bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal characterization of the gut microbiota in the ZDSD rat model of diabetes
Authors: Weninger Savanna , Ding Angela , Laubitz Daniel , Duca Frank 
Published: May 2023

The complex development of type 2 diabetes (T2D) creates challenges for studying its progression in animal models, which often lack transition through the prediabetic state or fail to fully develop the multifaceted aspects of T2D. However, studying T2D development and progression in humans is costly with extensive limitations. A newly developed rat model of T2D, the Zucker Diabetic Sprague Dawley (ZDSD) rat, more closely parallels the progression of T2D in humans. Our goal was to examine T2D progression and the associated changes in the gut microbiota in the ZDSD model and test whether the model can be used to examine potential therapeutics targeting the gut microbiota. As physiological parameters like blood glucose and insulin levels can impact the gut microbiota and vice versa, we anticipate significant shifts in the gut microbiota as the ZDSD rats progress from a healthy to prediabetic to overt diabetic phenotype. Bodyweight, adiposity, and fed/fasting blood glucose and insulin were recorded throughout the progression of T2D in male ZDSD rats over 24 weeks. Glucose and insulin tolerance tests were performed, and feces collected for microbiota analysis using 16s rRNA gene sequencing at 8, 16, and 24 weeks. At the end of 24 weeks, half of the rats were supplemented with oligofructose (OFS) in their drinking water and tests repeated. Over the 24 weeks, we observed a transition from nondiabetic to prediabetic and overtly diabetic states, via worsened insulin and glucose tolerance and significant increases in fed/ fasted glucose values, followed by a significant decrease in circulating insulin. Microbiota analysis demonstrated alterations in the gut microbiota throughout the development of diabetes with shifts in alpha and beta diversity as well as alterations in specific bacterial genera in healthy compared to prediabetic and diabetic states. OFS treatment significantly increased body weight and adiposity, improved glucose tolerance, and shifted the cecal microbiota of the ZDSD rats during late-stage diabetes. These findings demonstrate the translational potential of ZDSD rats as a T2D model and highlight the potential for the gut microbiota to both impact the development of the disease, as well as serve as a biomarker for T2D. Additionally, OFS treatment was able to moderately improve glucose homeostasis in the ZDSD model. Arizona Biomedical Research Commission New Investigator Award (ADHS18-198857), National Institute of Food and Agriculture (67017-29252), and NIDDK (R01ES033993). 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.
Intranasal Leptin Prevents Opioid-Induced Respiratory Depression in Obese, Opioid Tolerant Mice
Authors: Singer Michele , Freire Carla , Kim Lenise , Pho Huy , Latremoliere Alban , Polotsky Vsevolod 
Published: May 2023

Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia or causing withdrawal symptoms. We have previously shown that intranasal (IN) leptin can reverse apneas, hypoventilation, and upper airway obstruction while enhancing analgesia following acute morphine administration. Here we hypothesize that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin without acute withdrawal while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO). To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, sleep and breathing were recorded by barometric plethysmography following acute or chronic administration of IN leptin. Operant behavioral assays and Pavlovian conditioning procedures were used to determine the impact of IN leptin on the analgesic efficacy of morphine and opioid withdrawal symptoms. Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Chronic IN leptin induced > 50% reduction in the OIRD in morphine tolerant DIO male mice suggesting the protective effect of leptin remained after the two-week treatment. Morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. IN leptin did not modify naloxone conditional place aversion or naloxone withdrawal symptoms, suggesting that IN treatment does not induce opioid withdrawal. We conclude that IN leptin is ineffective in lean mice but prevents OIRD in obesity by increasing hypercapnic sensitivity when leptin resistance at the BBB is present without reducing analgesia or inducing withdrawal. NIH R61HL156240; NIH R01HL128970; NIH R41DA056239 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 a novel acetaminophen (APAP) analog on survival time after extremity trauma and moderate or severe conscious hemorrhage in rats
Authors: Pando Miryam , Ryan Kathy , Calderon Mariam , Klemcke Harold , Rodriguez Cassandra , Connor Brian , Perez Samantha , Hinojosa-Laborde Carmen 
Published: May 2023

