bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Review of the Historical Use of Sex and Gender in the American Journal of Physiology-Heart and Circulation
Authors: Vanden Noven Marnie , Anselmo Miguel , Tahsin Chowdhury Tasnova , Carter Jason , Keller-Ross Manda
Published: May 2023

Females continue to be underrepresented in research despite the 1993 National Institute of Health (NIH) Revitalization Act and 2016 NIH mandate for inclusion of sex as a biological variable. Recently, the American Journal of Physiology-Cirulation and Heart (Am J Physiol Heart and Circ) issued a call and published several papers with the focus on sex as a biological variable in an effort to improve inclusion and representation of females in journal articles. To determine the progress Am J Physiol Heart and Circ has made in sex/gender reporting we conducted a systematic review of the first six months of each decade from 1980 to 2020 using PRISMA guidelines. METHODS: In the first six months of 1980 to 2020, 1,729 articles were published, of which 979 articles were reviewed. Articles were excluded if they did not include subjects, were editorials, methodology papers, or other special topics that did not include original research. RESULTS: From 1980 to 2020, human (H) studies increased and animal (A) studies decreased (1980: H=0.8%, A=89.3%; 1990: H=5.1%, A=81.7%; 2000: H=13.9%, A=69.9%; 2010: H=15.4%, A=68.4%; 2020: H=21.2%, A=58.7%). These studies (n=724, 74%) included 42,269 participants. In human studies, the number of males compared to females reported in the journal for each decade was consistently higher (1980: males n=5, females n=3; 1990: males n=199, females n=70; 2000: males n=355, females n=305; 2010: males n=472, females n=186; 2020: males n=1,222, females n=1,157). In animal studies, male animals were included consistently more than females (1980: males n=1,291, females n=58; 1990: males n=2,628, females n=447; 2000: males n=3,083, females n=590; 2010: males n=4,517, females n=663; 2020: males n=1,973, females n=1,372). CONCLUSIONS: While there has been improvement in the inclusion of female participants, this systematic review clearly demonstrates disparities in reporting sex as a biological variable in the Am J Physiol Heart and Circ. The underrepresentation of females in animal and human studies compromises our understanding of female physiology, directly impacting clinical care and outcomes. The call for using sex as a biological variable by the Am J Physiol Heart and Circ will likely contribute to closing the gap on this disparity and set new standards and expectations for the inclusion of females reported in research articles. Further, it is imperative that organizations such as the American Physiological Society and NIH ensure the use of sex as a biological variable as the norm instead of the exception.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Identification of HMOX2 promoter variants linked to adaptation in Tibetans
Authors: Lin Andrew , Kong Mitchell , Gu Wanjun , Moya Esteban , Lawrence Elijah , Yu James , Simonson Tatum
Published: May 2023

Populations living at high altitude have been subjected to the selective pressure of hypoxia due to low atmospheric pressure for hundreds of generations. Adaptive genetic signals are apparent in the genomes of present-day populations, but the links to physiological changes and underlying mechanisms are not completely understood. Our recent physiological studies revealed that Tibetans residing at intermediate altitude (2200 m; 13,780 ft) have lower hemoglobin concentration ([Hb]) and elevated carbon monoxide (CO) relative to other populations resident at the same altitude. Our previous genetic studies revealed that Tibetans residing at 4200 m (13,780 ft) exhibit a haplotype (20 kilobases) encompassing the Heme Oxygenase 2 (HMOX2) gene region. Heme oxygenase 2 protein produces carbon monoxide (CO) as a byproduct of hemoglobin breakdown. We hypothesize that HMOX2 underlies the observed CO levels at high altitude. We further hypothesize that regulatory variants could be linked to elevated heme oxygenase activity and, therefore, elevated CO levels in people of Tibetan ancestry.We measured carboxyhemoglobin (COHb) in Tibetan (n = 10) and Han Chinese (n = 8) male residents of Xining (2,200 m; 7,218 ft), China, using a co-oximeter and Tibetan (13 women, 8 men) and Han Chinese (6 women, 10 men) residents of Salt Lake City, Utah (1,413 m/4,637 ft) with a finger pulse oximeter. In the Xining cohort, COHb levels were 97% higher in Tibetans (1.01 ± 0.59 %) compared to their Han Chinese counterparts (0.51 ± 0.39 %, p < 0.048). This result was replicated in Salt Lake City, where Tibetans exhibited significantly higher COHb (4.31 ± 0.48%) compared to Han Chinese (2.00 ± 0.6%, p = 0.004).We also examined localized signals of natural selection (Composite of Multiple Signals test, CMS) from 27 previously published Tibetan genomes and identified single nucleotide variants (SNVs) within the selected haplotype with potential functional impacts on heme-oxygenase expression. Eleven variants were located within the promoter region of the HMOX2 gene. These variants exhibit significant delta allele frequencies (DAF) between Tibetans and Han Chinese (DAF > 0.2, p < 0.005) and are in high linkage disequilibrium (R2 > 0.9) in both populations. Literature and in-silico prediction tools (CIS-BP, JASPAR) indicate some of these variants have a potential gain-of-function roles as transcription factor binding sites.These results suggest adaptive, regulatory variants in HMOX2 may contribute to the observed increased endogenous CO in highland Tibetans, conferring protection from the selective stresses of high-altitude hypoxia.

