bluuebunny/crossref_metadata_2025 huggingface dataset:
Heart Failure with Reduced Ejection Fraction Causes Limb Muscle Atrophy in Males, but Not Female Rats
Authors: Noriega Andrea M. , Kelley Rachel C. , Goldberg Emma , Ferreira Leonardo F.
Published: June 2021

Fatigue and muscle weakness are common symptoms in chronic heart failure that significantly compromise patients' quality of life. Skeletal muscle abnormality is an important contributor to these symptoms, independent of cardiac function. Heart failure with reduced ejection fraction (HFrEF) causes histological changes in limb muscles, including changes in muscle fiber type distribution and fiber atrophy. Metabolic alterations often accompany these changes, and several reports show shifts from oxidative to glycolytic fiber phenotype. There are conflicting reports on HFrEF‐related abnormalities in limb muscle. There are approximately 3–4 million patients with HFrEF in the United States, and while the disease is more prevalent in males, it affects a large number of females. Animal studies have largely focused on effects of HFrEF in males whereas studies in humans have included mostly males with mild or moderate HFrEF. We conducted the current study to determine whether the effects of HFrEF on limb muscle abnormalities are dependent on sex and disease severity. We performed myocardial infarction to induce HFrEF or Sham surgery in 8–9 week old male and female Sprague Dawley rats. Animals that underwent MI surgery were grouped into either moderate or severe HFrEF; severe HFrEF was determined by 1) transmural infarct ≥35% of left ventricle and septal area and 2) right ventricle hypertrophy. We have used SMASH code (MatLab) to analyze fiber type distribution and cross‐sectional area (CSA) in cryogenic sections of tibialis anterior of males and females Sham, moderate, and severe HFrEF rats (n=3–4 per group). Compared to Sham, type IIb/x CSA decreased in males with moderate (28% ± 11%) and severe HFrEF (39% ± 5%) (P < 0.05). Female rats with moderate and severe HFrEF had fiber CSA similar to Sham. Fiber type distribution did not change for either males or females animals with CHF compared to Sham. Overall, our initial data show that HFrEF causes muscle atrophy in males independently of disease severity, but not in females. However, we cannot exclude the possibility that limb muscle atrophy occurs in post‐menopausal females with HFrEF.

Support or Funding Information

R01‐HL130318 to LFF

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evolutionarily Conserved Notch‐Dependent and Independent Mechanisms Regulating Hypoxia Tolerance
Authors: Zhou Dan , Xue Jin , Hsiao Yu‐hsin , Stobdan Tsering , Haddad Gabriel G.
Published: June 2021

Hypoxia tolerance is an important trait for human populations living at high altitude. It is also clinically important for patients suffering from illnesses in which hypoxia represents a critical element in the pathogenesis, such as ischemic stroke, myocardial infarction and solid tumors. Our previous studies and those of others have shown that the mechanisms underlying hypoxia tolerance are polygenic and evolutionarily conserved. Indeed, we and others have found that Notch signaling regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanistic details underlying Notch‐conferred hypoxia tolerance are largely unknown. By comparing candidate genes identified through whole genome sequencing analysis of hypoxia‐adapted fruit flies and those from genome‐wide single nucleotide polymorphism data from four high‐altitude human populations (i.e., Sherpas, Tibetans, Ethiopians and Andeans), we have identified several, evolutionary conserved genes involved in hypoxia tolerance. In the current study, we developed a novel dual‐USA/Gal4 system to determine genetic interactions between Notch signaling and these conserved genes in terms of hypoxia tolerance. This unique system allows us to activate Notch signaling in the Eaat1 positive cells, which dramatically enhances hypoxia tolerance in flies, and, simultaneously, knockdown a candidate gene in the same glial cells. Using this system, we discovered that Notch‐conferred hypoxia tolerance requires HES1/hairy, FOXC1/croc and ZNF521/Oaz. In contrast, KCND2/Shal and EGFR/Egfr regulate hypoxia tolerance in a Notch‐independent manner. Furthermore, Notch activation can partially rescue lethality under hypoxic condition with FGF/bnl down regulation. In summary, we identified evolutionarily conserved, Notch‐dependent and independent mechanisms regulating hypoxia tolerance. These mechanisms have strong potential to be translated into humans and serve as novel targets for developing therapeutic strategies to treat hypoxia‐related diseases.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hormonal Drive of Cardiomyocyte Proliferative and Regenerative Potential Loss During the Acquisition of Endothermy
Authors: Huang Guo N.
Published: June 2021

