bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time-Dependent Association Between Agonal Respirations and Cardiopulmonary Resuscitation Hemodynamics in a Porcine Model of Cardiac Arrest
Authors: Cucinotta Daniel M , Rolland Tyler J , Weil Brian R 
Published: May 2024

Objective: Agonal respirations (AR) are common in patients with cardiac arrest (CA) and are associated with a higher likelihood of successful return of spontaneous circulation (ROSC). Prior preclinical studies suggest that the favorable effects of AR may be mediated by improved coronary perfusion pressure (CPP) during subsequent cardiopulmonary resuscitation (CPR) efforts, but whether this relationship is influenced by the duration of CA has yet to be studied. Accordingly, we measured CPR hemodynamics in swine following 7 minutes or 10 minutes of untreated ventricular fibrillation (VF) to determine if the frequency of AR is associated with CPP after prolonged CA. Methods: Swine (n=71) were subjected to either 7 minutes (n=50) or 10 minutes (n=21) of electrically-induced VF CA, during which the frequency of AR was recorded before the initiation of CPR with chest compressions (100/minute) and mechanical ventilation (16-20 breaths/minute). CPP was assessed during CPR by calculating the difference between aortic pressure and right atrial pressure during decompression. Animals were retrospectively stratified into two groups (high and low frequency of AR) based on the median number of AR in each cohort (7-minute CA median = 6 AR; 10-minute CA median = 9 AR).>Results: In the 7-minute CA cohort, the high AR group (9.7±2.9 AR; n=28) had a significantly longer time from first to last AR (102±6 vs. 34±6 seconds; p<0.001), shorter time from final AR to CPR initiation (208±8 vs. 280±15 seconds; p<0.001), and higher CPP during CPR (14.4±1.0 vs. 9.3±0.6 mmHg; p<0.001) than the low AR group (2.9±0.4 AR; n=22). In contrast, following 10 minutes of CA, the high AR group (12.0±0.4 AR; n=11) did not have a significantly different CPP during CPR (8.7±1.8 vs. 10.4±1.5 mmHg; p=0.48) when compared to the low AR group (6.2±0.5 AR; n=10). A greater number of defibrillation attempts were required to terminate VF after 10 minutes of CA (3.0±0.6) vs. 7 minutes of CA (1.2±0.1; p<0.001), but this was not impacted by the frequency of AR in either cohort. Conclusion: Consistent with prior studies in swine subjected to 5 minutes of untreated CA, a high frequency of AR during a 7-minute episode of CA was associated with higher CPP upon initiation of CPR. However, the favorable effects of AR frequency on CPP during CPR were no longer apparent when the duration of untreated CA was extended to 10 minutes. These results demonstrate that the beneficial effects of AR on CPR hemodynamics are time-dependent and highlight the importance of early initiation of CPR following CA. Supported by funding from the NIH and US Department of Veteran's Affairs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Advanced PamGene Coregulator Interactome Analysis of PPARgamma Reveals that Diet Influences Regulatory Protein Interactions and Signaling Mechanisms
Authors: Bates Evelyn , Kipp Zachary , Pauss Sally , Lee Wang-Hsin , Martinez Genesee , Xu Mei , Hinds Terry 
Published: May 2024