Background: Multiple analgesics are used for acute pain relief following trauma in both the military and civilian settings. However, in addition to their ability to relieve pain, medical providers must also be concerned about secondary effects of the analgesics, especially effects on the cardiovascular and respiratory systems when the pain of trauma is associated with hemorrhage. Kalyra Pharmaceuticals has developed novel analogs of APAP to circumvent liver toxicity and improve analgesic efficacy. These analogs have the potential to replace opioids for severe pain while minimizing adverse effects. The objective of this study is to test a pain-reducing dose of D-112, an APAP analog, for its effects on survival to hemorrhage after extremity trauma (ET). We hypothesize that D-112 will not affect survival after either moderate or severe hemorrhage. Methods: Male Rats (~360 grams) were randomly assigned to receive either 0.9% saline (V) or 50 mg/kg D-112 (D) after either ~37% or ~50% of blood volume hemorrhage. All rats were surgically implanted with a carotid catheter under anesthesia. Carotid catheters were used for blood withdrawal and for injection of V or D. 24 hrs later, rats were briefly (~10 min) anesthetized again and ET consisting of soft tissue injury (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps) and fibula fracture was performed. After completion of ET, rats were allowed to recover. 90 min after ET, rats underwent a conscious hemorrhage via the indwelling catheter. At the end of hemorrhage, rats received either V or D via the carotid catheter. Rats were observed for a maximum of 4 hrs after the start of the 25 min hemorrhage. Results: Survival after hemorrhage was recorded in the 4 groups: V-37% (n=13), D-37% (n=11), V-50% (n=10), D-50% (n=11). The survival proportions at 240 min were 92.3% for V-37%, 81.8% for D-37%, 60.0% for V-50%, and 18.1% for D-50%. While there was no significant difference in the survival curves of V-37% and D-37%, the survival curves of V-50% and D-50% were significantly different ( p = 0.036). Conclusions: The analgesic dose of D-112 tested decreased survival after ET and severe hemorrhage (~50% of blood volume), but not after ET and moderate hemorrhage (~37%). These results suggest that D-112 may not be an appropriate analgesic following traumatic hemorrhage. Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine/Joint Program Committee 8, and US Army Combat Casualty Care Research Program, US Army Medical Research and Development Command. 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.
TRPML channel activation and recovery of calcium signals in pulmonary arterial myocytes of fetal and adult sheep disrupted by long term hypoxia
Authors: Juarez Rucha , Williamson Grace , Levine Tessa , Ang Dylan , Boskind Madison , Chan Michelle , Zhang Lubo , Puglisi Jose , Wilson Sean 
Published: May 2023

Ca2+ signals are important for regulating vasodilatory function in the pulmonary vasculature. Previous studies demonstrate that there are developmental changes in rapid Ca2+ sparks and slower whole-cell Ca2+ oscillations. Long-term hypoxia (LTH) causes pulmonary hypertension and aberrations in these Ca2+ signals are thought to be important to the etiology of the disease. The LTH-induced dysregulation in Ca2+ sparks is linked to loss in communication between L-type Ca2+ channels on the plasma membrane and ryanodine receptors on the sarcoplasmic reticulum. Recent studies illustrate that Ca2+ filled lysosomes can be closely associated with the sarcoplasmic reticulum. Previous work shows that activation of TRPML channels on lysosomes releases Ca2+ into the cytosol and can trigger ryanodine receptor mediated Ca2+ sparks. The aim of this study was to test if TRPML channel activation recovers aberrant Ca2+ sparks and whole-cell Ca2+ oscillations after LTH exposure. Ca2+ sparks and whole-cell Ca2+ oscillations were measured on live fetal or adult sheep pulmonary arterial myocytes loaded with fluo-4 in an en face arterial preparation using confocal microscopy. The sheep were housed at either normoxic (700m) or hypoxic (3801m) conditions. Myocyte Ca2+ was measured in the absence and then presence of 10 μM MLSA-1, a selective TRPML channel agonist. Treatment with MLSA-1 increased overall spark and oscillatory activity. In the fetal hypoxic group, MLSA-1 significantly increased the number of cells with oscillatory activity. MLSA-1 also significantly increased Ca2+ spark activity in fetal and adult hypoxic, as well as adult normoxic myocytes. Interestingly, MLSA-1 did not influence amplitude of Ca2+ sparks or the area of whole-cell Ca2+ oscillatory events. These results suggest that activation of lysosomal TRPML channels may be a therapeutic target for pulmonary hypertension, through recovery of Ca2+ signals that regulate pulmonary vascular reactivity. Still, further exploration is needed to fully understand the impact of LTH on lysosomal function, the mechanisms by which aberrant Ca2+ signaling activity is recovered, and the effect on pulmonary vascular resistance and pressure. NIH R01HL155295, R01HL149608 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 social defeat stress promotes inflammation and severe hypertension in male mice
Authors: Scott Karen , Eikenberry Sophia , Oliveira Aline , Thomas Nagheme , Johnson Dominique , Baumer-Harrison Caitlin , Bryant Andrew , de Kloet Annette , Krause Eric 
Published: May 2023