Across phylogeny and ontogeny, pronounced differences are evident in the ability of organisms to regenerate damaged tissues and organs. However, the underlying mechanisms driving this phenomenon remain enigmatic. Mammalian hearts lose regenerative potential due to cardiomyocyte cell‐cycle withdrawal and polyploidization coinciding with the development of postnatal endothermy. Our phylogenetic analysis of cardiomyocyte ploidy in 41 vertebrate species including those from the clades of the smallest and largest mammals reveals that diploid cardiomyocyte abundance inversely correlates with standard metabolic rate and body temperature, suggesting that cardiac regenerative potential declines during the evolution of endothermy. In a targeted chemical screen we identify thyroid hormones, major metabolic regulators hypothesized to drive the ectotherm‐to‐endotherm transition, as potent triggers of mammalian cardiomyocyte cell‐cycle arrest in vivo. Further pharmacological and genetic manipulations in mice and zebrafish show thyroid hormones inhibit cardiomyocyte proliferation and heart regeneration. Collectively, our data supports a model where species‐specific regulation of thyroid hormone levels determines cardiomyocyte proliferative and regenerative capacity, suggesting that during the acquisition of endothermy in ontogeny and phylogeny, increases of thyroid hormones drive loss of cardiomyocyte regenerative capacity.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glucocorticoid‐Receptor Mediated Signaling Regulates Lipolysis in Northern Elephant Seal Pups
Authors: Juarez Pablo , Vasquez‐Medina Jose Pablo , Lee Debby , Croker Daniel E. , Ortiz Rudy
Published: June 2021

Northern elephant seals (NES) experience prolonged 2–3 month fasting periods, relying primarily on the oxidation of fatty acids to meet their energetic needs (RQ=0.71). Although fasting periods are characterized by an increase in circulating cortisol (F) and non‐esterified fatty acids (NEFA's), the functional relevance such increase in cortisol in NES is not defined. We hypothesized that F lipolysis is regulated through glucocorticoid receptor signaling (GR) in NES. The contributions of F and the GR were assessed by exogenous infusions of ACTH and/or concurrent blockade of the GR in the following groups: (1) untreated control, (2) ACTH (80 units intramuscular injection (IM)) and (3) ACTH + GR blocker (RU486) (80 units IM + 400mg RU486 in time release pellets). Plasma, and adipose and muscle biopsies were collected at days 0 (T0; immediately prior to infusion) and 6 (T6). Mean plasma NEFA levels increased 38% (0.84 ± 0.13 vs 1.16 ± 0.06mM) from T0 to T6 with ACTH infusion suggesting glucocorticoids contribute to increased lipolysis. ACTH infusion increased mean adipose HSP90 expression by 92%±18.2 while decreasing mean muscle HSP90 expression by 39%±14.5 from T0 to T6 suggesting that HSP90 may participate in GR‐mediated lipolysis in adipose while contributing to conserving lipid sources in muscle. Mean muscle CD36 expression decreased 46%±12.2 from T0 to T6 with ACTH infusion suggesting that there is a reduced intake of NEFA's by skeletal muscle, contributing to increased circulating NEFAs during lipolysis. These data suggest that the fasting‐associated increase in GR signaling is imperative for sustaining elevated levels of lipolysis during the post weaning fast, and is dependent upon the functional role of cortisol and HSP90.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leucine Supplementation in Mice during Pregnancy Does not Affect Birthweight or Offspring Growth prior to Weaning
Authors: McGuckin Molly Mae , Bartak Sarah Ann , Marini Juan , Peterson Daniel G. , Manjarin Rodrigo
Published: June 2021

Advances in nutritional care of low‐birth weight infants have significantly improved the outcome of premature infants; nonetheless, low‐birth weight still represents the main cause of newborn deaths in the U.S. Based on studies in cells and rodents demonstrating anabolic effects of branched‐chain amino acids, there is potential for use of supplementary leucine to improve muscle growth in children and adults. However, the effect of supplemental leucine during fetal development remains unknown. We tested the hypothesis that leucine supplementation during pregnancy would increase pup weight at birth and subsequent growth prior to weaning. Twenty‐five female CD‐1 strain mice were fed ad libitum 1 of 3 diets containing 5.5, 11 and 22 g/kg leucine throughout gestation. Alanine and sucrose were added to make the three diets is nitrogenous and isoenergetic. Diets were formulated to otherwise meet nutrient requirements during gestation. Feed intake was measured daily throughout pregnancy for 21 d. After parturition, litters were normalized to 8 pups, and average pup weight was collected every other day for 21 d until weaning. Statistical analysis was performed using linear mixed models which included treatment, time and their interaction as fixed effects, mouse nested within treatment as repeated measures, replicate as a random effect, and initial body weight, feed intake, and litter size as covariates. There was no significant effect of leucine on average birth weight (1.24 ± 0.05, 1.24 ± 0.06, 1.22 ± 0.05 for 5.5, 11 and 22 g/kg leucine, respectively; P = 0.36) or pup growth over 21 d of lactation (0.54 ± 0.06, 0.54 ± 0.05, 0.53 ± 0.04 g/d; P = 0.96). Number of pups born alive was positively correlated with total amount of feed consumed over 21 d gestation (R=0.64 and P=0.0003). Our results indicate that supplemental leucine during gestation does not improve birth weight or offspring growth in mice. However, these results do not preclude the effects of leucine on muscle fiber dynamics, fetal programming or the regulation of metabolic pathways related to muscle development, which may warrant further investigation.