Studies show a strong correlation with type 2 diabetes mellitus (T2DM) in obese patients developing congestive heart failure (CHF) with rosiglitazone treatment. Rosiglitazone, a thiazolidinedione, treats T2DM by improving insulin resistance. Its use has been halted due to a subset of patients developing CHF through unknown mechanisms. Rosiglitazone targets PPARγ, a nuclear receptor highly expressed in adipose tissue and, to a lesser extent, in cardiac tissue. An important mechanism of PPARγ regulation is through coregulators that can alter transcriptional activity through protein-protein interaction to drive PPARγ toward specific pathways. We hypothesized coregulator interaction with PPARγ may regulate its activity differently in adiposity, inducing CHF through adipose-derived peripheral signaling. To address this, we fed 8-week-old C57BL/6 mice a normal chow (NCD) or high-fat (HFD) diet for 16 weeks. Mice were then injected with rosiglitazone every 48 hours for 4 weeks. In NCD and HFD Rosi mice, we found significantly increased heart weights (p-value<0.05) and various weight changes in five adipose depots. To understand the roles of the PPARγ coregulator interactome in adiposity, we used our state-of-the-art PamGene PamStation Nuclear Hormone Receptor chip to measure the interaction of PPARγ with 155 coregulators in five adipose depots and the liver. In adipose depots increasing in weight due to Rosi treatment, such as retroperitoneal white adipose tissue (WAT) and mesenteric WAT, more coregulators associated with the PPARγ complex. Conversely, depots that did not change in weight with Rosi treatment, such as epididymal WAT and inguinal WAT, showed a reduction of coregulators leaving the PPARγ complex, indicating differential PPARγ regulation. Our data suggests that the coregulator interactome of PPARγ in adipose depots represents potential therapeutic targets, and understanding how PPARγ regulation is different in adiposity is crucial to understanding the negative side effects of rosiglitazone treatment. R01DK121797 (T.D.H.) R01DA058933 (T.D.H.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
N-acetyl cysteine (NAC) administration induces behavioral abnormalities in mice experiencing proteotoxic cardiac disease
Authors: Devarajan Asokan , Jarrell Matthew Thomas Cleveland , Natesan Sundaresan , Sunny Sini , Arulmani Ahila , Raveendran Ashvanthi , Might Matthew 
Published: May 2024

Background: The co-occurrence of cardiac and neurological complications is becoming increasingly common among individuals diagnosed with either of these disorders. Hypothesis: We tested the hypothesis that elevating glutathione (GSH) levels through N-acetyl cysteine (NAC), a precursor for GSH synthesis, leads to behavioral abnormalities in a mouse model with proteotoxic heart disease. Approach: We used a transgenic mouse model expressing a cardiac-specific human mutant R120G-αB-crystallin (hR120GCryAB-TG), which develops progressive heart failure due to proteotoxicity. Our investigation aimed to understand the effects of NAC on brain redox and behavior in this model. Results: Administering NAC for a period of 12 weeks, we observed an increase in glutathione levels and its redox state (GSH/GSSG) in both heart (1.0 vs. 3.0 Fold in NTG vs. TG; p>0.001) and brain (1.0 vs. 4.0 Fold in NTG vs. TG; p>0.01) tissues. Interestingly, this increase was associated with exacerbated cardiac dysfunction and abnormal behavior. The administration of NAC worsened both structural and functional defects in the hearts of the transgenic (TG) mice, indicating that enhancing antioxidant defense mechanisms could trigger proteotoxic insults through reductive stress (RS). Additionally, the brain of TG mice exhibited enhanced reductive capacity (p>0.01), accompanied by significant alterations in the levels of Tau and α-Synuclein proteins, when compared to non-transgenic (NTG) mice. While NTG mice, with or without NAC treatment, displayed normal behavior, TG mice treated with NAC developed severe behavioral abnormalities, including cognitive impairment (p>0.01). Conclusions: These findings suggest that increased GSH levels (i.e. RS) in progressive heart failure could cause behavioral issues. Thus, further research into the underlying redox mechanisms in other organs, including the brain, is necessary to better understand the use of antioxidant supplements for heart failure treatment. This study will aid in developing personalized therapeutic strategies. National Institute of Health - NHLBI R01 (R01-2RHL118067; Namakkal-Soorappan) American Heart Assocaition (20POST35200085; Sunny). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A potential role for GPR107 in the development of Hypoglycemia Unawareness
Authors: Hagena Lisa , Stafford Joshua , Samson Willis K. , Kolar Grant , Yosten Gina L.C. 
Published: May 2024

