bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Intermittent Hypoxia Facilitates Action Potential Firing in PVN-projecting MnPO Neurons
Authors: Jia Shuping , Farmer George , Little Joel , Paundralingga Obed , Cunningham Joseph 
Published: May 2023

Our previous results indicate that Chronic intermittent hypoxia (CIH) enhances glutamatergic neurotransmitter release in PVN-projecting MnPO neurons. Very little information exists regarding how CIH affects the excitability of PVN-projecting MnPO neurons. MnPO neurons exhibit a wide diversity of spontaneous and evoked firing patterns. Initial studies indicate CIH modulates resting membrane properties and AP firing patterns which may be associated with alterations in hyperpolarization-activated cyclic nucleotide-gated currents (Ih). The Ih current is an inward current activated by hyperpolarization from the resting potential and is an important modulator of action potential firing frequency. Data were collected in PVN-projecting MnPO neurons which play an important role in CIH-induced hypertension. Adult male Sprague Dawley rats (250-350g) received bilateral PVN injections of 200 nL retrograde adeno-associated virus pAAV-CAG-tdTomato. Three weeks following injections, rats were either exposed to a 7-day intermittent hypoxia protocol consisting of 6 min cycles (3 min 21% O2, 3 min 10% O2) repeated 10x/hr for 8 hours (during the normal inactive/sleep phase) or room air (Norm). Following CIH/Norm treatment, rats were deeply anesthetized and sagittal brain slices of MnPO were prepared using standard slice procedures. Spontaneous activity and responses to current injections were recorded from PVN projecting MnPO neurons using whole cell current-clamp. Data was analyzed off-line using Clampfit. There was a trend for spontaneous activity to be higher in PVN-projecting MnPO neurons from rats exposed to 7 days CIH when compared to normoxic controls (Norm: 2.29 ± 0.51 vs CIH: 3.3 ± 0.84) that was not due to a change in resting membrane potential. The threshold to evoke AP potentials was significantly lower in CIH neurons (5 pA injecting current, 17/19 CIH neurons vs 9/13 Norm neurons, CIH 8.6 ± 0.79 mv vs Norm 13.06±1.53 mv, p<0.01; 10 pA injecting current, 19 CIH neurons vs 12/13 Norm neurons CIH 14.74±0.92 mv vs Norm 19.72 ±1.64 mv, p<0.01). However, evoked action potentials were less sensitive to increasing current injection amplitudes in CIH vs Norm treated rats. Following bath application of the specific Ih blocker ZD7288 (ZD, 30 μm) spontaneous action potential activity was reduced by 24% in Norm neurons and 47% in CIH neurons (p=0.0313). These data demonstrate that CIH facilitates action potential generation in PVN projecting MnPO neurons and changes in Ih currents may contribute to this increase in excitability. R01 HL155977 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 HIF-prolyl hydroxylases have distinct and non-redundant biological roles in the pathogenesis of colitis-associated cancer
Authors: Harnoss Jonathan , Kennel Kilian , Burmeister Julius , Radhakrishnan Praveen , Giese Nathalia , Giese Thomas , Salfenmoser Martin , Gebhardt Jasper , Strowitzki Moritz , Taylor Cormac , Wielockx Ben , Schneider Martin 
Published: May 2023

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaption to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared to WT mice. In Phd3 -/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages (TAMs) in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin ( Ereg) in macrophages, and (iii) augmented signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic ( Vav:Cre-Phd2f/f) but not in intestinal epithelial cells ( Villin:Cre-Phd2f/f) increased CAC growth. In conclusion, the three different PHD isoenzymes have distinct and non-redundant, either promoting (PHD1), diminishing (PHD2), or neutral effects (PHD3) on CAC growth. KBK received funding from the German Cancer Aid. MJS. received funding from the German Research Foundation (DFG; STR 1570/1-1) and the Braun Foundation (Braun®; BBST-D-18-00018). MSch received funding from the German Federal Ministry of Education and Research (BMBF; 031L0084). JMH received funding from the Heidelberg Stiftung Chirurgie. 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.
Impact of heart failure with preserved ejection fraction on large conducting airways in humans
Authors: Johnston Jessica , Borlaug Barry , Johnson Bruce , Smith Joshua 
Published: May 2023

