bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant Human MG53 Mediated Protection against Injury to Neuronal Cells
Authors: Paleo Brian J , Madalena Kathryn , Mital Rohan , Bodnar Tom , Rose Aubrey , McElhanon Kevin , Lerch Jessica , Weisleder Noah 
Published: June 2021

Injuries to the nervous system can cause irreversible damage to mental and motor function. This has led to extensive interest in studying mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, increasing the emphasis on maintaining cell survival could provide more translational potential for treatment of neuronal diseases and injuries. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair in diseases affecting neurons. Much of the current understanding of the plasma membrane repair response comes from studies of these repair processes in striated muscle cells. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle‐enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle, cardiac muscle, liver, and alveolar epithelial cells. Interestingly, recombinant human MG53 (rhMG53) when applied exogenously can increase membrane repair and integrity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. While there have been previous studies of membrane repair mechanisms in skeletal muscles that are relevant to neurotrauma, there has been little investigation of membrane repair specifically in neurons. While the action of rhMG53 has been proven to be robust, lack of knowledge of membrane repair in the nervous system leads to questions of the potential efficacy of membrane repair in neurons. In this study we assess the therapeutic potential of rhMG53 in the treatment of various traumatic neuropathies. We find a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair in vitro and in vivo. These findings provide novel, direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for the treatment of neuronal injury.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Peroxynitrite induces depolarization and impairments of respiration in isolated murine brain mitochondria
Authors: Albuck Aaron L. , Sakamuri Siva S. V. P. , Sperling Jared A. , Sure Venkata N. , Zheng Sufen , Katakam Prasad V. G. 
Published: June 2021

ObjectivePeroxynitrite, generated from nitric oxide and superoxide, plays a pathological role in both ischemic and neurodegenerative brain injury. Mitochondrial dysfunction is a key initiator of cerebrovascular and neurological pathologies. Thus, understanding the acute effects of peroxynitrite on brain mitochondrial physiology will help identify potential therapeutic targets. The objective of the study was to investigate the impact of peroxynitrite on respiratory function and membrane potential of isolated murine brain mitochondria.MethodsMitochondria were isolated from the brains of 12‐week‐old C57bl6 (n= 5–6) mice and treated with various concentrations of peroxynitrite (0.1μM, 1μM and 5μM) for one hour in assay buffer containing 10mM pyruvate and 2mM malate. Mitochondria (10μg/well) were plated into cell plates and oxygen consumption rate (OCR) was measured using Seahorse XFe24 Analyzer after serial injection of ADP (5mM), oligomycin (5μM), FCCP (5μM) and antimycin (10μM)/rotenone (2μM). Respiratory parameters were reported as OCR (pmoles/minute). Mitochondrial membrane potential was measured using fluorescence probe rhodamine 123 dye. Western Blots were then performed to detect the nitrotyrosine residues in the mitochondrial proteins.ResultsAcute peroxynitrite treatment decreased basal, or state II respiration, by 55.5 % (46.7±4.7 vs 102.5±2.5, n=6, p=0.0004) in brain mitochondria. Similarly, 5μM peroxynitrite treatment of isolated mitochondria diminished the uncoupler‐induced, or state III respiration, by 58% (94.5±12.9 vs 225.9±45.3, n=6, p=0.03). In addition, 5μM peroxynitrite reduced the mitochondrial membrane potential by 65.6% compared to untreated mitochondria (34.4 ±13.2 vs. 100, n=6, p‐value < 0.05). Notably, isolated mitochondria treated with peroxynitrite displayed increased nitrotyrosine content confirming the nitrotyrosination of the mitochondrial proteins.ConclusionsAcute treatment with peroxynitrite depolarizes isolated mitochondria leading to impairment of mitochondrial respiration which in turn impairs the ability of mitochondria to provide energy at the basal level and in response to increasing demand. Thus, peroxynitrite exhibits direct effects on the mitochondrial respiration which has deleterious consequences for neuronal survival in ischemic and neurodegenerative brain injury.Support or Funding InformationUndergraduate Summer Research Fellowship by American Physiological Society (Albuck); and National Institute of Health: National Institute of General Medical Sciences and National Institute of Neurological Disorders and Stroke (Katakam: R01NS094834).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Primary Cilia of Supraoptic Nucleus Regulate Drinking and Blood pressure
Authors: Jiang Jingwei , Morgan Donald , Rahmouni Kamal 
Published: June 2021