Diabetes remains one of the largest health burdens in modern society and while an estimated 37.3 million people suffer from either type 1 or type 2 diabetes worldwide, a further 96 million people are currently estimated to be prediabetic. So far, most efforts for diabetic therapies have been focused on insulin-replacement therapies and secretagogues; however, a common risk associated with these therapies is hypoglycemia. Hypoglycemia is defined as low plasma glucose levels (< 70 mg/dl) and can lead to loss of consciousness and death. Recently, it has been established that repeated exposure to bouts of hypoglycemia in diabetic individuals likely impairs sympathoadrenal counter regulation, and shifts the glycemic threshold for symptoms to lower plasma glucose concentrations, close to levels which result in cognitive failure. This pathology has been titled hypoglycemia unawareness (HU) and constitutes a major risk factor for developing severe hypoglycemia. The development of severe hypoglycemia in diabetics accounts for a six-fold increase in mortality, compared to diabetic individuals who do not experience severe hypoglycemia. Thus, it is important to understand how to prevent and reverse its development. We have developed a novel rat model of HU in which rats are exposed to insulin-induced recurrent hypoglycemia for five consecutive days. In this model of HU, we found that GPR107 expression is dramatically increased in the hypothalamus of rats exhibiting loss of hypoglycemia-induced food intake. Our group previously identified GPR107 as a receptor for neuronostatin (NST), a 13 amino acid peptide derived from the somatostatin prepro-hormone, which can exert anorexigenic actions in the hypothalamus. Using a GPR107-flox rat model we are currently evaluating the effect of hypothalamic knock-down of GPR107 on the development of HU and basal feeding behavior. We anticipate that if knock-down of GPR107 reverses HU, the development of NST antagonists could potentially be useful therapeutically for diabetic patients who experience recurrent hypoglycemia. Our GPR107-flox rat model will enable us to identify upstream and downstream interacting partners of GPR107/NST. This could reveal hypothalamic pathways involved in the development of HU that also could serve as potential therapeutic targets for this devastation consequence of iatrogenic hypoglycemia. Internal Funds St. Louis University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Investigating the Role of CART/GPR160 Signaling in Stress-Induced Anorexia
Authors: Mirian Niloufarsadat , Stafford Joshua , Samson Willis K. , Yosten Gina L.C. 
Published: May 2024

Stress-induced anorexia represents a conserved adaptive response across diverse species. While this response can be crucial for survival in specific situations, it may become detrimental when prolonged stress exposure leads to unhealthy eating patterns, contributing to eating disorders like anorexia nervosa and bulimia. Feeding behavior is intricately connected to the stress response, as stress levels can influence appetite and energy expenditure. Central to the stress response are corticotropin-releasing hormone (CRH)-producing neurons, which secrete CRH, stimulating the production of ACTH in the pituitary gland and subsequently triggering the release of cortisol, a stress hormone, from the adrenal glands. The presence of CRH in the hypothalamus, a brain region involved in controlling feeding, suggests a complex interplay where stress and metabolic signals converge. One such signal is the peptide cocaine- and amphetamine-regulated transcript (CART) which has been shown to regulate feeding behavior, satiety, and metabolic function by signaling through its receptor GPR160 and downstream glucagon-like peptide (GLP)-1 signaling. In this study, we hypothesize that CART/GPR160 signals within CRH-producing neurons to control feeding behavior and stress responses. To test this hypothesis, we used a multifaceted approach, utilizing both wild type and GPR160-floxed rats in which GPR160 was knocked down specifically in CRH neurons using an AAV-Cre under the control of the CRH promoter injected bilaterally into the paraventricular nucleus. We monitored food and water intake, investigated CRH secretion from hypothalamic explants treated with CART, and assessed physiological changes in GPR160, CART, and other related molecules in various brain regions following acute stress. We also examined the effects of GPR160 knockdown in PVN neurons on plasma cortisol levels in response to restraint stress. While further studies are necessary to fully define the roles of CART and GPR160 in stress responses and feeding behavior control, our preliminary findings indicate that this ligand-receptor pair could serve as a novel therapeutic target for treating psychiatric diseases related to eating disorders. NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Essential Roles of Mitochondrial Reactive Oxygen Species Signaling in Airway Smooth Muscle from Mice following Nicotine, Pyoverdine, and their Co-exposure Authors: Subika Khatoon, Ed Wilson Santos, Yun-Min Zheng, Yong-Xiao Wang Corresponding Author: Yong-Xiao Wang, wangy@amc.edu
Authors: Khatoon Subika , Wang Yong-Xiao , zheng Yun-Min , SANTOS ED WILSON 
Published: May 2024