This project is funded by NIH R01HL145470.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Hepatocyte PHB1 Deficiency Causes Sex-Specific Changes in Glycemic Control and Body Composition in Mice
Authors: Alowaisi Amany , Mahoney Jo , Berdaweel Islam , Anderson Ethan
Published: May 2023

Prohibitin 1 (PHB1) is a dynamic lipid raft associated protein that is located in plasma membrane and in the inner mitochondrial membrane complexed with its homolog PHB2 in a tight 1:1 stoichiometric ratio. The PHB1/2 ‘supercomplex’ has been linked to many cellular processes including proliferation, apoptosis, transcription, inflammation, signaling and metabolism. Previous studies have shown that PHB1 plays a role in modulation of insulin signaling via PIP3→AKT pathway. Moreover, a recent report showed that male and female mice with adipocyte-specific PHB1 overexpression developed obesity, while only the obese males developed glucose intolerance and fatty liver. These and other findings strongly implicate a sex-specific role for adipocyte PHB1 as a key mediator in glucose metabolism, although mechanisms remain obscure and it is further unclear whether this sex-specific effect is exclusive to adipocytes. Here, we examined the role of hepatocyte PHB1 in regulating glucose metabolism with diet induced obesity. Mice with hepatocyte specific PHB1 deficiency (hPHB1def) were generated by crossing homozygous PHB1 floxxed mice (PHB1fl/fl) with Albumin-Cre (Alb-Cre+/+) mice. Male and female mice were randomly assigned to normal chow diet (CTL diet) or high fat high sucrose diet (HFHS) for 20 weeks. Female hPHB1def mice were found to have a lower body weight compared with WT in both diet groups. However, male hPHB1def mice had increased body fat (gonadal fat) and decreased lean mass compared with WT males, even on CTL diet. At the same time, female hPHB1def mice had reduced brown fat mass compared to WT females on HFHS diet, but not CTL diet. Male hPHB1def mice on CTL diet are insulin resistant compared with WT males; however, female hPHB1def mice have improved glucose tolerance compared with WT females, due in part to decreased gluconeogenic capacity in female hPHB1def mice. Surprisingly, circulating PHB1 levels decreased with diet induced obesity in both males and females, with hPHB1def having lower hepatocyte-PHB1 content compared with WT, regardless of diet. Collectively, these findings reveal that hepatocyte-PHB1 is an important regulator of systemic glucose metabolism and adiposity in a sexually dimorphic manner.

American Heart Association (AHA)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Acute Radiation Exposure Increases Mortality to Traumatic Hemorrhage
Authors: Torres Luciana , Niland Casey , Ybarra Jennifer , Marshall Stephanie , Ryan Kathy
Published: May 2023

It is anticipated that both ionizing radiation and traumatic injury may occur simultaneously in future terrorist attacks and battlefield scenarios. However, it is not known how radiation combined with injuries (RCI) will impact physiological compensatory responses to traumatic hemorrhage and survival. We hypothesized that the addition of radiation to our established traumatic hemorrhage model (Klemcke et al., J Appl Physiol 2021) would increase mortality. Male rats (n=6/group) were randomly assigned to 1 of 4 groups: sham (no injury; no radiation); radiation injury (RI) only; traumatic hemorrhage alone (CI); or RI combined with traumatic hemorrhage (RCI). For RI and RCI rats, whole-body irradiation was performed with a single, sub-lethal X-ray dose of 5.5 Gy delivered at 1 Gy/min (MultiRad 350). CI consisted of extremity trauma (fibular fracture + penetrating and soft tissue injury, performed under isoflurane anesthesia) followed by conscious hemorrhage of 37% of blood volume. Rats were monitored for 14 days following injury or sham procedures. Sham rats had 100% survival to Day 14, while RI and CI rats had 50% and 50% mortality, respectively, at this point. RCI rats, however, demonstrated 100% mortality at Day 14; differences in survival proportions were significant (P=0.005). We therefore developed a new rat model of RCI by combining X-ray irradiation with traumatic hemorrhage which allows acute (hours) as well as chronic (days) observations. While RI alone produced significant mortality, the addition of traumatic hemorrhage increased mortality to 100%. Future work will elucidate physiological mechanisms potentiating the lethal effect of either RI or CI alone.

