bluuebunny/crossref_metadata_2025_split huggingface dataset:
Western diet exacerbates aristolochic acid-induced nephropathy in mice
Authors: Oe Yuji , Kim Young Chul , Kanoo Sadhana , A Goodluck Helen , Lopez Natalia , Maher Pamela , Vallon Volker 
Published: May 2023

Aristolochic acid (AA) ingestion causes Balkan nephropathy, characterized by tubular injury and progression to chronic kidney disease (CKD). AA is taken up by proximal tubule cells via organic anion transport (OAT3) and induces p53-mediated DNA damage, but little is known about modulating factors. The Western diet (WD) is rich in saturated fats, sugars, and salt and contributes to the development of metabolic disorders such as obesity and diabetes, but also to the progression of CKD. The aim of this study was to elucidate the impact of WD on AA-induced kidney injury. 5-week-old male C57BL6 mice were fed with WD or normal chow (NC) for 8 weeks, followed by administration of AA every 3 days at a dose of 3 mg/kg for 3 weeks. Samples were collected after a 3-week recovery period (n=4/group for vehicle; n=7-8/group for AA). The AA-induced increase in plasma creatinine and the reduction of hematocrit were significantly greater in WD vs NC. This was associated with increased kidney gene expression in WD vs NC of markers of DNA damage ( p53), injury ( Kim1 and Ngal), and inflammation ( Tnfa). The WD group had a greater body weight and, therefore, received a higher total dose of AA (0.73 and 0.6 mg), which may have worsened kidney injury. Therefore, in a second series, the same total dose of AA (0.9 mg) was administered to WD and NC groups. WD similarly increased the AA-induced fall in hematocrit and rise in plasma creatinine and renal p53, Kim1, Ngal, and Tnfa mRNA expression compared to the NC group. Moreover, WD increased renal mRNA expression of Oat3. These findings suggest that WD increases the susceptibility to AA nephrotoxicity, possibly through upregulation of OAT3. This model may be useful for studying the mechanistic impact of Western diet on the development and progression of CKD caused by nephrotoxic agents. Supported by National Institutes of Health (NIH) Grants RF1AG061296 (PM, VV), R01DK132690 (VV), and P30 DK079337 (VV), the Department of Veterans Affairs, and a fellowship of the Manpei Suzuki Diabetes Foundation (YO). 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.
Intermittent activation of large diameter phrenic afferents induces phrenic motor plasticity
Authors: Popp Nicole , Holmes Taylor , Streeter Kristi 
Published: May 2023

We recently showed that in anesthetized rats, 30 minutes of electrical stimulation applied to the diaphragm muscle induces phrenic afferent dependent plasticity characterized by a long-lasting increase in diaphragm electromyography amplitude. Our previous data also indicate that large diameter phrenic afferents may be most effective at eliciting plasticity. Here we directly test the hypothesis that intermittent activation of large diameter phrenic afferents induces phrenic motor plasticity. In urethane anesthetized and mechanically ventilated male Sprague-Dawley rats, we isolated the left and right phrenic nerves. We applied inspiratory-triggered electrical stimulation (biphasic; 40Hz; 160mA) to one phrenic nerve in a sustained (n= 5, 25 minutes) or intermittent (n=5; 5 X 5-minute episodes) pattern, and recorded contralateral motor output before, during, and for 60 minutes after stimulation. We used a narrow pulse width (0.1ms) to preferentially activate large diameter afferents. At 60 minutes, rats receiving sustained stimulation showed no difference in contralateral phrenic motor amplitude compared to time controls not receiving stimulation (n=5; P=0.1320). In contrast, rats receiving intermittent stimulation had an increase at 60 minutes compared to time controls (P=0.0005) and sustained stimulation (P=0.0024). This suggests that intermittent, but not sustained, phrenic nerve stimulation induces contralateral phrenic motor plasticity. To test the hypothesis that phrenic afferents are necessary for intermittent induced plasticity, separate animals received either a left, C3-C6 dorsal rhizotomy (n=3) or laminectomy (n=4) prior to intermittent stimulation. Laminectomy controls expressed a long-lasting increase in contralateral phrenic motor amplitude compared to time controls (n=5) at 60 minutes after stimulation (P=0.0112). Animals receiving a dorsal rhizotomy were not different than time controls at 60 minutes (P=0.4058), indicating phrenic afferents are necessary for the induction of plasticity. These data show for the first time that intermittent activation of large diameter phrenic afferents induces phrenic motor plasticity. A detailed understanding of afferent mediated plasticity will be beneficial in the development of therapeutic techniques utilizing electrical stimulation of the diaphragm muscle (i.e., diaphragm pacing). This work was supported by funding from the National Institute of Health, grant numbers: R00 HL143207-01 (KAS). The authors declare no competing financial interests. 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.
Students prefer final projects that are scaffolded to avoid procrastination and negative impact on mental health
Authors: Lopez Savannah , Hsu Jeremy , Halpin Patricia 
Published: May 2023

