bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progranulin and Lysosomal pH: Implications for the Proinflammatory Response in Neurodegenerative Diseases
Authors: Yang Andrew Z. , Harrison Alisha M. , Uppalapati Chandana K. , Pascual Agnes S. , Biparva Pegah , Leyva Kathryn J. , Hull Elizabeth E. 
Published: May 2024

Progranulin (PGRN) deficiency and lysosomal dysfunction have been independently linked to Alzheimer's disease. Several lines of evidence suggest that there is a link between PGRN and lysosomal function. PGRN is a pleiotropic signaling molecule whose activity depends upon differential proteolytic processing. The different PGRN subunits generated during processing can regulate inflammation, lysosomal function, and/or growth. Not only is the lysosome a site of PGRN processing, the resulting PGRN subunits promote the function of several lysosomal proteases. In addition, in models of PGRN insuffciency, increasing the levels of PGRN restores lysosomal function and reduces inflammation. As microglial inflammation is key to the development of neurodegenerative diseases, this work investigates the link between lysosomal function, PGRN, and inflammation utilizing two cell lines, each for a distinct set of experiments. The SW13 human adrenal carcinoma cell line that exists in two epigenetically distinct subtypes was used to focus on differences in lysosomal pH and PGRN processing. The HMC3 human microglial cell line was used to measure microglial activation and cytokine production. We hypothesize that PGRN, when appropriately processed, will restore lysosomal function to reduce pro-inflammatory cytokine production. Results suggest that differential processing of PGRN is correlated to both differences in rate of growth, inflammatory cytokine production, and lysosomal pH as PGRN expression and processing varies when cells are stimulated which may be related to observed changes in lysosomal pH and proteases. Ongoing experiments address the possibility that decreasing lysosomal pH may shift the processing of PGRN, influencing the biological activities associated with this versatile signaling molecule. As mutations in the PGRN gene are implicated in both dysfunctional lysosomal pH and a variety of neurodegenerative diseases, these results may provide a novel approach to regulate proper intracellular functions to slow or prevent the development of disease. Midwestern University Biomedical Sciences Program Funds awarded to AZY and PB; Kenneth A. Suarez Research Fellowship Funding awarded to PB; Arizona Alzheimer's Consortium Pilot Grant Funding awarded to EEH and KJL; Midwestern Arizona Alzheimer’s Consortium (MAAC) Grant Funding awarded to EEH and KJL; Midwestern University Intramural Funding awarded to EEH and KJL. 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.
Insulin-Dendrimer Nanocomplex for Multi-Day Glucose-Responsive Insulin Therapy in Ossabaw Miniature Swine with Type 1 Diabetes
Authors: Xian Sijie , Xiang Yuanhui , Liu Dongping , Fan Bowen , Mitrová Katarína , Ollier Rachel , Alloosh Muhammad Ali 
Published: May 2024