Biomedical Advanced Research and Development Authority (BARDA).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Physiological characterization of instrumental learning in the spinal cord using the Paw Withdrawal Learning paradigm
Authors: Aldana Efren , Araiza James , Wang Y. Curtis , Zhong Hui , Tillakaratne Niranjala , Edgerton V Reggie , Joseph Michael
Published: May 2023

Following spinal cord injury (SCI), sensory and motor functions are severely disrupted yet the spinal circuitry below the injury site continues to maintain active and functional neuronal properties (Edgerton, 2004). The spinal cord is endogenously capable of several forms of adaptive plasticity, including functional re-training with exercise, instrumental, and Pavlovian learning. The paw withdrawal learning (PaWL) paradigm represents a simple spinal instrumental learning model (Jindrich 2019). Briefly, in mice whose spinal cords are completely transected (ST) at mid-thoracic (T7-T9) level, the tibialis anterior (TA) muscle is given a sub maximal threshold shock to a hind leg when the leg is extended below a 1mm imposed threshold from a baseline starting position. The contingent group mice learn to maintain the shocked leg, in a flexed position while the experimentally coupled noncontingent group of mice do not acquire the flexed position. To demonstrate the acquisition of the flexed paw hold is mediated through muscle-specific proprioceptive inputs and a time dependent modification of the spinal interneuronal network associated with the TA motor pool, we measured the TA muscle activity using acute EMG during PaWL in both Contingent stim and non-contingent stim groups. To demonstrate that TA specific sensory afferents are critical in PaWL, we blocked the proprioceptive muscle and the cutaneous afferents using Lidocaine. During PaWL, the TA muscle showed significant EMG activity when compared to medial gastrocnemius and vastus lateralis muscles. We detected greater TA muscle activity in the Contingent stim compared to the non-contingent groups. The significant increase in the EMG amplitude in the TA muscle and time-frequency and power relationships in the contingent group, but not the non-contingent group, suggests that the successful learning requires a temporal engagement of the spinal sensorimotor network.

CSULA Mini-Grant 2020 and Joseph/Gomez-Pinilla R01NS056413 (Diversity Supplement)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Vagal C-fibers mediate HDM induced airway hyperreactivity via PAR1 receptors
Authors: Patil Mayur , Pavelkova Nikoleta , Taylor-Clark Thomas , Akopian Armen
Published: May 2023

Airway hyperreactivity (AHR) is a hallmark of allergic asthma, and the major cause of exacerbations. Although acute bronchospasm can be mitigated by bronchodilators and corticosteroids, no therapeutics effectively target AHR. Recent studies have shown that airway afferent/sensory nerves play a critical role in AHR, but the mechanisms are not well understood. Here we show employing two-photon ex vivo imaging of the vagal ganglia of PirtCre;R26 ‐ GCaMP6s mice, HDM extract caused a robust activation of the majority of naïve airway-specific C-fibers. Importantly, diphtheria toxin-mediated ablation of C-fibers using Nav1.8Cre, caused a significant reduction in HDM induced AHR in mice. HDM extract is made up of proteases and can activate PARs, the G-protein coupled receptors (GPCR). We analyzed PAR receptor expression in airway specific C-fibers using single neuron RT-PCR and found that all airway C-fibers expressed PAR1 and only 5% expressed PAR2 receptors. Ex vivo imaging of the vagal ganglia of PirtCre;R26 ‐ GCaMP6s mice we observed that pretreatment (10mins) with an antagonist (FR171113, 15μM) to PAR1 but not PAR2 receptors, significantly blocked the stimulatory effect of HDM on C-fibers. We created sensory neuronal conditional knockout of PAR1 and PAR2 using the PirtCre mice crossed with PAR1 and PAR2 floxed mice to generate experimental PirtCre/PAR1fl/fl and PirtCre/PAR2fl/fl CKO mice. We found that PirtCre/PAR1fl/fl (CKO) mice exposed to HDM over a period of 12 days had significantly reduced HDM-induced AHR. Our data suggests that direct activation of airway vagal C-fiber afferent PAR1 receptors by HDM allergens leads to HDM-induced airway hyperreactivity.

Supported by AHA predoctoral grant 14PRE18490009 and Warren Alpert Foundation grant

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Role of Acetyl-CoA Synthetase Short Chain Family Member-1 on Adipocyte Thermogenic Capacity
Authors: Zhang David , Chocron Sandra , Mota Linda , Brey Eric , Gius David , Gonzalez Porras Maria
Published: May 2023

Obesity is characterized by an increase in adipose mass and is the leading risk factor for type 2 diabetes. Recent research suggests that activation of brown or beige fat and white adipose tissue browning represent a new therapeutic strategy for metabolic diseases. Fatty acid oxidation is required for the browning of white adipose tissue (WAT) and the induction of uncoupling protein 1 (UCP1) in WAT. The Acyl-CoA Synthetase Short Chain Family Member-1 (ACSS1), an established SIRT3 deacetylation target, is central to fatty acid oxidation (FAO) and mitochondrial bioenergetics by converting acetate and CoA to acetyl-CoA. However, the biological function of ACSS1 acetylation (ACSS1-Ac) in thermogenic adipose tissue and how it contributes to metabolic changes in adipocytes has not been investigated. We have generated a novel acetylation mimic mouse where lysine 635 (K635) was mutated to glutamine (K635Q), representing constitutive ACSS1-K635-Ac. Male mice expressing Acss1K635Q/K635Q exhibited a reduction in size and body weight. Upon 48-hour fasting, these mice exhibited hypothermia as well as decreased ATP and lactate levels. Interestingly, UCP1 gene expression was upregulated in brown adipose tissue (BAT) of the Acss1K635Q/K635Q compared to WT and also in WAT from fasted animals. Differentiated beige adipocytes also showed higher UCP1, PGC1a and adiponectin gene expression in cells isolated from Acss1K635Q/K635Q mice compared to WT cells. Oxygen consumption rate of these cells was lower with lower basal and ATP-coupled respiration. Acss1K635Q/K635Q beige adipocytes failed to respond to beta-adrenergic stimulation and did not increase their respiration capacity when compared to WT cells. No differences were observed in glucose uptake and lipolysis functional assays. These results suggest that the mutation leads to a disruption of downstream signaling of UCP1. In conclusion, ACSS1-K635-Ac is a novel thermoregulator in adipose tissue that could lead to further development of new therapies for metabolic diseases.