Many life science classes include final projects. Such projects are often due at the end of the term, though may involve several sub-parts that students can work on throughout the term. Instructors can take different approaches to these sub-parts, with some instructors requiring student submission throughout the term and others only collecting the project at the end. Our project aimed to investigate if students prefer having instructors scaffold a final project, and their reasons behind their preferences. Methods- We surveyed students from a range of colleges from community college through professional school. By using a Qualtrics survey that was sent to their instructors for disbursement we were able to collect 324 responses to both closed- and open-ended questions. For open-ended questions, each researcher independently generated a codebook using 18% of samples, before the research team discussed to generate a consensus codebook. Interrater reliability was checked with another 18% of the responses. Fleiss’s kappa was 0.65, indicating substantial agreement. Thus, one researcher coded the remaining responses. Results- The majority of students with final projects (69.45%) stated that they preferred to have their final projects broken into parts with separate due dates. Students primarily stated that they preferred this scaffolding because it keeps them on track, reduces procrastination and makes the project more manageable (55.12% of respondents). The second most common response provided (15.12 %) was that students preferred having the project broken into smaller parts led to less stress or anxiety, decreased feeling of being overwhelmed and helped reduce stress at the end of the term. Of those that stated they did not prefer to have the project scaffolded the primary reason was that scaffolding caused more pressure, anxiety, stress or changed their perception of the project. In conclusion using scaffolding to design and assign final projects benefits the student because they can work on separate parts of the assignment throughout the term and not wait until the end of the semester to begin. Using this project design can also reduce negative impacts on mental health. The results of this study can inform instructors of a way to design final projects that minimize student procrastination while decreasing negative impacts on mental health and aids in student management of the assignment Funded by Promoting Active Learning and Mentoring (PALM) Fronds 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.
Sex differences in oxidative stress-mediated reductions in microvascular endothelial function in young e-cigarette users
Authors: Halstead Kristen , Wetzel Elizabeth , Brustkern Kaila , Stanhewicz Anna 
Published: May 2023

Tobacco and nicotine use cause vascular endothelial dysfunction, increasing lifetime cardiovascular disease risk. Chronic e-cigarette use is reported to decrease endothelial function, however the mechanism(s) mediating this reduction remain unclear. Using the cutaneous circulation as a model, we examined endothelium- and nitric oxide (NO)-dependent dilation, and the role of oxidative stress in attenuating these responses, in otherwise healthy, young chronic (≥6 months) e-cigarette users (EC) compared to healthy controls (HC). We hypothesized that: EC would have reduced endothelium- and NO-dependent dilation, and local tempol (superoxide scavenger) administration would increase these responses in EC. We further examined the effect of sex within HC and EC and hypothesized that female EC would have the greatest reduction in endothelium- and NO-dependent dilation. 20 HC (21±2 yrs; 10M/10F) and 18 EC (21±2 yrs; 10M/8F) underwent a standard local heating protocol (42°C; 0.1°C·s-1). Two intradermal microdialysis fibers were placed in the ventral forearm skin for local delivery of lactated Ringer’s (control), or 10μM tempol. After full expression of the local heating response, 15mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibition) was perfused. Red cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC=flux/MAP) was standardized to maximum (%CVCmax; 28mM SNP + 43°C). Between groups, endothelium- (EC: 73 ± 15 vs HC: 87 ± 9 %CVCmax; p<0.001) and NO-dependent (EC: 48.1± 17.0% vs. HC: 61.8 ± 14.7%; p=0.011) dilation were attenuated in EC compared to HC. Local tempol perfusion increased endothelium- (83.8 ±12.1% p=0.007) and NO-dependent (61.4 ± 14.2% p=0.011) dilation in EC but had no effect in HC (all p>0.05). Within sex, female EC had lower endothelium- (EC: 69.9±3.4 vs HC: 89.1±3.5 %CVCmax; p<0.001) and NO-dependent (EC: 46.9±5.5 vs HC: 69.4±5.0%; p=0.005) dilation compared to female HC, but there were no differences between these responses in HC and EC males (both p>0.05). Tempol perfusion augmented endothelium- (83.4±4.4 %CVCmax; p=0.31) and NO-dependent (60.2±5.1%; p=0.04[AS1] ) dilation in EC females but had no effect in EC males (both p>0.05). These data suggest that otherwise healthy young adult e-cigarette users have reduced microvascular endothelium- and NO-dependent dilation. Within e-cigarette users, these results are driven by greater reductions in females, and superoxide contributes to these impairments. Supported by NIEHS/NIH P30 ES005605 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.
Cross talk between histone 3 acetylation, methylation and phosphorylation by intermittent hypoxia.
Authors: Nanduri Jayasri , Wang Ning , Prabhakar Nanduri 
Published: May 2023