The worldwide prevalence of hypertension continues to rise, shortening lifespan and contributing to the risk of cardiovascular disease and stroke. Although there are numerous contributing risk factors, social adversity is believed to be one that may account, in part, for disparities in rates and treatment outcomes. We have recently begun to evaluate whether chronic social defeat stress (CSDS) can effectively model aspects of stress-induced cardiovascular disease. Adult male C57BL/6J mice were implanted with telemetry devices that recorded blood pressure, heart rate, core body temperature, and activity. Male CD1 mice were used to defeat C57BL/6J mice 1h before the onset of the dark cycle. Immediately following submission, the defeated mouse was housed in the same cage as the aggressor, physically separated by a perforated divider that allows for continuous visual, auditory, and olfactory contact. The C57BL/6J mouse was defeated and housed with a different CD1 mouse each day, to reduce the likelihood of habituation. Initial social defeat resulted in significant increases in blood pressure, activity, and temperature in comparison with control mice. Interestingly, while blood pressure returned to basal levels by the start of the light cycle for the first few days of defeat, chronic social defeat resulted in sustained elevations in blood pressure, lower activity and lower body temperature. Mice exposed to CSDS also exhibited anxiety-like behaviors, spending significantly more time in the closed arms of the elevated plus maze and less time in the center of an open field arena. At the end of the experiment, flow cytometry was performed on spleen and lung tissue from a subset of mice. Splenomegaly was observed in CSDS mice, with an increase in CD11b and monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs), consistent with chronic inflammation. There were significant increases in PMN-MDSCs isolated from lung, a strong predictor of pulmonary hypertension, as well as enhanced immunosuppressive capability of MDSCs which is associated with the severity of disease. CSDS also resulted in increases in body, heart and adrenal weights and fluid retention. These data suggest that CSDS may be useful for modeling aspects of hypertension and immune dysfunction induced by chronic social stress, thereby enabling us to better understand the mechanisms that contribute to cardiovascular disease. R35HL150750 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.
Potent anti-inflammatory effects of the adiponectin receptor agonist, ALY688
Authors: Tang Jialing , Lone Abdul Hadee , Pignalosa Anglica , Crawford Kathryn , Abdul-Sater Ali A , Sweeney Gary 
Published: May 2023

Low circulating levels of adiponectin are associated with increased inflammation in a wide-range of disease states. In particular, this applies to obesity-related diseases such as type 2 diabetes, heart failure and non-alcoholic fatty liver disease. Numerous studies have shown that adiponectin exerts anti-inflammatory and beneficial metabolic effects. Hence there has been tremendous interest in developing adiponectin-based therapeutics. Here we examined the effect of ALY688, a small peptide adiponectin receptor agonist, on lipopolysaccharide (LPS)-driven inflammation in vivo and in vitro. We show that ALY688 administration significantly diminished LPS-driven production of pro-inflammatory cytokines and chemokines (i.e., IL-1β, TNF-α, IL-12, IFN-β, MCP-1, KC, RANTES) in mice. Moreover, mice injected with ALY688 exhibited a rapid increase in the anti-inflammatory cytokine, TGF-β. Apart from an increase in total CD3+ T cells, there were no marked changes in the circulating immune cells following ALY688 injection. No alterations in cytokine profile was seen in normal mice given ALY688, suggesting that the effects of ALY688 are context-dependent. Mechanistically, we employed phospho-flow cytometry to demonstrate that circulating immune cells responded rapidly to ALY688 injection by upregulating p-AMPK and p-P38, two well established adiponectin downstream signaling events. These results were confirmed in human peripheral blood mononuclear cells (PBMCs), where ALY688 treatment led to a robust increase in phospho-AMPK and phospho-P38. Altogether, these results show that the adiponectin agonist, ALY688, has strong anti-inflammatory effects by triggering AMPK and P38 activation in vivo and in vit Canadian institutes of Health Research & Allysta Pharmaceuticals 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 pearls and perils of “Flipping” the Classroom
Authors: Osborne David 
Published: May 2023