1. Mays Cancer Center CCSG (P30 CA054174); 2. National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, under Award Number F32-0DK122754

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Heat Index as a Measure of Future Heat Stress with Climate Change
Authors: Romps David , Lu Yi-Chuan
Published: May 2023

The wet-bulb temperature and wet-bulb globe temperature (WBGT) have been widely used to forecast the physiological consequences of extreme heat associated with climate change. Unfortunately, those metrics are not based in any physiological model of thermoregulation, which means their values do not map one-to-one onto physiological states. In contrast, the widely used heat index is based on a model of human thermoregulation: each value of the heat index maps onto a unique state of the human body. This mapping is obscured in practical applications of the heat index, which use the National Weather Service's empirical fit to values tabulated in Robert Steadman's seminal 1979 paper. In addition, that empirical fit is used, without scientific justification, to extrapolate the heat index to high heat and humidity, where Steadman's paper gave no values because of an apparent failure in the underlying physiological model. In recent work, Steadman's model has been extended, allowing the heat index to be calculated for extreme heat and humidity while retaining full backward compatibility. This reveals that the extrapolation used by the National Weather Service underestimates the heat index during severe US heat waves by as much as 10 degrees Celsius. For example, the peak heat index at Chicago's Midway International Airport was underreported by 9 degrees Celsius during the July 1995 heat wave, which killed hundreds of people. This correction has important implications for physiology: these corrected values reveal that even walking in the shade would have brought a healthy person close to the point of hyperthermia. This highlights how close global warming is to making the most severe US heat waves a fatality risk for even young and healthy adults.

Department of Energy's Atmospheric System Research Program

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Three main nitrate reservoirs in the mammalian body
Authors: Piknova Barbora , Park Ji Won , Tunau-Spencer Khalid , Schechter Alan
Published: May 2023

Nitric oxide (NO) is a free radical with multiple functions in virtually all cells. In mammals, NO is generated by nitric oxide synthase from arginine and by reduction of nitrate/nitrite by tissue xanthine oxidoreductase (XOR) or microbiome. Previously, we reported in several mammalian species, including human, that skeletal muscle is a major nitrate reservoir in the body and that nitrate from this reservoir is systemically available and used to generate nitrite and NO. In our recent large animal study, we found that there are similar levels of nitrate stored in bone and skin. In our prior study, skeletal muscle showed a high level of nitrate at 57±39 nmol/g, relative to other tissues, such as liver and plasma at 15±5 nmol/g and 34±19 nmol/g, respectively. Here, we found that the average level of nitrate in the bone is 45±17 nmol/g and in the skin 41±19 nmol/g.Considering that the skeletal muscle, skin and skeleton are three largest organs in mammals, forming about 35-50%, 21% and 14% of body weight, respectively, these results highlight the importance of skeletal muscle as a main nitrate reservoir and the role of skin and bone as new auxiliary nitrate reservoirs. Along with skeletal muscle, the bones and skin likely play an important role in maintaining homeostasis of the nitrate-nitrite-nitric oxide pathway.Also, important from therapeutic point of view, all three organs are well responding to dietary nitrate interventions by increasing their respective nitrate levels, which leads to general increase of systemic and local NO availability and perhaps could be used as one of the ways to increase NO availability in some diseases.

This work was supported by intramural NIDDK/NIH grant ZIA DK 025104-15 to Alan N. Schechter.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Once Weekly 24 Hour Intermittent Fasting Improves Arterial Stiffness and Alters the Relative Abundance of Aortic T Cells in Obese Mice
Authors: Graham Elliot , Risk Briana , Zhang Mingyue , Weir Tiffany , Gentile Christopher
Published: May 2023