We have previously identified histone 3 (H3) post translational modifications, specifically acetylation and methylation as an early epigenetic mechanism associated with sympathetic nerve activation and hypertension in rodent models of intermittent hypoxia (IH), a hallmark feature of sleep apnea (Nanduri et al, Physiol genomics 2021, Ning et al, Front Physiol 2021). Phosphorylation of H3 serine (S) residues that are adjacent to acetylation and methylation sites are also shown to regulate chromatin structure and gene expression. The aim of the present study is to assess whether IH affect H3 phosphorylation and whether phosphorylation influences H3 acetylation by IH. Studies were performed on rat pheochromocytoma (PC12) cells and adrenal chromaffin cells of rats treated with 10d IH as well as heme oxygenase (HO)-2 null mice, which exhibit spontaneous apneas. IH increased H3 lysine (K) 27 acetylation in PC12 cells, rat adrenal chromaffin cells and HO-2 null mice. These effects were associated with dephsophorylation of H3 at S28 and demethylation of K27. Inhibition of S28 dephosphorylation by protein phosphatase inhibitor (PIC) or Calyculin A, a specific inhibitor of protein phosphatase (PP)-1 and -2, inhibited H3K27 acetylation by IH. Conversely, inhibition of K27 acetylation with CTK7A a specific inhibitor of acetyl transferase p300/CBP increased S28 phosphorylation and K27 methylation in IH exposed cells. These results demonstrate that effects of IH on H3 lysine acetylation, methylation and phosphorylation are complex and a cross-talk between the three events regulate IH-induced transcriptional activity. 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.
Early Interleukin-6 Mediated Activation of SGK1 is Primarily via Variant 6
Authors: Nnah Favour , Yoshigi Masaaki , Wynne Brandi 
Published: May 2023

Hypertension is associated with inflammation, including elevated interleukin-6 (IL-6) levels. IL-6 is an inflammatory cytokine, which we have previously shown to activate the mineralocorticoid receptor (MR) and the downstream sodium (Na) transporters- Na-chloride cotransporter (NCC) and the epithelial Na channel (ENaC). However, how IL-6 activates the MR is still unknown. IL-6 is also linked to Serum and Glucocorticoid-regulated Kinase 1 (SGK1), which is a downstream effector of the MR. SGK1 regulates both NCC and ENaC, increasing activity and tubular reabsorption of Na. This increased Na reabsorption favors water retention, thus increasing blood pressure. Previously, IL-6 has also been linked with SGK1 activation. We hypothesize that IL-6 increases SGK1 mRNA and protein expression in renal epithelial cells. To test this, we used in vitro renal epithelial cell models of both the late distal convoluted tubule (DCT2) and inner medullary collecting duct (IMCD), mDCT15 and IMCD3, respectively. Cells were treated with an IL-6 time-course (100ng/ml for 1, 3 and 6 hours). There are 6 known transcriptional variants for SGK1. We designed variant-specific PCR primers and, a pilot study based on regular PCR concluded that expression levels of only variants 5 and 6 (V5, V6) are significant. Using Real Time quantitative RT-PCR, we were then able to quantify transcript levels of both SGK1 V5 and V6 variants. With IL-6 treatment, we observed a 160%-211% increase at early time points (30mins-1hr) in SKG1 V6 and a lesser response (26%-88% increase) with V5 as compared to vehicle treated mDCT15 cells. Since SGK1 has been observed in the membrane fraction and in the cytoplasm, protein extracts from cells were fractionated (mPER kit) to assess membrane and cytosolic SGK1 protein levels using immunoblots. Densitometric analysis of immunoblots demonstrated a 5.5- and 3.1-fold increase in SGK1 protein expression at 1hr in mDCT15 and IMCD3 cells, respectively. These data suggest that IL-6 induces increases in SGK1 transcription and translation. Interestingly, we also found that majority of SGK1 was in the membrane fraction and the level was consistent. Together, these data suggest that SGK1 V6 may be responsible for the increased sodium reabsorption in response to IL-6 stimulation in renal epithelial cells. NIH funding 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.
Social isolation stress favors cardiometabolic comorbidities of sleep apnea
Authors: Gagnon Marianne , Fournier Stéphanie , Marcouiller François , J. T. Arnold Alexandre , Joseph Vincent , Michael Natalie , Kinkead Richard 
Published: May 2023