Fluid intake is tightly related to blood pressure control through balance between electrolytes and water in the body. Virtually, every mammalian cell is equipped with a primary cilium, a cell surface protrusion that is thought to act as a sensory organelle. However, the contribution of primary neuronal cilia to cardiovascular regulation and fluid homeostasis has not been addressed. We hypothesized that primary neuronal cilia contribute to the control of fluid intake and blood pressure. For this, we first examined the length of primary neuronal cilia in the brain nuclei that contribute to osmolarity and cardiovascular regulation in 3‐week DOCA‐salt treated mice vs sham controls (n=5/group). Cilia length was examined by immunostaining a ciliary protein, adenylate cyclase 3 (AC3), followed by confocal 3D reconstruction, and quantification by IMARIS imaging analysis software. We found changes in cilia length in a number of brain nuclei of DOCA‐salt mice. The supraoptic nucleus (SON), a key brain nucleus in the regulation of osmolarity and fluid homeostasis, displayed the most significant changes in cilia length (average primary cilia: 7.46±□□□□□m in DOCA‐salt mice vs 6.76±□□□□□m in sham, p=0.0509). Moreover, the number of primary cilia that are over 10□□m was significantly increased in the SON of DOCA‐salt mice by 8% (p=0.0114). On the other hand, the number of cilia that are 4–5□□m in length was significantly decreased in the SON of DOCA‐salt mice (11.73±1.70%) compared to sham controls (18.73±2.02%, p=0.0385). Next, we assessed the relevance of SON cilia by targeting the ift88 gene which encodes a protein necessary for the formation of cilia. For this, we performed targeted stereotaxic injection of AAV‐Cre into the SON of IFT88flox/flox mice. We found that disruption of SON ift88 (AAV‐Cre group had a 38% ift88 expression level relative to AAV‐GFP control group) caused impairment in water intake in response to 24h water deprivation (30min water intake: 0.78±0.06 ml in AAV‐Cre vs 1.07±0.08 ml in AAV‐GFP, p=0.0129) without affecting total daily water and food consumption. Moreover, ift88 deletion in SON increased systolic blood pressure (133.7±1.71 mmHg vs 115.8±2.33 in AAV‐GFP, p=0.0008) without altering heart rate. Our data demonstrate the importance of primary cilia in the SON in the regulation of water intake and blood pressure. We speculate that primary neuronal cilia may function as part of environmental surveillance system in the brain that ensures cardiovascular homeostasis.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Pre‐autonomic corticotropin‐releasing hormone neurons in the paraventricular nucleus of the hypothalamus may contribute to chronic unpredictable stress‐induced blood pressure hyperreactivity
Authors: Wang Lei A , Cross Sissy , Mifflin Steve 
Published: June 2021

Exposure to chronic unpredictable stress (CUS) has been shown to augment the pressor response to novel stress. The neural circuits mediating the CUS induced blood pressure hyperreactivity are not fully understood. Exposure to CUS is known to increase the production of corticotropin‐releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN). A subpopulation of PVN CRH neurons project to the rostroventral medulla (RVLM), a key nucleus regulating sympathetic outflow and blood pressure. To study how CUS exposure affect RVLM‐projecting CRH neurons in the PVN, we injected retrograde AAV expressing Cre‐inducible mCherry into the RVLM of CRH‐Cre mice. We then exposed mice to the a CUS paradigm. The CUS paradigm included the following stressors: hot air stream (10 min), cold temperature (4°C, 1h), fox urine exposure (10 min), hypoxia (10% oxygen, 20 min), shaker (100 oscillations/min, 1h), forced swimming (10 min). These stressors were randomly assigned to the mice twice daily for 14 days. We found that mice exposed to the CUS had significantly increased number of RVLM‐projecting CRH neurons in the PVN compared to mice that were not exposed to the CUS (CON, 32 ± 4 vs CUS 81 ± 9; p = 0.003). To study whether RVLM‐projecting CRH neurons in the PVN regulates blood pressure, we expressed Channelrhodopsin 2 (ChR2) specifically into the PVN CRH neurons by injecting AAV expressing Cre‐inducible ChR2 into the PVN of CRH‐Cre mice. Optogenetic activation of CRH fibers in the RVLM significantly increased blood pressure (7 ± 1 mmHg). These results indicate that CUS can induce CRH production in a large population of PVN preautonomic neurons that do not produce CRH in basal condition. This population of plastic RVLM‐projecting CRH neurons in the PVN may contribute to CUS induced blood pressure hyperreactivity.Support or Funding InformationThis work was supported by American Heart Association Postdoctoral Fellowship 18POST34050013 and National Heart, Lung, and Blood Institute PO1 Grant HL‐088052.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Low doses of Intrarenal Bradykinin induce a Monophasic Sympathoinhibitory Response
Authors: Hindermann Martin , Ditting Tilmann , Rodionova Kristina , Loosen Sonja , Ott Christian , Schmieder Roland , Amann Kerstin , Veelken Roland 
Published: June 2021