BACKGROUND: Intermittent fasting (IF) is a popular dietary strategy that reduces body weight and improves cardiovascular health. However, questions remain whether IF can reduce arterial stiffness, an independent risk factor for cardiovascular disease that is associated with vascular inflammation. Thus, the primary purpose of this study was to determine whether IF reduces obesity-associated arterial stiffness and alters the abdominal aortic immune cell landscape. METHODS: Wild-type (WT) and obese (Ob) mice were randomized for a 10 week protocol to receive either ad libitum (Ad-Lib) control diet or a once weekly 24 hr fast (IF), yielding four groups: WT+Ad-Lib; WT+IF; Ob+Ad-Lib; and Ob+IF. Throughout the 10 week protocol, early- (weeks 1-2), mid- (weeks 5-6), and endpoint (weeks 9-10) indices of arterial stiffness were measured via arterial pulse wave velocity (aPWV). Following the intervention, mice were euthanized, and abdominal aortic immune cells were quantified via spectral flow cytometry. RESULTS: Fasting mitigated weight gain in Ob mice without affecting weekly food intake (change in body weight; Ob+Ad-Lib= 22.6 ± 0.8 g; Ob+IF= 20.0 ± 0.4 g; p=0.02). Earlypoint aPWV was similar between Ob+Ad-Lib and Ob+IF mice (Ob+Ad-Lib= 420.9 ± 15.6 cm/sec; Ob+IF= 450.7 ± 9.3 cm/sec; p=0.50), with aPWV in both Ob cohorts being significantly higher than in WT mice. At both the midpoint and endpoint, Ob+IF mice had reductions in aPWV that were significantly different from Ob+Ad Libs (midpoint=-36.5 ± 20.0 cm/sec, p= 0.02; endpoint= -21.6 ± 15.9 cm/sec, p=0.04). The number of aortic-resident lymphocytes was similar between the four groups. However, endpoint reductions in aPWV in Ob+IF mice were associated with reductions in the abdominal aortic CD4+ T cell: B cell ratio (r=0.50, p=0.04). An increase in the aortic CD4+ T cell: CD8+ T cell ratio was associated with reduced weight gain in Ob+IF mice (r=0.78, p<0.01). CONCLUSIONS: IF reduced weight gain and improved arterial stiffness in obese mice. Although the number of aortic-resident lymphocytes was similar between Ob+Ad-Lib and Ob+IF groups, reductions in arterial stiffness correlated to changes in the relative abundance of aortic CD4+ T cells in Ob+IF mice.

This research was funded by NIH-HBLI (R01 HL144611)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of Adolescent Ethanol Exposure on Lingual Taste Receptor Expression
Authors: Primeaux Stefany , Primeaux Jolie , Holmgren Eleanor , Wills Tiffany
Published: May 2023

Adolescent alcohol use is prevalent in the U.S. and there is increasing evidence that neural and behavioral consequences of adolescent alcohol use may differentially alter the developing neural circuitry in males and females. Taste has been implicated in the preference for and intake of alcohol and alcohol exposure regulates taste perception. The detection of tastants (e.g. sweet, bitter, fat) is dependent on the density of lingual papillae and taste receptor expression. The goal of the current study was to examine the effects of adolescent ethanol exposure (AIE) on the density of fungiform papillae and lingual taste receptor expression from the circumvallate papillae (CV) in male and female C57/Bl6 mice. Mice (postnatal day (P)27) were exposed to intermittent ethanol vapor or volatilized water. The AIE protocol was run for two, 4-day cycles of 16h in-chamber sessions and 8h out-of-chamber sessions separated by 3 days from P27-P35. Ethanol vapor chambers were maintained to achieve blood alcohol concentrations ~ 200mg/dL. Mice were sacrificed 4-5 hours after their last ethanol exposure, and tongues were collected. Fungiform papillae were counted and density was determined in tongues stained with 0.5% methylene blue. Taste receptor expression for sweet (T1R2, T1R3), bitter (T2R138), and fat (CD36) tastes were assessed in the CV of the tongue using qPCR. Ethanol exposure significantly decreased fungiform papillae density and increased CD36 mRNA levels in the CV of male and female mice. A significant interaction between sex and ethanol exposure was detected for T2R138 and T1R2 mRNA levels in the CV. T2R138 mRNA was higher in control males compared to females, and AIE increased T2R138 mRNA levels in females, but not males. T1R2 mRNA level was increased by AIE in both male and female mice, however, there was a greater increase in females, compared to males. T1R3 mRNA levels did not differ between male and female mice and were not affected by AIE. Increased expression of fat and sweet taste receptors on the CV of male and female mice suggest that AIE may increase the sensitivity to and preference for foods and beverages that are high in fat and sugar. In females, AIE increased the expression of the bitter taste receptor, T2138, suggesting an increase in the sensitivity to and avoidance of bitter foods and beverages. Fungiform papillae density was decreased following AIE in males and females, which suggests an overall decrease in taste sensitivity following ethanol. Further understanding of ethanol’s effect on taste sensitivity is needed to better understand the long-term effects of adolescent ethanol exposure on food and beverage preferences and consumption patterns.