Background: Heart failure patients with preserved ejection fraction (HFpEF) exhibit exercise intolerance and exertional dyspnea. The underlying pathophysiology is complex and involves multiple physiological systems. To this point, HFpEF patients exhibit pulmonary abnormalities at rest and during exercise. For example, HFpEF patients have higher work of breathing during exercise due to greater inspiratory and expiratory resistive work of breathing. Importantly, this greater resistive work of breathing is not associated with higher inspiratory and expiratory flow rates suggesting pulmonary resistance is elevated in HFpEF patients. One potential explanation for the increase in resistive work of breathing during exercise in HFpEF patients is smaller luminal area of the airways. Purpose: The purpose of this study was to determine if differences exist in the luminal area of the large conducting airways in HFpEF patients compared to controls. We hypothesized that HFpEF patients will exhibit smaller luminal areas of the large conducting airways compared to controls. Methods: HFpEF patients (n=9; 67±7 yrs; 30±3 kg/m2) and controls (n=8; 62±9 yrs; 24±3 kg/m2) were enrolled. All participants performed pulmonary function testing and a thoracic computerized tomographic (CT) scan (assessed at total lung capacity). The airway luminal area was quantified from three-dimensional reconstructions from the high-resolution CT scans. The luminal areas of the large conducting airways were measured at three discreet points (corresponding to the beginning, middle, and end of the airway), averaged, and indexed to height. Results: The luminal area of the trachea was not different between groups (p=0.95). HFpEF patients had smaller luminal area of the right main bronchus (control: 1.38±0.21 vs. HFpEF: 1.18±0.13 mm2/cm) and left main bronchus (control: 0.98±0.20 vs. HFpEF: 0.79±0.15 mm2/cm) (both, p<0.04) than controls. HFpEF patients also had smaller luminal area of the bronchus intermedius (control: 0.82±0.14 vs. HFpEF: 0.67±0.15 mm2/cm) and left lower lobe bronchus (control: 0.48±0.13 vs. HFpEF: 0.36±0.07 mm2/cm) compared to controls (both, p<0.04). No differences were present between groups in the right and left upper lobe bronchi (both, p>0.40). Conclusion: HFpEF patients have smaller luminal areas of some, but not all large conducting airways compared to controls. These findings provide support for smaller large conducting airways in HFpEF contributing to the pulmonary abnormalities during exercise in these patients. 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.
Compartment-specific calcium dynamics and their role in somatodendritic exocytosis and autoregulation of vasopressin neurons
Authors: Kirchner Matthew , Althammer Ferdinand , Shook Erin , Montanez Juliana , Stern Javier 
Published: May 2023

Vasopressin (VP) neurons exhibit somatodendritic release (SDR) of their neuropeptide cargo, in addition to axonal release. The phasic firing of these neurons dictates the volume and pattern of this exocytosis. This phasic patterning and SDR are dependent on intracellular changes in Ca2+ (Δ[Ca2+]i). When SDR occurs, VP acts in an autocrine manner to inhibit VP firing activity via activation of V1aR-mediated increases in [Ca2+]i. Because SDR and subsequent autoinhibition are dictated by Δ[Ca2+]i, we investigated whether this Ca2+-dependent inhibition involved afterhyperpolarizations (AHPs) and how compartment-specific Ca2+ dynamics affected neuronal properties. Using a combination of patch clamp electrophysiology, simultaneous Ca2+ imaging, and targeted photolytic uncaging, we investigated the properties of Ca2+ spread in soma and dendrites of VP magnocellular neurons of supraoptic nucleus (SON). We found that whereas Ca2+ uncaging in soma efficiently invades dendrites, dendritic Ca2+ uncaging fails to propagate into the soma, supporting unidirectional Ca2+ movement between cellular compartments. Moreover, we found that Ca2+ uncaging in the soma but not dendrites evoked AHPs, indicating compartmental localization of AHP mechanisms and/or channels. Blockade of mitochondrial Ca2+ reuptake (Ru360 in the pipette) prolongs Δ[Ca2+]i elevations and AHPs triggered by Ca2+ uncaging, indicating that mitochondria in VP neurons plays an important role in shaping Ca2+ dynamics and AHP properties in these neurons. Consistent with previous reports, we found that bath application of VP (1 μM) inhibits VP neuronal activity. Moreover, we found that VP enhances the apamin-insensitive slow AHP by prolonging its duration but not its amplitude, whereas a V1aR antagonist SR49059 (1 μM) per se inhibits slow AHPs in these neurons. These results expose vital aspects of the mechanisms that dictate phasic firing, SDR, and the autoinhibitory nature of VP in SON. NHLBI F32HL158172 (MKK), NHLBI HL090948 (JES), NINDS NS094640 (JES) 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 life stress in mice leads to impaired colonic corticosterone production and prolonged inflammation following induction of colitis
Authors: Muir Rachel , Klocke Barbara , Jennings Melissa , Molina Patrick , Hsu Jung-Shan , Kellum Cailin , Alexander Katie , Lee Goo , Foote Jeremy , Lorenz Robin , Pollock Jennifer , Maynard Craig 
Published: May 2023