Consumption of nicotine, a major active component of cigarettes or e-cigarette smoke, is a global health problem, causing a myriad of life-threatening diseases. Pseudomonas aeruginosa is a common cause of lung infections and often exacerbate nicotine-associated lung diseases. However, the underlying cellular and molecular mechanisms remain poorly understood. In this study, we aim to address these important questions by performing a series of experiments. establish a clinical threshold of Pseudomonas Aeruginosa Infection in a COPD animal model and determine the underlying molecular mechanisms underlying the mitochondrial dysfunctions in Airway Smooth Muscle Cells (ASMCs). Utilizing in vitro and in vivo models, our data revealed that mice following inhalation of nicotine showed increased lung resistance, decreased lung compliance, and elevated airway resistance in vivo. In support, nicotine caused airway hyperresponsiveness in isolated mouse tracheal and bronchial smooth muscles. We also found that reactive oxygen species (ROS) production was largely increased in isolated mitochondria from mice after nicotine inhalation. Application of pyoverdine, a primary active component of Pseudomonas aeruginosa, produced a similar effect on ROS production in isolated mouse airway smooth muscle (ASM) mitochondria. Furthermore, mice co-exposed to nicotine inhalation and pyoverdine had a higher increase in ROS production in isolated ASM mitochondria compared with mice following nicotine or pyoverdine exposure alone. In conclusion, our findings for the first time demonstrate mitochondrial ROS signaling plays essential roles in airway dysfunctions following nicotine, pyoverdine, and their co-exposure and may also offer new strategies to treat lung diseases induced by nicotine inhalation and/or Pseudomonas aeruginosa. Funding: This work was supported by the NIH (R01HL122865, R03AG070784, and R01HL108232, to Yong-Xiao Wang). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Deletion of Piezo2 from renal Foxd1+ stromal progenitors and descendent cells results in abnormal mesangial development and sex-specific differences in kidney function
Authors: McLarnon Sarah , N’Guetta Pierre , O'Brien Lori L 
Published: May 2024

Piezo2 is a mechanically activated ion channel recently identified in glomerular mesangial cells and renin+ juxtaglomerular (JG) cells. Despite several studies which confirm this localization of Piezo2 in the kidney, the function of Piezo2 in these cells remains ambiguous. In the current study, we hypothesized that loss of Piezo2 in mesangial and JG cells would result in abnormal glomerular development during nephrogenesis and impaired salt and water balance in adult mice. To test this hypothesis, we generated mutant mice lacking Piezo2 in Foxd1+ stromal progenitors and their cell lineages, which include mesangial and JG cells. Kidney morphology was assessed by immunofluorescent staining and z-stack confocal microscopy during late nephrogenesis (post-natal day 0, P0) and following maturation of the nephron (P20) in wild-type (Piezo2fl/fl, n=3), heterozygous (Foxd1GC/+Piezo2fl/+, n=3), and mutant (Foxd1GC/+Piezo2fl/fl, n=3) mice. In adult male and female mice (n=2/genotype/sex), blood pressure was measured by tail cuff (CODA Systems) between 1-4pm following 3 days of acclimation. In a separate group of control and mutant male and female mice (8-10 weeks, n=3-5/group/sex), a 4-hour saline challenge (i.p. 10% body weight) was performed to assess diuresis and natriuresis. At P0, we found that deletion of Piezo2 from Foxd1+ stromal progenitors and their cell lineages resulted in the abnormal distribution of mesangial cells within glomeruli, such that the mesangial area appears compressed compared to control or heterozygous mice. This phenotype was exacerbated in mutant mice by P20. In adult mice, female mutants had an increase in daytime mean arterial pressure (~10mmHg, mean 79 vs 88) compared to female controls. Cumulative urine excretion (4 hours, percent injected) was decreased in females compared to males, regardless of genotype (p<0.001). Further, female mutant mice had a delayed diuresis response compared to control (2 hour, mean 16% vs 28% cumulative urine volume). However by 4 hours following a saline bolus both groups were similar. Taken together, these data indicate that deletion of Piezo2 in Foxd1+ stromal progenitors results in impairments in mesangial cell development during nephrogenesis and alterations in water and salt balance in adult female mice. Understanding the sex-specific roles of Piezo2 in kidney development and physiology is critical to identify the role of mechanosensation on renal homeostasis. NIH R01DK121014 to LO. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Characterizing Mitochondrial Maturation in the Heart
Authors: Torniainen Andrea , Mikkila Jennifer , van Berlo Jop 
Published: May 2024