IntroductionAs recently reported intrarenally administered bradykinin induced a biphasic renal sympathetic nerve response (RSNA) with increases and decreases of RSNA but not uniform sympathoexcitation as previously assumed. The high doses necessary to evoke this biphasic response to bradykinin did not suggest a major physiological role of this observation in renal salt and water handling. Hence, we wanted to test the hypothesis that significantly lower doses of intrarenal bradykinin as previously used will induce a merely monophasic renal sympathoinhibition.Material and MethodsGroups of anesthetized SD rats (n=6–12) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for one time intrarenal administration (IRA) of Bradykinin (BK 5 nM, 5 μl) or Capsaicin (CAP 1 nM, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10−3M, 15 μl) was givenResultsIRA Bradykinin and IRA CAP decreased RSNA from baseline 3.8±1.2 μV*sec to 1.3±0.7 μV*sec (5 μl, 5 nM BK, p<0.05) and 4.0±0.6 μV*sec to 1.6±0.4 μV*sec (10 μl, 1 nM CAP, p<0.01). After reaching the lowest point of RSNA activity at 95 min, both groups showed a slight re‐increase of RSNA within the following 55 min (from 1.3±0.7 μV*sec up to 2.4±1.3 μV*sec (BK) and from 1.6±0.4 μV*sec up to 1.9±0.4 μV*sec (CAP)). Suppressed RSNA in both groups could be unmasked by systemic (i.v.) administration of the NK1‐blocker (1.4±0.4 μV*sec to 5.0±1.9 μV*sec; p<0.05 (BK); 3.5±0.6 μV*sec to 9.7±1.7 μV*sec; p<0.01 (CAP)).ConclusionBradykinin is able to reduce renal sympathetic nerve activity in doses that are significantly lower than doses inducing a biphasic sympathoexcitatory/‐inhibitory response suggesting a physiological role of bradykinin in renal sympathetic nerve control and hence in neurogenic salt and water handling.Support or Funding InformationDFG, German Research Foundation Interdisciplinary Center for Clinical Research ‐ University of Erlangen, Erlangen, GermanyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Novel Sympathoexcitatory Pathway between The Deep Superior Colliculus and The Rostral Ventromedial Medulla
Authors: Lynch Erin , Turner Anita , Dempsey Bowen , Dampney Roger , Goodchild Ann , McMullan Simon 
Published: June 2021

IntroductionThe superior colliculus plays key roles in the immediate processing of threatening sensory stimuli and generates rapid behavioural responses that are critical for survival. We have previously found that disinhibition of the deep superior colliculus (dSC) unmasks coordinated respiratory, sympathetic and somatomotor outputs that are independent of processing in higher centres. We postulate that these effects are a result of direct innervation of autonomic and respiratory medullary neurons based on the results of neuroanatomical tracing studies that identified dSC synaptic contacts on spinally projecting neurons within the rostral ventromedial medulla (RVMM). In the present study we investigate the physiological significance of this relay and compare effects of dSC stimulation to activation of dSC‐RVMM terminals.MethodsWe used an AAV vector to express Channelrhodopsin2 (ChR2) in the dSC and chronically implanted a fibre optic cannula into the dSC. After transgene expression electrophysiology experiments were conducted under urethane anesthesia with rats instrumented to record blood pressure, diaphragmatic EMG and splanchnic sympathetic nerve activity (SNA). One subset of experiments then positioned the optrode in the RVMM to deliver light to the terminal projections from the dSC. For the other subset of experiments, extracellular recordings were made of spinally projecting RVMM neurons.ResultsdSC photoactivation evoked an increase in respiratory frequency (35±8.7%, P=<0.01, N=7) and heart rate (11±2.6 bpm, P=<0.01, N=7), and a modest change in blood pressure when compared to controls. Stimulus‐triggered averaging of SNA revealed short‐latency excitatory potentials in most cases. Photoactivation of ChR2‐expressing dSC‐RVMM terminals evoked similar effects on cardiorespiratory outputs as dSC stimulation, with an increase in respiratory frequency (14 ±9.2%, P<0.001, N=6) and blood pressure (13 ±2 mmHg P<0.01, N=7), as well as qualitatively similar sympathoexcitation. In preliminary experiments that recorded extracellular action potentials in bulbospinal RVMM neurons we recorded excitatory effects of dSC stimulation in 6/8 spontaneously active neurons.ConclusionWe conclude that optogenetic activation of dSC neurons that project to the RVMM can drive cardiorespiratory effects that are consistent with our previous findings and that dSC stimulation evokes excitatory effects in some RVMM bulbospinal neurons. This confirms our hypothesis of the existence of a previously uncharacterized excitatory pathway between the dSC and RVMM. Ongoing experiments will functionally characterize RVMM neurons that receive dSC input.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Breathing Exercises Modulate Heart Rate Variability in Individuals with Chronic Stroke
Authors: Larson Mia , Chantigian Dan , Van de Winckel Ann , Keller‐Ross Manda 
Published: June 2021