NIHAA028011 T.W.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Chronic Vagotomy Alters Glutamate Transmission in the Nucleus Tractus Solitarii (nTS)
Authors: Khodadadi Fateme , Hofmann Gabrielle , Kline David , Hasser Eileen
Published: May 2023

The nTS is the first site of integration and processing of sensory afferent information and is one of the crucial brainstem nuclei involved in cardiorespiratory reflexes. This nucleus receives afferent information from many visceral structures in the thorax and abdomen via the peripheral branches of the vagus nerve. Vagal afferents release glutamate (Glu) which initiates signaling processes that leads to chemo- and baroreflex-mediated changes in sympathetic and phrenic nerve activity. Previous studies by us have shown that decreasing afferent input via unilateral vagotomy augmented nTS astrocyte complexity. Astrocytes contribute to regulation of Glu concentration by removing Glu from the synaptic cleft via excitatory amino acid transporters (EAATs). We hypothesized that vagotomy attenuates Glu signaling in the nTS due to increased Glu uptake by greater EAAT expression or function. Surgical transection or sham surgery of the right cervical vagus nerve caudal to the nodose ganglion was performed in male Sprague-Dawley rats. One week after surgery, mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA) were recorded in anesthetized and ventilated rats. Intact vagus nerves and the right phrenic nerve were acutely transected. Nanoinjections of Glu (30 nl, 1-10 mM) into the nTS decreased MAP, HR, SSNA and PhNA in both sham and vagotomy groups. Vagotomy blunted the HR, SSNA and PhrNA responses, indicating that Glu signaling was attenuated. To determine if increased EAAT function contributed to blunted Glu responses, the EAAT blocker TFB-TBOA (10nM, 60nl) was nanoinjected into the nTS. EAAT blockade mimicked the effect of Glu, producing similar depressor, bradycardic, and apneic responses in both groups. TBOA also enhanced the cardiorespiratory responses to Glu injection in both groups. EAAT blockade did not restore Glu responses in the vagotomy group compared to sham. Taken together, these data suggest that increased EAAT function did not account for the attenuated Glu signaling in the nTS. Further studies are needed to uncover the mechanisms by which vagotomy affects Glu signaling in the nTS.

NIH R01 HL098602

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of pulmonary hypertension on diaphragm blood flow
Authors: Schulze Kiana , Horn Andrew , Weber Ramona , Ade Carl , Behnke Bradley , Poole David , Musch Timothy
Published: May 2023

Pulmonary hypertension (PH) is a disease characterized by pulmonary vascular remodeling, respiratory muscle and cardiac impairments, and exercise intolerance. Specifically, impaired gas exchange increases work of the diaphragm; however, muscle fiber atrophy and compromised contractile function preclude the diaphragm from meeting the increased metabolic demand of chronic hyperventilation in PH. Given skeletal muscle contractile function is largely determined by adequate blood flow (Q̇), diaphragm contractile dysfunction may be predicated by an inability to match oxygen delivery with oxygen demand. Therefore, we hypothesized that diaphragmatic blood flow would be reduced in the diaphragm of PH rats. Additionally, we hypothesize that PH rats will demonstrate increased vascular resistance compared to healthy counterparts. Methods: Female Sprague-Dawley rats were randomly assigned to healthy (HC, n=5) or PH (n=5) groups. PH rats were administered monocrotaline (MCT; 50 mg/kg, i.p.) while HC rats were administered saline as a vehicle control. Disease progression was monitored via echocardiography. Fluorescent microspheres were used to determine regional and total blood flow (Q̇) and vascular resistance (VR) in the diaphragm at baseline and during 3 minutes of electrically-stimulated contractions. Results: All PH rats displayed morphometric and echocardiographic criteria for disease including right ventricular (RV) hypertrophy and a reduced pulmonary artery acceleration time (PA AT) compared to HC. In PH and HC rats, total Q̇ to the diaphragm increased and VR decreased during contractions. PH rats displayed a lower non-contracting baseline and contracting steady-state Q̇ to the whole diaphragm and the medial costal region (P<0.05) Medial costal VR was greater during contractions (0.90 ± 0.15 vs. 0.49 ± 0.06 mmHg/ml/min/100g; P=0.04) in the PH rats compared to HC. Conclusions: These findings support that bulk and regional diaphragm perfusion is reduced in PH, which suggests that PH comprises diaphragm vascular function and oxygen delivery, providing a putative mechanism for PH-induced diaphragm contractile dysfunction. Future studies will focus on investigating diaphragm arteriolar structural and functional properties to help resolve the mechanistic bases for these deficits and develop therapeutic countermeasures.