Support or Funding Information

ARI#58982 and Cal Poly Summer Undergraduate Research Program

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Parallel genomic analysis: Hi‐C analysis pipeline for open‐source Torque resource manager
Authors: Stodola Timothy , Liang Mingyu , Greene Andrew
Published: June 2021

Genomic sequencing has become more available as technology has advanced and costs have decreased, making efficient data analysis crucial for keeping up with the rate of data generation. This is particularly true when generating 3D maps of chromatin structure using Hi‐C datasets, which can generate terabytes of data per experiment. One of the best ways to do this is with parallel computing, distributing a single job across multiple cores in single server or a large cluster of networked computers. We have adapted the Hi‐C software, Juicer, designed by Durand et al to run on a computing cluster managed by the open‐source Torque Resource Manager software. Juicer is a pipeline that converts fastq reads to Hi‐C maps and operates using only a single command line input making it amenable to a parallel computing environment. Using this implementation does not require the user to purchase server time or license distributed computing software. Through parallel computing it is possible to optimize the efficiently of determining alignment, sorting, duplicate identification, and data analysis necessary for Hi‐C. The software works as a pipeline, but is modular and can be used parallelize more conventional alignment jobs, and easily optimized as an individual user requires.

Support or Funding Information

NIH HL121233, Advancing a Healthier Wisconsin Endowment

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The role of c‐Kit/sGC signaling axis in vascular reactivity and hypertension
Authors: Hernandez Diana Rosa , Song Lei , Zigmond Zachary M. , Wei Yuntao , Martinez Laisel , Lassance‐Soares Roberta M. , Vazquez‐Padron Roberto I.
Published: June 2021

A. Introduction

The receptor tyrosine kinase c‐Kit has been recently found to have a role in vasculoprotection. Genetic deletion of c‐Kit in smooth muscle cells increases aortic plaque accumulation and atherosclerosis burden in conditional hyperlipidemic mice. The present study tests whether a c‐Kit deficiency in mutant mice (KitW/Wv) leads to hypertension and impaired vascular relaxation.

B. Methods

Female and male c‐Kit mutant (KitW/Wv) and littermate (Kit+/+) control mice were commercially available (Jackson lab). Blood pressure was determined in conscious mice using the tail‐cuff method. The first‐order branch of mesenteric artery was mounted into a pressure myograph (DMT, Aarhus, Denmark) to assess endothelium‐dependent and ‐independent vasoreactivity under isobaric conditions. A search for differentially expressed genes between c‐Kit mutant and control SMC was performed using the Mouse MI‐Ready microarray (Ocean Ridge Biosciences).

C. Results

The deficiency of c‐Kit causes hypertension in mutant mice with respect to their control littermates (mean arterial pressure: 137.5 ± 5.0 vs. 113.06 ± 0.0, p=0.007). Acetylcholine (ACh) induced a concentration‐dependent relaxation of norepinephrine pre‐contracted vessels in both mutant and littermate mice. The Cox inhibitor indomethacin compromised ACh‐induced vasorelaxation only in c‐Kit deficient vessels but not in those from control mice, which highlighted the importance of endothelium‐derived prostaglandins for vasorelaxation in the absence of c‐Kit. Conversely, arteries of mutant mice were poor responders to a NO agonist (SNP). The secondary messenger, cyclic guanosine monophosphate, vasodilated both types of vessels in a similar manner, which indicated that defective NO activity in mutants was due to deficiencies in soluble guanylyl cyclase (sGC) or NO synthesis. A significant downregulation of smooth muscle sGC beta 1 subunit was further found in c‐Kit mutant cells using transcriptomics analysis.

