerization, supported by decreased cell adhesion to extracellular matrices in vitro Taken together, the data identify a novel pharmacologic mechanism for the modulation of tumor cell migration and invasion in the context of metastatic disease. Implications: This study investigates a signaling mechanism by which GPCR heterodimerization inhibits cancer cell migration. Mol Cancer Res; 16(4); 728-39. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Premise of the Study: Herbarium specimens provide a robust record of historical plant phenology (the timing of seasonal events such as flowering or fruiting). However, the difficulty of aggregating phenological data from specimens arises from a lack of standardized scoring methods and definitions for phenological states across the collections community., Methods and Results: To address this problem, we report on a consensus reached by an iDigBio working group of curators, researchers, and data standards experts regarding an efficient scoring protocol and a data-sharing protocol for reproductive traits available from herbarium specimens of seed plants. The phenological data sets generated can be shared via Darwin Core Archives using the Extended MeasurementOrFact extension., Conclusions: Our hope is that curators and others interested in collecting phenological trait data from specimens will use the recommendations presented here in current and future scoring efforts. New tools for scoring specimens are reviewed.

Black adults have a higher risk of hypertension compared with non-Hispanic white (NHW) adults, but physiological mechanisms underlying this predisposition remain unclear. This study compared muscle sympathetic nerve activity (MSNA) responses to mental stress in a group of young black and NHW participants. We hypothesized that the sympathoexcitation associated with mental stress would be greater in black adults compared with NHW participants. Thirty-five male adults (19 black, 23 ± 1 yr; 16 NHW, 22 ± 1 yr) were examined during 5-min supine baseline and 5 min of mental stress (via mental arithmetic). Baseline mean arterial pressure (80 ± 2 vs. 82 ± 1 mmHg), heart rate (61 ± 4 vs. 61 ± 2 beats/min), MSNA (13 ± 1 vs. 15 ± 2 bursts/min), and sympathetic baroreflex sensitivity (-1.1 ± 0.4 vs. -1.5 ± 0.3 bursts·100 heart beats -1 ·mmHg -1 ) were not significantly different between NHW and black adults ( P > 0.05), respectively. MSNA reactivity to mental stress was significantly higher in NHW compared with black adults (time × race, P = 0.006), with a particularly divergent responsiveness during the first minute of mental stress in NHW (Δ4 ± 1 burst/min) and black (Δ-2 ± 2 burst/min; P = 0.022) men. Blood pressure and heart rate reactivity to mental stress were similar between groups. In summary, black participants demonstrated a lower MSNA responsiveness to mental stress compared with NHW adults. These findings suggest that, despite a higher prevalence of hypertension, black subjects do not appear to have higher neural and cardiovascular responsiveness to mental stress compared with NHW. NEW & NOTEWORTHY Black men have a blunted muscle sympathetic nerve activity response to mental stress compared with non-Hispanic white (NHW) men, especially at the onset of mental stress when muscle sympathetic nerve activity decreased in blacks and increased in NHW men. Thus, despite a high prevalence of hypertension in blacks, normotensive NHW men display a greater peripheral sympathetic neural reactivity to mental stress than black men.