This work was funded by the Sustained Momentum for Investigators with Laboratories Established (SMILE) Grant at Kansas State University College of Veterinary Medicine and the National Institute of Aging (1 R15 AG 078060).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Reduced Hypoxic Ventilatory and Heart Rate Responses to Hypoxia in Post- versus Pre-menopausal Tibetan Women in Mustang, Nepal
Authors: Moya Esteban , Yu James , Craig Sienna , Buchanan Christina , Powell Frank , Beall Cynthia , Simonson Tatum
Published: May 2023

Populations living at high altitudes exhibit distinct cardiovascular and ventilatory responses to hypoxia, which may result from exposure to the selective pressure of chronic hypoxia throughout hundreds of generations at high altitude. Compared to Andean highlanders and some acclimatized lowlanders, many Tibetans show an increased hypoxic ventilatory response (HVR) and lower hemoglobin concentration ([Hb]). While the effects of menopause on [Hb] have been well studied, its effects on HVR and heart rate responses to hypoxia (HHRR) in Tibetan women residing at high altitude have not been elucidated. We hypothesized that hypoxic ventilatory and heart rate responses to hypoxia decrease with menopausal status in Tibetan women, suggesting a change of adaptation during post-reproductive years in women. We measured minute ventilation (VI) and heart rate (HR) during room air and acute hypoxia in 376 Tibetan women (age range 46-86 years old) living in in Mustang, Nepal (>11,482ft / 3,500m) and compared responses between pre- and post-menopausal groups (mean ± SEM). Using a rebreathing system, we induced hypoxia to produce events of at least 10% desaturation (from 91 ± 0.2% to 78 ± 0.2%), expressed HVR and HRR as -ΔVI / ΔSpO2 and -ΔHR / ΔSpO2, respectively, and tested for associations between HVR and HHRR with age and [Hb]. HVR, HHRR, and [Hb] associated negatively with age in the post- but not pre-menopausal group. During hypoxia, post-menopausal women had lower VI (14.2 ± 0.2 L/min) and HR (80 ± 1 BPM) when compared (p<0.01) to pre-menopausal women (16.9 ± 0.4 L/min for VI and 85 ± 1 BPM for HR). VI was also lower in room air conditions (p<0.01) for post-menopausal (11.5 ± 0.1 L/min) versus pre-menopausal women (12.6 ± 0.2 L/min). HVR and HHRR was lower in post- (0.21 ± 0.01 L/%O2 and 0.65 ± 0.02 BPM/%O2 respectively) versus pre-menopausal women (HVR: 0.34 ± 0.03 L/%O2 and HHRR: 0.92 ± 0.05 BPM/%O2). Pre-menopausal women also exhibited negative correlations with HVR and HHRR with increasing [Hb]; however, these correlations were not significant in the post-menopausal group. A non-blunted HVR is a hallmark of adaptation in Tibetans, and physiological changes observed in Tibetan women during later life stages may result in a loss of such traits. These data suggest a hypothesis of menopause-related loss, or change, of adaptation to high-altitude hypoxia among middle-aged to elderly Tibetan women.

Supported by NSF award 1831530 to CMB and NIH 1R01HL145470 to TSS.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Influence of Various Legwear on Arterial Stiffness
Authors: Alhalimi Taha , Wang Tianyu , Tanaka Hirofumi
Published: May 2023

Background: Carotid-femoral pulse wave velocity (cfPWV) has become a reference standard measure of arterial stiffness. This methodology requires a precise detection of pulse waves in the carotid and femoral arteries. A possible source of variability is the type of legwear when detecting femoral pulse waves since participants typically come in with their own legwear. In brachial blood pressure measurements, different types of fabric materials and thicknesses were founded to skew blood pressure readings. Accordingly, we investigated the effects of common legwear on cfPWV measured with both tonometery and oscillometry. We hypothesized that thicker and stiffer legwear would reduce both cfPWV. Methods: A total of 50 adults (36 women) varying widely in age (19-78 years old) and medical conditions were studied. Two devices that utilized a tonometric sensor (Omron VP-1000plus) and a cuff-based oscillometric sensor (Vicorder) to derive cfPWV were evaluated. The participants wore either khaki pants, sweatpants, athletic shorts, or medical shorts as a reference condition with an optional bare skin condition. These legwear were chosen as common legwear that participants wore when they were getting tested. All the legwear were provided to the participants with at least 10 minutes of rests between conditions. Results: As expected, the range of the means of cfPWV for the tonometric device was (659–672 cm/s) and (484–490 cm/s) for the oscillometric device. Both devices produced similar cfPWV values among different types of legwear as there were no systematic differences. Mean values of cfPWV measured with a bare skin condition did not differ significantly from all other conditions (20 - 27 cm/s) for the tonometric device and (2 - 5 cm/s) for the oscillometric device. Failure to obtain cfPWV using the tonometry were 13% for khaki, 6% for sweatpants, 3% for each of medical shorts and athletic shorts, and <1% for bare skin while the oscillometric device has a 0% failure rate among all conditions. Conclusion: Arterial stiffness as assessed by cfPWV was not affected by the type of legwear. Stiffer and thicker legwear increases the difficulty of detecting femoral pulses and increases the noise when measured using a tonometric sensor. When the oscillometric sensor was used, cfPWV was not affected by the type of legwear. Our present findings suggest that different legwear that participants wear may not be a concern when cfPWV is being assessed.