Early life stress (ELS) is an environmental trigger linked to increased risk of inflammatory bowel disease (IBD). Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to, and/or severity of, intestinal inflammation. We hypothesized that ELS alters the delicate balance of typical homeostatic mediators in the intestinal microenvironment, predisposing ELS-exposed individuals to IBD onset or worsened disease upon a pro-inflammatory triggering event within the gut. We utilized 2 published animal models of ELS. In the first model, newborn mice were separated from the dam daily for 4-8 hours beginning on postnatal day 2, then weaned early on postnatal day 17. Normally reared (NR) control mice were left undisturbed with the dams until standard weaning on postnatal day 21. In the second model, dams were fed the synthetic glucocorticoid – dexamethasone, or vehicle ad libitum in drinking water (3 μg/mL) on post-partum days 1-14. Colitis was induced in 4-week-old mice via intraperitoneal injection of IL-10 receptor blocking antibody (100 μg) every 5 days for 15 days. Five or 15 days later, histological colitis scores and colonic transcripts for Tnf, glucocorticoid receptors, and steroidogenic enzymes were measured. ELS-exposed mice displayed altered mucosa-associated immune cell balances, with an initial deficit in anti-inflammatory IL-10-producing CD4 T cells at 4-wks of age (n≥11, p<0.05), followed by an increase in IFNγ-producing CD4 T cells at 8-wks of age (n≥7, p<0.05). ELS-exposed mice also displayed reduced levels of the glucocorticoid, corticosterone in the plasma (n≥10, p<0.01) as well as locally within the colon (n≥7, p<0.05). Upon colitis induction, NR control animals showed improvements in indices of inflammation following cessation of IL-10 receptor blockade, whereas ELS-exposed animals maintained high levels of intestinal Tnf (n≥7, p<0.01) and histological signs of colitis (n≥7, p<0.05). In colitic animals, prior exposure to ELS was associated with significantly lower expression of genes associated with corticosterone synthesis ( Cyp11a1; n≥5, p<0.05) and responsiveness ( Nr3c1, Nr5a2; n≥5, p<0.01). Finally, ex-vivo TNF stimulation of colonic crypt cells from ELS mice led to increased inhibition of corticosterone synthesis, relative to NR control mice (n≥4, p<0.05). Our study identifies impaired local colonic glucocorticoid production and responsiveness as a potential mechanism whereby ELS predisposes to chronic colitis in susceptible hosts. Crohn's and Colitis Foundation Research Initiatives Award 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.
T cell pro-inflammatory cytokine production in young adults with major depressive disorder
Authors: Joseph Blessy , Darling Ashley , Sharma Sunita , Grotle Ann-Katrin , Saunders Erika , Greaney Jody , Trott Daniel 
Published: May 2023

Background: Major Depressive Disorder (MDD) is increasingly prevalent in young adults and is a significant contributor to disease burden worldwide. Previously we have shown that young adults with MDD produce greater T cell mitochondrial ROS compared to their heathy non-depressed counterparts. Because evidence from rodent models of stress-related mood disorders demonstrates that increased T cell mitoROS drives excessive proinflammatory cytokine production, we next sought to determine if either CD4+ (Helper) or CD8+ (cytotoxic) T cells likewise produce increased proinflammatory cytokines in young adults with MDD. We hypothesized that there will be elevated proinflammatory cytokine production in young adults with MDD compared to their healthy non-depressed counterparts. Methods: Peripheral blood mononuclear cells were isolated by density centrifugation from 5 young adults with MDD having mild to moderate symptom severity and 9 non-depressed young healthy adults. Interleukin 2 (IL-2), Interleukin 6 (IL-6), Interferon Gamma (IFN-γ), and Tumor Necrosis Factor alpha (TNF-) production were assessed by flow cytometry. All data are expressed as mean SE and group differences were assessed by unpaired T test. Results: We found that adults with MDD exhibited a greater proportion of CD8+ Interleukin 6 (IL-6) (n= 8; 5 HA, 3 MDD) (HA = 22 3.5%, MDD = 255.6%; P= 0.004) producing cells compared to healthy. There were no significant differences in the proportions of CD8+ cells producing IFN-γ (HA = 14 1.2%, MDD = 3.1%; P= 0.31), IL-2 (HA =76 3.9%, MDD = 69 6.6%; P= 0.17), and TNF- (HA = 21 2.3%, MDD = 23.5%; P= 0.11) in those with MDD compared to controls. Additionally, there were no differences in CD4+ production of these same cytokines. We also assessed phenotype of the T cells using CD27 (central vs effector) and CD45 RA (Naïve vs TEMRA). Interestingly, a greater proportion of TNF- producing CD8+ and CD4+ cells exhibited an effector memory phenotype in adults with MDD compared to controls (CD8: HA = 25.8 2.4%, MDD = 46.8 3.3%; P= 0.0001; CD4+: HA=31 2.9%, MDD = 394.3%; P= 0.05). These data provide insight into the T cell subtypes that may be driving the inflammation associated with MDD. Conclusion: These preliminary findings suggest that young adults with MDD may exhibit a proinflammatory T cell phenotype characterized by greater IL-6 and TNF- production. NIH R21 MH123928 and R00133414 (JLG), NIH K01AG061271 and R01AG060395 (DWT). 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 renal ischemia-reperfusion injury following deletion of Netrin-1 in the kidney
Authors: McLarnon Sarah , Honeycutt Samuel , O'Brien Lori 
Published: May 2023