Background: Therapy for type 1 diabetes resulting from immunogenic destruction of the insulin-producing pancreatic beta cells has been a challenge for over 100 years. Delivering exogenous insulin to maintain euglycemia is a delicate balance between plasma glucose transport to insulin-responsive tissues, glucose absorption in the gut, and the pharmacodynamics of insulin. The synthesis of short- and long-acting insulins and use of insulin pumps have made great strides in the standard of diabetes care. Despite advances, hypoglycemia is a major limitation. There is no approved therapy that offers glucose-responsive insulin function. Toward this end we engineered a nanoscale complex combining both electrostatic and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affnity glucose-binding motif. Hypothesis: This insulin nanocomplex will yield an injectable insulin depot providing both glucose-sensitive and long-lasting insulin availability in a translation preclinical model. Methods: Ossabaw minature swine (41-59 kg; N=6) were made diabetic with alloxan, which was confirmed by stable hyperglycemia (228±43 mg/dL). Oral glucose tolerance tests (OGTT) were conducted at the diabetic baseline and each of the following 6 days after one subcutaneous injection of the insulin nanocomplex. Results: The basline OGTT elicted blood glucose of 350-450 mg/dL for 90 min of the 150 min OGTT, while serum insulin remained at ~5 μU/mL, nearly the detection limit. In contrast, 3 h after injection of insulin nanocomplex (~0.8-0.9 mg/kg) blood glucose decreased to 71±12 mg/dL. Subsequent OGTTs on days 1-6 increased blood glucose from normoglycemia to ~200 mg/dL and serum insulin increased to ~60-220 μU/mL, followed by return to nearly normolgycemia hours after the OGTT. Hypoglycemia was avoided in all pigs. Conclusions: The subcutaneous nanocomplex of a modified insulin and a synthetic dendrimer carrier produced a glucose-responsive insulin depot for week-long glycemic control following a single routine injection. These findings offer great promise for overcoming the hypoglycemia risk of intensive glucose control. Future studies should include additional physiological challenges of exercise and nutritional states. Support: Juvenile Diabetes Research Foundation 5-CDA-2020-947-A-N, Helmsley Charitable Trust 2019PG-T1D016 and 2102-04994, American Diabetes Association Pathway 1-19-ACE-31, National Science Foundation BMAT1944875, European Union-Next Generation EU LX22NPO5104, Czech Academy of Sciences RVO 6138963. 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.
Daunorubicin Treatment Impairs Cardiac Function in The Ts65Dn Mouse Model Of Down Syndrome
Authors: Buckman Michelle , Vasileva Anastasiia , Vasilyev Mikhail , Jedlicka Charles , DeRuisseau Lara , Tomasson Michael , Bates Melissa 
Published: May 2024

Anthracycline treatment for leukemia is effective but has toxic side effects on the cardiovascular system. Few studies regarding the impact of anthracyclines on the heart in individuals with Down syndrome have been addressed although they are at a higher risk of developing leukemia. It is unknown if established mechanisms apply to individuals with Down syndrome. We hypothesize that anthracycline cardiotoxicity will lead to the enhanced impairment of cardiac function and initiate pronounced vascular dysfunction in a mouse model of Down syndrome. We used the Ts65Dn mouse model of Down syndrome to investigate the impact of daunorubicin chemotherapy on survival, arterial stiffness and left ventricular function. Four-month-old Ts65Dn (n=12) and wild-type control Ts65Dn (WT, n=8) mice were treated with 2mg/kg of daunorubicin or saline. Following treatment, left ventricular catheterization was performed to assess cardiac function. Serum cardiac troponin levels were evaluated using ELISA. Histological analysis was conducted on the heart and aorta of mice to assess the accumulation of elastin and collagen. We found decreased end-diastolic pressure (p=0.016) and ejection fraction (p=0.029) in Ts65Dn daunorubicin-treated mice compared to WT control. However, contractility (end-systolic pressure-volume relationship, p=0.221) and diastolic stiffness coeffcient (end-diastolic pressure-volume relationship, p=0.418) remained unchanged. Ts65Dn mice had a higher cardiac troponin concentration (p=0.02). Histological assessment showed no significant difference in collagen (p=0.841) and elastin (p=0.768) content. Daunorubicin negatively impacted end-diastolic pressure and ejection fraction of the Ts65Dn mouse model of Down syndrome. We demonstrated that we could recapitulate the findings of anthracycline cardiotoxicity in Ts65Dn mice indicating this is a good model to investigate toxicity. Continued work with this model will better elucidate the mechanisms underlying anthracycline cardiotoxicity in Down syndrome. This shows the need for constant screening after anthracycline treatment which will improve the survival of this population. NIH R21 HD099573. 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.
In Vivo Tissue Distribution of Microplastics and the Systemic Metabolic Changes After Gastrointestinal Exposure in Mice
Authors: Romero Aaron 
Published: May 2024