BackgroundAutonomic dysfunction is common after stroke and increases risk of mortality. Heart rate variability (HRV) is an index of autonomic function and is lower in individuals after a stroke compared with healthy adults. Slow, paced breathing at six breaths per minute has been shown to increase HRV and may be an important therapeutic strategy to improve autonomic function in people with stroke.ObjectiveTo determine the influence of a slow, paced breathing intervention on HRV after stroke.MethodsNine participants (3 women, 52 ± 13.2 years old) with chronic stroke attended two counterbalanced visits, where they completed a 15 min breathing exercise. The slow, paced, device‐guided breathing exercise (SB) consisted of 6 breaths/min and the device‐guided control breathing exercise (CB) was set at 12 breaths/min. A 3‐lead electrocardiogram (ADInstruments) was used to measure heart rate (HR) and calculate measures of HRV during a ten‐minute, spontaneous breathing rest period before and after the breathing exercise. HRV measures were calculated in the frequency domain and included total power (TP), high frequency percent of total power (HF%) and low frequency percent of total power (LF%).ResultsTP did not change pre to post SB (146±198.6%, p = 0.1), but did increase during CB (101.8±107.6%, p = 0.01). LF% increased more for SB compared with CB (15.1±13.98%, 6.8±7.03%, respectively, p = 0.04). HF% did not change after SB (−7.04±11.73%, p = 0.13) nor after CB (−3.23±7.61%, p = 0.26). Heart rate decreased after CB (4.03±4.31 beats/min, p = 0.03), but did not change after SB (−0.34±6.37 beats/min, p = 0.92).ConclusionUnexpectedly, the control breathing (12 breaths/min) resulted in a consistent, moderate increase in HRV and a decrease in heart rate. Although slow breathing (6 breaths/min) had a greater effect on HRV for some individuals, the response was much more variable, suggesting that some individuals with chronic stroke may have a difficult time maintaining the slow pace. Consequently, we found 12 breaths/min to be sufficient and more manageable for some individuals after stroke. Further, controlled device‐based breathing can increase HRV and may serve as a complimentary adjunct therapy to improve autonomic function in people after stroke.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cerebral Blood Flow Response to a Sympathoexcitatory Stimulus in Postmenopausal Women with a History of Preeclampsia
Authors: Miller Kathleen B , Miller Virginia M , Harvey Ronee E , Ranadive Sushant M , Joyner Michael J , Barnes Jill N 
Published: June 2021

A history of preeclampsia (PE) places women at higher risk for future cardiovascular disease and cognitive decline. We have previously shown that postmenopausal women with a history of PE demonstrated a reduced cerebral blood flow response to hypercapnia compared with postmenopausal women with a history of a normotensive pregnancy (NP). These findings suggest cerebrovascular effects of PE 30+ years postpartum. In addition, we have reported that women with a history of PE did not have an exaggerated pressor response to a sympathoexcitatory stimulus. However, it is possible that women with a history of PE may have an altered cerebral blood flow response to a sympathoexcitatory stimulus. In this study, middle cerebral artery blood velocity (MCAv) and beat‐to‐beat mean arterial blood pressure (MAP) were measured during isometric handgrip to fatigue (IHG) at 30% of maximal voluntary contraction followed by post‐exercise ischemia (PEI) for 90 seconds and a two minute recovery period (REC). Participants were postmenopausal women with a history of PE (n = 21; age at study = 58±5 y; years since last pregnancy = 35±3 y) and NP (n = 27; age at study = 58±5 y; years since last pregnancy = 35±3 y). Baseline MAP and MAP responses to IHG and PEI were similar between groups (p>0.05). PE women demonstrated lower MCAv at baseline (NP: 72±3 cm/s vs. PE: 57±4 cm/s), IHG (NP: 78±4 cm/s vs. PE: 63±4 cm/s), PEI (NP: 74±4 cm/s vs. PE: 60±4 cm/s), and REC (NP: 70±3 cm/s vs. PE: 58±4 cm/s) compared with NP women (p<0.05 for all). MCAv, when calculated as a percent change from baseline, was elevated during IHG in both PE and NP women as expected (p<0.05); however, PE women had an augmented MCAv response during the last third of IHG compared with NP women (NP: 9±2 % vs. PE: 13±2 %; p<0.05). PE women also had a higher MCAv response during REC compared with NP women (NP:−2±2% vs. PE: 3±2%; p<0.05). Importantly, these elevated MCAv responses occurred despite the fact that MAP was not different between groups. In summary, PE women demonstrated a lower basal cerebral blood velocity but an elevated cerebrovascular response to a sympathoexcitatory stimulus compared with NP women. This suggests that in postmenopausal women, there is an effect of pregnancy history on the sensitivity of the cerebral blood flow response to a sympathoexcitatory stimulus.Support or Funding InformationNIH: AG 044170. This investigation was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin‐Madison Cardiovascular Research Center.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.