Sleep apnea (SA) is a multifactorial and sex-specific respiratory disorder characterized by repeated respiratory arrests during sleep. However, the origins of this disease are not clearly identified. Chronic stress increases risk for obesity, hypertension, and depression, which are common comorbidities of SA. With the increasing prevalence of obesity and about one-third of the world population reported feeling stressed, the study of the impact of stress on respiratory homeostasis has never been so relevant. Since chronic stress induces the main comorbidities of SA, we hypothesized that social isolation (SI) stress induces sex-specific cardiorespiratory and metabolic disorders in rats similar to patients with SA.80 Sprague Dawley male and female rats (8 weeks old) were kept in: 1) standard housing (2/cage; controls) or in 2) social isolation (1/cage). At the end of the three-week protocol, apneas were quantified by whole-body plethysmography during sleep; respiratory variability was assessed by Poincaré plot analysis. Cardiovascular measurements were obtained by tail cuff, body composition by preclinical magnetic resonance, and plasma leptin and corticosterone levels by multiplex immunoassay. The amount of food was weighed before and after the experiments to calculate the intake.By comparison with controls, SI elevated corticosterone levels in male but not females. SI increased the apnea index in intact rat by 21% and augmented respiratory instability. SI also increased blood pressure (+11mmHg) and food intake (+11g/day); however, females had lower increases than males. In males, SI increases weight gains, fat mass, and decreases plasma leptin levels; these effects were not observed in females.SI promotes the emergence of apnea and respiratory instability during sleep. Since the cardiorespiratory and metabolic disturbances are similar to clinical features of SA patient, we propose that stress plays an important role in the etiology of SA. SI offers a novel and unique opportunity to study the origins and pathophysiology of SA. This research is supported by operating grants from the Canadian Institutes of Health Research (CIRH, RK and VJ). N.J.M. was supported by a Sentinel North Partnered Research Chair in Sleep Pharmacometabolism and a Fonds de Recherche du Quebec Sante (FRQS) Research Scholar J1 award. MG is the recipient of a doctoral scholarship from the FRQS. 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.
Senolytics do not prevent muscle loss in Sod1 knockout mice
Authors: Borowik Agnieszka , Lawrence Marcus , Piekarz Katarzyna , Miller Benjamin , Van Remmen Holly , Brown Jacob 
Published: May 2023

The accumulation of senescent cells is a hallmark of aging and age-related disease. Cellular senescence is a state of cell cycle arrest resulting, in part, from metabolic stress and reactive oxygen species (ROS) production. The importance of senescent cells in sarcopenia is underexplored with limited data for or against their contribution to the age-related loss of muscle mass and function. Oxidative stress is an imbalance between ROS production and neutralization. Mice with a knock-out of the endogenous antioxidant superoxide dismutase 1 (Sod1KO) have high levels of oxidative stress and a phenotype resembling accelerated frailty. Because of this association of oxidative stress and cellular senescence, we reasoned that Sod1KO mice would have a high senescence burden. Recently, the senolytic treatment of dasatinib and quercertin (DQ) in Sod1KO mice eliminated senescent cells and restored markers of liver health. Therefore, we hypothesized that reduction of senescent cells with DQ could prevent sarcopenia in Sod1KO mice. To test this hypothesis, we treated wildtype (WT) and Sod1KO mice with DQ or vehicle (Veh) from 6 months of age, the age at which the Sod1KO mice showed first signs of sarcopenia. Sod1KO mice had reduced muscle mass compared to WT mice, however, there was no effect of DQ treatment. In contrast, after 7 months of DQ treatment, the specific force generated by the extensor digitorum longus muscle in Sod1KO mice was greater than untreated by ~11% (Sod1KO-Veh 14.542 ± 0.550 N/cm2; Sod1KO-DQ 16.212 ± 1.464 N/cm2, p=0.013), although there were no differences between Veh and DQ in maximum force. There was a main effect of genotype in fragmentation of the neuromuscular junction in Sod1KO, regardless of DQ treatment (WT-Veh 0.87 ± 1.52% vs Sod1KO-Veh 77.10 ± 2.09&%, p <0.001; WT-DQ 0.0 ± 0.0% vs Sod1KO-DQ 70.5 ± 18.1%, p <0.001). We also observed a genotype effect in protein turnover analysis, as Sod1KO mice had higher mitochondrial and myofibrillar protein synthesis rates than WT mice, while there was no effect of DQ treatment. There was a trend for greater maximally stimulated complex I respiration in muscle mitochondria from Sod1KO-DQ mice compared to Sod1KO-Veh mice (97.32 ± 29.47 vs 61.78 ± 33.89 pmol/(s·mg), p=0.065, respectively). However, there were no effects of genotype or treatment in maximally stimulated complex I+II and complex II respiration, as well as hydroperoxide generation among groups. Our study suggests that DQ senolytic treatment does not prevent oxidative stress-induced sarcopenia in Sod1KO mice. P01AG051442, 1 IK6 BX005234, 1 IK2 BX005620-01A1 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.