D. Conclusion

These results suggest the existence of a novel c‐Kit/sGC signaling axis in SMC that may be relevant for the control of vascular reactivity and hypertension.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Transient ACE‐Inhibitor Treatment Produces Persistent Change in Cardiac Fibroblast Physiology
Authors: Perez Octavio , Garvin Alexandra , Hale Taben
Published: June 2021

Heart failure is a debilitating illness that is characterized by excessive extracellular matrix (ECM) accumulation. Cardiac fibroblasts maintain homeostasis of collagen production and degradation ‐ a tightly regulated process that is critical for normal heart function. Pathological cardiac fibrosis results from uncontrolled proliferation of fibroblasts and excessive production of ECM proteins including collagens – which may be mediated by reactive oxygen species. The pro‐fibrotic effects are mediated by a differentiated and activated fibroblast phenotype termed a myofibroblast. We have previously shown that angiotensin converting enzyme (ACE) inhibitors induce apoptosis of 30% of cardiac fibroblasts in adult spontaneously hypertensive rats (SHR). In addition, a 10% (p<0.05) reduction in left ventricular mass, compared to untreated control and was accompanied by a 12% (p<0.05) reduction in left ventricular DNA content. Moreover, transient ACE inhibition induces persistent changes that protect against future fibrosis and macrophage infiltration in response to injury. Based on these findings, we hypothesize that cardiac fibroblasts isolated from SHR previously treated with an ACE inhibitor will display a less fibrogenic phenotype than those isolated from control SHR. Adult male SHR were treated for 2 weeks with the ACE inhibitor enalapril (30mg/kg per day, p.o.) or water followed by a 2‐week washout period. Cardiac fibroblast were isolated from left ventricle and cultured to P1. Fibroblasts isolated from SHR previously treated with enalapril secreted significantly higher levels of TGF‐β1 in media (↑30%, p<0.05), and tended to have increased expression of the matricellular protein periostin (↑62%, p=0.052) relative to fibroblasts isolated from untreated SHR. Levels of the pro‐oxidant enzyme NOX2 were not different between treatment groups. Taken together, our data demonstrate that cardiac fibroblasts isolated from SHR that were transiently treated in vivo with an ACE inhibitor are different from those isolated from control SHR hearts. Future studies will further determine the extent to which ECM regulatory proteins differ in cells isolated from ACE inhibitor treated rats, and the response of these cells to an in vitro pro‐fibrotic stimulus. We predict that this altered cell population is primarily responsible for the cardio‐protection that we have shown to persist even after stopping ACE inhibitor treatment.

Support or Funding Information

Funding: Springboard Grant, UA College of Medicine – Phoenix

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Helicobacter pylori Infection of the Gastric Epithelium Promotes Programmed Death Ligand 1 Expression and the Formation of Premalignant Lesions
Authors: Holokai Loryn , Chakrabarti Jayati , Chang Julie , Hawkins Jennifer , Sundaram Nambirajan , Mahe Maxime , Helmrath Michael , Zavros Yana
Published: June 2021

Background

Helicobacter pylori (H. pylori) is the number one risk factor for gastric cancer. Currently the 5‐year‐survival rate for gastric cancer is only 29%. Our laboratory has reported that H. pylori infection results in the up‐regulation of the Sonic Hedgehog (SHH) signaling pathway mediated by an increase in the transcriptional activity of NF‐kB. In addition, H. pylori infection induces the expression of programmed death ligand 1 (PD‐L1) on gastric epithelial cells. This expression inhibits T cell proliferation and effector function.

Hypothesis

H. pylori‐induced PD‐L1 expression on the surface of gastric epithelial cells is mediated by the SHH signaling pathway.

Methods

Human‐derived gastric organoids (huFGOs) were generated from sleeve gastrectomies. These huFGOs were then transferred to a collagen‐coated transwell where they readily formed a 2D gastric epithelial cell monolayer (huGEM). The huGEM culture was apically treated with H. pylori. A second experimental group was also infected with H. pylori, but was treated with Vismodegib, a smoothened inhibitor. Gli2 and PD‐L1 expression was analyzed by qRT‐PCR and immunofluorescence. A chromatin immunoprecipitation (ChIP) assay was used to analyze Gli2 binding to the PD‐L1 promoter region. Gli3 was used as a positive control.

Results

1) HuGEM cultures infected with H. pylori express significantly more PD‐L1: H. pylori infection significantly increased PD‐L1 expression in huGEM cultures 48 hours post‐infection, when compared to uninfected monolayers. This response was blocked by pretreatment with Hedgehog inhibitor vismodegib. 2) Transcriptionally active Gli2 promotes PD‐L1 expression in H. pylori infected huGEM cultures: Transcriptionally active Gli2 was bound to the zinc finger motif of the promoter region of PD‐L1 upon the infection of gastric epithelial monolayers in response to H. pylori infection.