Marcus M. Garcia, Aaron S. Romero, Seth D. Merkley, Jewel L. Meyer-Hagen, Charles Forbes, Matthew J. Campen, Julie G. In, and Eliseo F. Castillo Microplastics (MP) are slated to be the next environmental threat to humans. It is estimated humans consume approximately 5 grams of MP per week. To date, the systemic impact of MP ingestion on metabolic pathways in systemic organs have not been studied utilizing environmentally relevant doses and mixtures. To investigate the impact of ingested MPs on target metabolic pathways, mice were exposed to either polystyrene (5 μm) microspheres or a mixture of MPs consisting of polystyrene (5 μm), polyethylene (1-4 μm), and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid) (5 μm). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier and accumulate in distant tissues. Additionally, we report on the metabolic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. This study provides critical insight into the pervasive issues of plastic pollution and highlights dose-dependent and polymer type specific metabolic changes in the colon, liver and brain caused by MPs exposure. NIH/NIEHS 1R01 ES032037-01A1. 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.
Chronic intermittent hypoxia alters CD8+ expression in the bone marrow of C57BL/6 mice
Authors: Edwin Immaculate , Jedlicka Charles , Zhang Zishan , Vasilyev Mikhail , Vasileva Anastasiia , Tomasson Michael , Bates Melissa 
Published: May 2024

Cytotoxic CD8+ cells are critical in anticancer immune response and have become prevalent in immunotherapies over the past decade. Anti-LAG3/anti-PD1 combined immunotherapies increase the number of CD8+ cells. Moderate to severe sleep apnea increases the risk of cancer-related mortality. Chronic intermittent hypoxia, a feature of sleep apnea, decreases the percentage of perforin-expressing CD8+ cells, impairing cytotoxicity. Our objective is to determine the distribution of Prf1(perforin), LAG3(lymphocyte-activation gene 3), and PDCD1(programmed cell death 1) in C57BL/6 mice exposed to chronic intermittent hypoxia (CIH). We hypothesize that Prf1, PDCD1, and LAG3 will be expressed on three discrete clusters with a higher expression of LAG3 and PDCD1 and lower expression of Prf1 between C57BL/6 mice exposed to chronic intermittent hypoxia and normoxia. Bone marrow from the femur of C57BL/6 mice exposed to chronic intermittent hypoxia or normoxia was harvested. Bone marrow mononuclear cells were isolated, RNA was extracted, and single-cell RNA sequencing was performed. Loupe browser was used to re-cluster and quantify expression for genes of interest. Prf1 and PDCD1 are expressed in CD3+CD8−CD4− cluster and LAG3 is expressed in CD3−CD8+CD4+ cluster. LAG3 and Prf1 are present among the top ten genes, while PDCD1 is not in those clusters. Further analysis of the top ten genes of CD3+CD8−CD4− has demonstrated they are a group of natural killer cells. Contradictory to our expectation, Prf1 and PDCD1 are present in CD3+CD8−CD4− cluster while LAG3 is present in CD3−CD8+CD4+ cluster. Further analysis is necessary to determine the underlying mechanisms causing these changes. 5R01CA244271-02. 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.
E-Cigarette Aerosol Alters Pulmonary Surfactant Function
Authors: Graham Emma , McCaig Lynda , Abu Al-Burak Salem , Veldhuizen Ruud 
Published: May 2024

Introduction: E-cigarette (EC) and vaping use continue to remain popular, particularly in young populations despite several clinical reports of vaping associated lung injury. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. A complex mixture of lipids and proteins, surfactant reduces surface tension in the lungs maintaining compliance and preventing collapse. Currently, information on how EC aerosols impacts pulmonary surfactant remains limited, particularly in the in vivo scenario. We hypothesized that exposure to EC aerosol will impair the surface tension reducing ability of surfactant. Methods: In vitro EC aerosol exposure : Bovine Lipid Extract Surfactant (BLES) was used as a model surfactant in a direct exposure syringe system. BLES (2ml) was placed in a syringe (30ml) attached to an EC. The generated aerosol was drawn into the syringe and then expelled, repeated 30 times. In vivo EC aerosol exposure : Male and female Wistar rats were exposed to vehicle or menthol flavoured EC aerosol. Rats were exposed for 15 minutes for either a single or multiple (up to 8) exposures, with control animals receiving room air. Animals were euthanized and bronchoalveolar lavage was performed to collect surfactant. Analyzing surfactant function: Samples underwent dynamic compression and expansion, and biophysical analysis after exposure, completed using a constrained drop surfactometer (CDS). Results: Significant increases in minimum surface tensions were observed after exposure to EC aerosol across 20 compression/expansion cycles. Surfactant function was altered in vitro independent of vaping device, temperature, or inclusion of nicotine. Vehicle aerosol exposure produced alterations in surfactant properties, however addition of menthol flavouring significantly increased surface tensions compared to control and vehicle exposure. Preliminary in vivo studies indicate that aerosol exposure is well-tolerated by both male and female animals. Further experiments will analyze the function of surfactant isolated from these animals. Discussion: EC aerosols alter surfactant function through increases in minimum surface tension in vitro. This effect was more pronounced with menthol flavoured EC aerosol. It is anticipated that our in vivo experiments will corroborate these findings. Ultimately, impairment of surfactant due to EC aerosol exposure may contribute to lung dysfunction and susceptibility to further injury. Western University, NSERC, OGS. 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.
The consequences of environment-induced heat stress on the kidney in female mice
Authors: Roths Missey , Rudolph Tori , Krishna Swathy , Michael Alyona , Selsby Joshua 
Published: May 2024