In 2010, an administrative decision to record all class lectures and the subsequent drop in class attendance by the students led my physiology colleague and I to prerecord our lectures and provide them to the students ahead of time. We then utilized class time for more active learning sessions. We subsequently found out that we had inadvertently, “flipped the classroom.” The pearls experienced have been many. Our initial focus was to get students back into the classroom as this was a belief that we can better serve them. Historically, attendance in my flipped classes at two different institutions has been significantly greater (2X) than that I experience if all I do is lecture. In prepping for and executing my flipped class sessions I have been re-inspired and reinvigorated to maximize my teaching activities. The preparation for these activities has kept me delving into the literature and consulting colleagues to keep myself up-to-date and fresh on the material that I am presenting. However, the most rewarding aspect of flipping the classroom has been watching the student performance on the physiology portions of our tests, as well as the boards improve. We basically have seen an approximate 10% increase in the ability of our students to answer physiology questions in situations where we could test them in a controlled fashion. Correspondingly, students in the lower quartile of the class achieved an approximate 21% increase in student performance (previously published and presented at FASEB meetings). The perils related to flipping the classroom have been surprising but not unexpected. The initial issue with flipping the classroom is that it requires a greater investment in the process by the individual faculty member. I basically produce two slide sets as opposed to one. One slide set for the lecture recording and a second slide set for class presentation. Another complaint from faculty is related to the potential for losing “control” of the class which is of particular concern to faculty who are earlier in their careers that this is a potential discomfort with the process of flipping the classroom. Another complaint that I have heard from faculty comes from those who are not flipping the classroom (just lecturing) and they consider that the flipped classroom process gives me extra time. I have spent a lot of time in discussions with students, faculty and administration discounting this complaint. I love to talk with any faculty who wish to flip the classroom because I believe the pearls far outweigh the perils regarding flipping the classroom. To see the students’ faces, light up when they understand the concept during class and see their increase in performance on tests is the only reward necessary. 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.
Gromphadorhina portentosa as a model for traumatic brain injury
Authors: Cisneros Kessia , Sossa Kenny 
Published: May 2023

Traumatic Brain Injuries (TBI) cause neurophysiological and neurodegenerative dysfunctions. One aspect that is of interest to model in the laboratory and worthy of further exploration is TBI-induced memory impairment. To investigate the impact of TBI on the behavior and memory of Gromphadorhina portentosa (Giant Madagascar Hissing Cockroach) a close-head mechanical device was utilized at a range of 20°- 30° to induce head injury. Here preliminary data for 25° is shown because it yielded the lowest mortality rate. We conducted behavior tests to examine locomotion and motivation; the former showed that head injuries resulted in a limited range of movements and ataxia, while the latter showed that brain trauma was consistent with delayed or lack of preference behavior. Ongoing work suggests that traumatic brain injury decreases memory compared to the control. The behavior work is further supported by neurochemistry results that show alterations in glucose metabolism correlating with the TBI. Our data indicates that G. portentosa is a compelling model for studying TBI. Future work will explore mechanisms and treatments for TBI using cockroaches. APU 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.
Midbrain regions activated during copper-sulfate induced emesis in felines
Authors: Sampson Jacob , Dong Xiaoying , Balaban Carey , Yates Bill 
Published: May 2023

The neural pathways that mediate emesis are still poorly defined. Most studies that considered emetic circuitry focused on the brainstem. The goal of this study was to map the distribution of Fos labeling in the feline midbrain following intragastric administration of copper sulfate (CuSO4). In 10 felines (6 male, 4 female), doses of CuSO4 ranging from 83 to 322 mg were administered through an intragastric catheter or gavage, and ~2 hours later animals were euthanized and perfused with paraformaldehyde. The brain was sectioned and processed for Fos labeling as in our prior study (Balaban et al., PLoS ONE 9(1): e86730, 2014). Three additional animals served as controls and did not receive intragastric CuSO4. Animals with emetic responses to CuSO4 exhibited extensive differential labeling in longitudinal columns within central/periaqueductal gray through the entire extent of the aqueduct of Sylvius. Labeling was present in the dorsolateral column of all animals, and differentially in the lateral column, ventrolateral column, ventromedial column, and the ventromedian area that caps the dorsal raphe nucleus. Fos labeling was also heavy in the dorsal tegmental area, superficial to the dorsal tegmental nucleus, locus coeruleus, pontine nuclei including the nucleus reticularis tegmenti pontis, and the dorsal raphe nucleus. Additional labeling was observed in the cuneiform nucleus, raphe centralis superior, and the Edinger-Westphal and anteromedial nuclei. This Fos labeling pattern is less circumscribed that reported for brainstem areas activated during CuSO4-induced vomiting in felines. Only diffuse labeling was noted in control animals. Ongoing studies are correlating physiologic responses to Fos labeling patterns induced by intragastric CuSO4. Midbrain neurons activated during emesis likely mediate affective responses during nausea, and likely also transmit visceral inputs elicited by CuSO4 to higher brain regions. NIH grant R01-DC018229 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.