There was no funding source for this study.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Antiaging hormone Klotho derived from renal distal-convolution regulates calcium but not phosphate homeostasis
Authors: Pathare Ganesh , Kopper Klaudia , Trnjanin Adisa , Loffing-Cueni Dominique , Wengi Agnieszka , Loffing Johannes
Published: May 2023

Soluble-Klotho (sKl) is the shed ectodomain of the transmembrane protein-Klotho (mKl) that exhibits pleiotropic actions, including lifespan extension, mineral metabolism, slowing-down kidney diseases and cardioprotection. The sKl is derived from the kidneys, but what type/s of renal cells secrete it is unknown. Secondly the respective roles of mKl versus sKl in regulating mineral metabolism is unclear due to the lack of appropriate in vivo models. Here, using scRNA-seq of renal distal-convolution (DC) cells, we found an unexpected pattern revealing that Klotho transcripts ( Kl) are moderately expressed in overall distal convoluted tubule (DCT), but highly enriched in the end of DCT and in connecting tubule (CNT). Immunohistochemistry further confirmed this pattern for mKl protein as well. Next, Kl was knocked-out only in renal DC to check if it affects sKl production. Interestingly, deleting Kl in the DCT and late-DCT+CNT in mice showed ~20% and ~80% reduction in sKl levels, respectively. Expectedly, knocking-out Kl along the entire DC in mice (Kl-KODC) abolished sKl levels. Furthermore, we found that compared to control mice, Kl-KODC mice exhibited reduced renal TRPV5-Ca2+ channel expression, profound calciuria, and loss of bone mineral density. The RNA-seq of automated-sorted DC cells from Kl-KODC mice revealed enhanced caveolae-mediated endocytosis of TRPV5. On the other hand, Kl-KODC mice had normal phosphate metabolism as confirmed by unchanged serum FGF23, serum phosphate, urinary phosphate excretion, and renal NaPi-IIa expression. Our findings reveal that a small population of renal DC cells accounts for the sKl levels. The lack of sKl may leads to disturbed Ca2+ homeostasis and bone loss without affecting phosphate balance in mice.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pkd1 loss induces renal injury while strengthening colonic integrity in an early ADPKD model
Authors: Sedaka Randee , Lovelady Caleb , Shinde Sejal , Yamaguchi Shinobu , Saigusa Takamitsu
Published: May 2023

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, initiated by a germline PKD1 mutation in nearly 80% of patients. Although polycystin-1 (PC-1), the protein encoded by PKD1, is vital to maintaining renal epithelial cell integrity, its role in the intestines has yet to be elucidated. Considering macrophage infiltration precedes accelerated cyst growth in Pkd1 knockout ( Pkd1KO) mice, and the intestines are the body’s largest reservoir of inflammatory cells, we hypothesized that loss of Pkd1 would weaken the intestinal epithelial cell barrier and increase inflammation, potentially preceding renal damage. Plasma, kidney, and intestines were collected from 11-12 week old male and female conditional Pkd1KO (CAGG-creER; tamoxifen-induced at 5-6 weeks) and flox (control) mice. Tissue was utilized for RT-PCR and immunohistochemistry. Plasma was used to measure intestinal permeability and monocyte chemoattractant protein-1 (MCP-1). Pkd1KO mice exhibited significantly elevated kidney-to-body weight ratio (flox: 4.68±0.22, KO: 6.83±0.20; n=6-9/group, P<0.001) and cyst ratio % (flox: 2.7±0.4%, KO: 20.6±1.2%; n=4-5/group, P<0.001) compared to flox mice. Likewise, expression of renal tubular injury markers, hepatitis A virus cellular receptor 1 (Havcr1) (flox: 1.00±0.26, KO: 2.83±0.41; n=6-9/group, P=0.003) and lipocalin 2 (Lcn2) (flox: 1.00±0.23, KO: 1.79±0.25; n=6-9/group, P=0.047) , were significantly increased in Pkd1KO over flox mice, with epithelial integrity marker tight junction protein 1 ( Tjp1) decreased (flox: 1.00±0.11, KO: 0.76±0.05; n=6-9/group, P=0.04). No overt physiological changes were observed in the intestines of either genotype. However, Pkd1KO mice had significantly reduced colonic epithelial cell permeability versus flox mice (flox: 1.00±0.08, KO: 0.50±0.10 AU; n=6-10/group, P<0.001), corresponding to elevated expression of colonic integrity markers occludin ( Ocln) (flox: 1.00±0.26, KO: 1.72±0.16; n=6-9/group, P=0.03), plasmalemma vesicle associated protein (Plvap) (flox: 1.00±0.14, KO: 1.45±0.14; n=6-9/group, P=0.045), and focal adhesion kinase (Ptk2) (flox: 1.00±0.15, KO: 1.40±0.12; n=6-9/group, P=0.05). Pkd1KO mice did not have altered pro-inflammatory or pro-fibrotic gene expression in the kidneys or the intestines compared to flox mice; nor were there differences in plasma MCP-1 levels. All in all, lack of Pkd1 strengthens the colonic epithelial barrier, while simultaneously increasing renal damage at this early timepoint, prior to cyst progression by inflammatory involvement.

These studies were supported by NIH T32 DK007545 to RS and R03 DK119717 to TS.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.