Environment-induced heat stress (EIHS) is caused by a sustained elevation in body temperature, due to prolonged exposure to excess heat and humidity. Given the present and increasing frequency of EIHS and the gap in knowledge regarding EIHS-mediated impacts to the kidney, the purpose of this investigation was to determine the extent to which EIHS alters kidney health. We hypothesized EIHS would cause kidney injury and cellular dysfunction. To test this hypothesis, 7 wk old C57 female mice were assigned to either EIHS (n=14; 36.7 ± 0.16 °C, 36.3 ± 0.5 % humidity) or thermoneutral (TN) conditions (n=12, 31.2 ± 1.01 °C, 35 ± 0.7% humidity) for 24 h, kidneys were removed, weighed, and were either fixed for histology or frozen for biochemical measures. Environment-induced HS increased rectal temperature by 2.1 °C (p< 0.001), decreased body weight by 10% (p=0.03), and decreased absolute kidney weight (10%; p=0.02) compared to TN. Environment-induced HS increased relative protein abundance of heat shock proteins 70 (48%, p<0.01), 90 (37%, p<0.01), and 60 (36%, p=0.02), as well as heat shock factor 1 (2-fold, p=0.02) compared to TN. Histological inspection revealed EIHS animals had increased vacuolation in the proximal convoluted tubules (p<0.01) compared to TN animals. Using a western blot approach, we measured biomarkers of kidney tubular health and discovered EIHS increased protein abundance of NGAL (88%, p<0.01), IL-10 (36%, p=0.05), IL-6 (46%, p<0.01), MCP-1 (74%, p=0.04), and L-FABP (99%, p<0.01), which are suggestive of kidney injury. Environment-induced HS increased markers of inflammatory signaling including TLR4 (44%, p=0.04), phosphorylated (p-) NFκB (93%, p<0.01), p-JNK (54 kD; 51%, p=0.02), p-JNK (46 kD, 35%, p=0.02), AP-1 (33%, p=0.02), and TNFα (39%, p=0.05). Endoplasmic reticulum stress was increased by EIHS as Bip, p-IRE1α, Perk, XBP1s, ATF4, and CHOP were increased 27-190% (p<0.05-0.01) compared to TN animals. Markers of mitochondrial abundance remained similar between groups; however, EIHS may alter mitochondrial fusion and fission as Opa1 (71%, p=0.01), MFN2 (29%, p=0.04) and DRP1 (59%, p=0.04) were increased compared to TN; however, MFN1, FIS1, and p-DRP1 were similar between groups. Collectively, these data suggest that 24 h of EIHS causes kidney injury, but may also be suffcient to initiate changes that contribute to acclimation. This study was supported by USDA 2020-02716. 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.
Sympathetic Transduction to Blood Pressure in Patients with Chronic Kidney Disease
Authors: Trotter Claire E. , Young Benjamin E. , Conley Rie V. , Kaur Jasdeep , Mohan Ponnaiah C. , Fadel Paul J. 
Published: May 2024