Cardiovascular disease is the leading cause of death around the world and the burden is projected to become worse. Because of their ability to supplant the heart’s weak regenerative capabilities, stem cells and their derivatives have been investigated as a potential therapy. However, stem cell-derived cardiomyocytes are less mature than the cells they would be replacing in a clinical setting, causing many functional shortcomings such as unorganized and weak contraction. An in-depth study of how maturation normally occurs is necessary to identify targets to enhance it. As one of the best-known aspects of cardiomyocyte maturation, the mitochondria, and their substrate preferences, dictate the amount of energy a cell produces as well as modulate a cell’s contraction, differentiation, and survival. Similar to the cell itself, the mitochondria mature over time. However, to what extent mitochondrial maturation drives cardiomyocyte maturation is not clear. In this study, we used mass spectrometry to identify the developmental changes across normal cardiac maturation in mitochondria from mice. We detail key shifts in the mitochondrial proteome over time and identify possible regulators of mitochondrial and cardiomyocyte maturation. Pathway and transcription factor analyses highlight transitions over time to more organized, productive mitochondria. Mechanistic evaluation of identified pathways might reveal current bottlenecks for complete maturation of stem cell-derived cardiomyocytes. This work was supported by RMM091621DS008, NIH155993, and NIH160665. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Stiffer gymnastics floors result in more dorsiflexed ankles, potentially increasing the risk for Achilles tendon ruptures
Authors: Muhlenhaupt Emily , Stauss Harald 
Published: May 2024

One in five female collegiate gymnasts suffers an Achilles tendon rupture (ATR), primarily on floor exercise. Training floors are used daily, sometimes for over 10 years, while floors at competition sites are often new. Consequently, training floors feel “soft” and competition floors feel “stiff”. We hypothesized that the ankle joint angle is in a more dorsiflexed position on a “stiff” compared to a “soft” floor during impact, resulting in greater tension of the Achilles tendon and, consequently, a higher incidence of ATRs during competition. Female gymnasts from 78 US collegiate teams were invited to complete a survey, assessing whether ATR occurred at the training or competition sites, among other items. The ankle joint angles during landing from back-tumbling-take-offs on “soft” and “stiff” gymnastics floors were determined using video imaging. Statistical analysis was performed by Pearson’s Chi Square test or t-tests, as appropriate. Twenty-one out of 103 gymnasts (20.4%, 95% CI: 13.6% to 29.4%) experienced an ATR. Relative to time, ATRs occurred only 0.08±0.01 (95% CI: 0.06 to 0.11) times per 1000 hours on training floors, but 1.85±0.11 (95% CI: 1.60 to 2.10) times per 1000 hours (p<0.05) on competition floors. Ankle joint angles were in a more dorsiflexed position on the stiff (103.5±1.1 degree) than the soft floor (117.0±4.1 degree, p<0.05), implying greater tension on the Achilles tendon. We conclude that stiff floors favor more dorsiflexed ankle joints, increasing the tension on the Achilles tendon, and potentially explaining the higher relative incidence of ATRs at competition compared to training sites. This research was supported by the Offce of Research and Sponsored Programs at Burrell College of Osteopathic Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.