Netrin-1, an angiogenic guidance cue, is heavily expressed in the kidney. Our lab has previously reported that deletion of Netrin-1 in Foxd1-positive stromal progenitors ( Foxd1GC/+Netrin1fl/fl ) results in abnormal vascular patterning during kidney development, including a reduction in interlobar branching. It remains unknown how these changes in vascular patterning affect kidney function and physiology. In the current study, we hypothesized that changes in developmental patterning of the kidney vasculature would protect from renal ischemia-reperfusion injury in a sex-specific manner due to ischemic preconditioning to the kidney tubular cells. To test this hypothesis, we performed warm, bilateral ischemia-reperfusion by clamping the renal pedicles for 26-minutes in wild-type ( Netrin1fl/fl or Netrin1fl/+ )(3M, 3F), heterozygous ( Foxd1GC/+Netrin1fl/+ ) (2M, 4F), and mutant ( Foxd1GC/+Netrin1fl/fl ) (3M, 1F) male (M) and female (F) mice. Following 24-hours of reperfusion, blood and kidneys were collected for analysis of kidney injury markers. We found that plasma creatinine (p2-wayANOVA=0.021) and blood urea nitrogen (p2-wayANOVA=0.009) were decreased in female mice compared to male mice regardless of genotype. In both male and female mutant mice, there was a decrease in these markers of injury compared to heterozygous and wild-type control mice, although this did not reach statistical significance. In agreement, immunofluorescent staining of kidney injury marker 1 (KIM-1) indicated less tubular injury in female mice compared to males. These data suggest that female mice are less susceptible to ischemic injury than male mice despite both sexes having similar alterations in vascular patterning following deletion of Netrin-1. Further, our results indicate a protective effect of these developmental patterning changes due to Netrin-1 deletion. We suspect that changes in the vasculature in our mutant mice provide a preconditioning-like environment to mediate this effect. Future studies will investigate the underlying mechanisms which drive this injury phenotype between sexes. Understanding how renal vascular development impacts kidney injury is critical to the development of new therapeutic strategies to prevent the sustained injury following periods of ischemia. NIH R01DK121014 to LO 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 endoplasmic reticulum acetyl-CoA transporter AT-1 plays a role in the protective unfolded protein response in the exocrine pancreas
Authors: Cooley Michelle , Thomas Diana , Deans-Fielder Kali , Peng Yajing , Lugea Aurelia , Waldron Richard , Pandol Stephen , Puglielli Luigi , Groblewski Guy 
Published: May 2023

Pancreatic acinar cells are responsible for the synthesis and secretion of digestive enzymes. In order to sustain high rates of secretory protein production, acinar cells rely on adaptive mechanisms to mitigate endoplasmic reticulum (ER) stress and maintain secretory homeostasis. The adaptive unfolded protein response (UPR), mediated by the IRE1-XBP1s axis, is essential for acinar function and protects against cellular injury. Recent work has demonstrated that the ER acetyl-CoA transporter, AT-1, is necessary for nascent secretory protein acetylation and export out of the ER and is regulated by IRE1-XBP1s. Furthermore, AT-1 is rapidly downregulated during experimental pancreatitis. To investigate the role of AT-1 in exocrine pancreas function, we generated inducible, acinar-specific AT-1 knockout mice (Ela-Cre AT-1-/-). Loss of AT-1 produced a chronic pancreatitis phenotype characterized by inflammation, immune cell infiltration, tissue fibrosis, and aberrant intracellular activation of the proteolytic digestive enzyme trypsin. Despite the histological and biochemical dysfunction observed, Ela-Cre AT-1-/- mice grow normally, have typical lifespans, and do not lose pancreatic mass. Interestingly, XBP1s expression is significantly upregulated in Ela-Cre AT-1-/- and may confer a protective effect with loss of AT-1. Our data suggests a role for AT-1 in the IRE1-XBP1s axis and highlights the previously undescribed role of protein acetylation in exocrine pancreas physiology. Given the numerous potential downstream effects of dysregulated acetyl-CoA transport, this model will advance our understanding of pancreatic function and disease. NIH 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.