Chronic kidney disease (CKD) is a major health problem affecting more than 35 million Americans. Notably, more patients with CKD die of cardiovascular complications than progress to end-stage renal disease. An overactive sympathetic nervous system is a well-known cardiovascular risk factor. Previous research has suggested elevated resting sympathetic nerve activity and a heightened α-adrenergic receptor sensitivity in patients with CKD, both of which may predispose this population to greater sympathetic transduction. Therefore, we tested the hypothesis that patients with stage III CKD have an augmented sympathetic transduction to blood pressure (BP) compared to controls without CKD. In 7 patients with stage III CKD and 8 controls muscle sympathetic nerve activity (MSNA; peroneal microneurography) and beat-to-beat BP (finometer) were continuously recorded during 10 minutes of quiet supine rest. Modelflow was used to estimate stroke volume and calculate total vascular conductance (TVC). Sympathetic transduction was quantified as the peak change in mean arterial pressure (MAP) and the nadir reduction of TVC over 10 cardiac cycles following spontaneous MSNA bursts using signal averaging. Patients with CKD and controls had similar resting MAP (CKD: 102 ± 14 mmHg; CON: 95 ± 8 mmHg; P = 0.27), MSNA burst frequency (CKD: 33 ± 10 bursts/min; CON: 31 ± 14 bursts/min; P = 0.78) and MSNA burst incidence (CKD: 53 ± 15 bursts/100 heartbeats; CON: 47 ± 24 bursts/100 heartbeats; P = 0.60). Peak increases in MAP following all bursts of MSNA were not different between patients with CKD and controls (CKD: 2.1 ± 0.7 mmHg; CON: 2.2 ± 0.9 mmHg; P = 0.83). Likewise, nadir reductions in TVC following all bursts of MSNA were not different in patients with CKD (CKD: -1.2 ± 0.6 ml/min/mmHg; CON: -1.4 ± 0.5 ml/min/mmHg; P = 0.46). Similar results were observed when considering burst patterning. MSNA bursts occurring in multiples (adjacent to other bursts) produced comparable peak MAP (CKD: 2.6 ± 0.6 mmHg; CON: 2.8 ± 1.2 mmHg; P = 0.67) and nadir TVC (CKD: -1.5 ± 0.7 ml/min/mmHg; CON: -1.9 ± 0.7 ml/min/mmHg; P = 0.25) responses between groups. There were also no differences in peak MAP and nadir TVC responses following single bursts of MSNA (bordered by cardiac cycles lacking bursts; both P > 0.30). These preliminary data suggest that, in contrast to our hypothesis, sympathetic transduction to BP is not augmented in patients with stage III CKD. This project was supported by the National Heart, Lung, and Blood Institute R01 HL-127071 (PJF). 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.
Antioxidant-induced modulation of sympathetic transduction to arterial blood pressure in humans
Authors: Veach Jodi , Kovarik Jack , Gangwish Megan , Clonch Davina , Thyfault John , Miles John , Holwerda Seth 
Published: May 2024

Purpose: Excess plasma free fatty acids (FAA) promote oxidative stress and an increase in peripheral resistance. Therefore, we tested the hypothesis that excess FAA limits sympathetic control of arterial blood pressure (BP) and that sympathetic control would be restored during co-administration of ascorbic acid, which is an antioxidant with vasodilatory properties. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 5 lean, healthy adults with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Sympathetic control of BP was examined by determining the BP response to individual bursts of muscle sympathetic nerve activity (MSNA) (microneurography). Briefly, beat-to-beat mean arterial pressure (MAP) was measured continuously (finger cuff) and signal-averaged over 15 cardiac cycles following each detected burst of MSNA over a 10-min resting period. Results: In contrast to our hypothesis, no change was observed in sympathetic transduction during lipid infusion (1.5 ± 0.4 vs. 1.4 ± 3 mmHg, P=0.75). However, co-infusion of ascorbic acid significantly increased sympathetic transduction compared with baseline (1.5 ± 0.4 vs. 2.0 ± 3 mmHg, P=0.04), in addition to reducing peripheral resistance (0.73 ± 0.11 vs. 0.53 ± 12 mmHg·min·mL−1, P=0.07). MSNA and MAP were not significantly changed during the 2-hr infusions. Conclusions: These preliminary findings suggest that excess FAA do not modulate sympathetic transduction in lean, healthy adults. However, ascorbic acid infusion reduces peripheral resistance and increases sympathetic transduction, demonstrating an inverse relation between peripheral resistance and sympathetic transduction in healthy adults. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366) The contents are solely the responsibility of the authors and do not necessarily represent the offcial views of the NIH or NCATS. 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.