Conclusion

H. pylori‐induced PD‐L1 expression is mediated by the SHH signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD‐L1 may freely gain mutations while being protected from the immune response, creating premalignant lesions progressing to gastric cancer.

Support or Funding Information

Steven Goldman Memorial Pancreatic Cancer Research Grant (Zavros) 1RO1DK083402

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neuroanatomical Reprogramming Produced By Perinatal Exposure to Indoor Flame Retardants (PBDEs) May Underlie Abnormal Affective/Social Behavior
Authors: Kozlova Elena V. , Anchondo Laura , Krum Julia Megan , Rohac David , Uddin Syed , Huffman Nicole , Huffman Kelly , Curras‐Collazo Margarita C.
Published: June 2021

Polybrominated diphenyl ethers (PBDEs) are flame retardant pollutants with adverse neurobehavioral effects. In this study, we examined affective and social behaviors in male offspring of pregnant/lactating mothers exposed to a penta‐BDE mixture DE‐71 (low dose (LD) (0.1 mg/Kg/day), high dose (HD) (0.4 mg/Kg/day), corn oil vehicle (control). LD exposure significantly decreased pup litter size which may be associated with changes in dam parameters in gestation. Adult offspring were subjected to behavioral testing that measure social memory, sensorimotor integration/anxiety and depressive like behavior: Social Recognition Task (SRT), SUOK and forced swim tests (FS). HD male offspring showed abnormal SRT ability showing no preference for novel over familiar stimulus mice as compared to control (p<.0001). For SUOK test HD males showed significantly less falls/segments crossed relative to control (p=.024), indicating altered sensorimotor ability. For FS, LD mice spent significantly less time immobile compared to control (p=.002), suggesting that PBDE exposure alters affective behavior and/or promotes hyperactivity. To examine altered neurodevelopment that may underlie behavioral results, we examined intraneocortical connections (INCs) in male offspring at postnatal day 7 (PN7). DiI and DiA fluorescent dyes were injected into the frontal and visual cortices, respectively and dyes were localized to cell layers containing the cells with fibers projecting to dye projection zones (DPZs). DiI and DiA tracing revealed significantly wider normalized DPZs over the visual cortex in LD (p=.04, n=3–8 per group): control 37%, LD 53%, HD 48%. A similar but insignificant change was observed in HD. Frontal association cortex DPZ showed an apparent increase in HD (p=.09, n=3–7 per group): control 47%, LD 53%, HD 57%. The larger dye distribution in LD offspring is not due to gross anatomical differences (cortical length). These results suggest that PBDEs may produce changes in affective behavior in LD male offspring, in part, by altering neurodevelopment of the neocortex.

Support or Funding Information

Supported by APS (L.A.), UCMEXUS (E.K.,) UCR Chancellor's Research Fellowship (J.K), DOE HSI‐STEM Fellowship (E.K, N.H ).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Noradrenergic Enhancement of Synaptic Strength in Paraventricular Nucleus Neurons that Innervate the Nucleus Tractus Solitarius
Authors: Brackley Allison Doyle , Toney Glenn M.
Published: June 2021

Autonomic neurons of the hypothalamic paraventricular nucleus (PVN) integrate synaptic inputs activated by a wide array of internal (homeostatic) and external (perceived stress) stimuli. A well‐recognized yet poorly understood neurochemical modulator of PVN‐driven autonomic function is norepinephrine (NE). Visceral afferent inputs terminate in the brainstem nucleus tractus solitarius (NTS) and strongly modulate local A2 noradrenergic neurons, which densely project to the PVN, and a number of studies report reciprocal connections between the PVN and NTS. To investigate synaptic modulatory actions of NE on NTS‐projecting PVN neurons, retrograde axonal tracing was used to label PVN‐NTS neurons and slice electrophysiology was performed to investigate effects of NE on the strength of glutamatergic synaptic transmission. In whole cell voltage‐clamp recordings during blockade of activity‐dependent synaptic transmission (TTX, 1 μM) and with Vm held at −20 mV, bath application of NE (100 μM) for 5 min increased the frequency and amplitude of 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX)‐sensitive AMPA receptor mediated mEPSCs by 584 ± 141% (n=3) and 143 ± 10% (n=3), respectively. Unlike amplitude, mEPSC frequency remained significantly increased 25 min after NE washout (453 ± 166%, n=3). Holding Vm at −60 mV during NE exposure blunted the increase of mEPSC frequency (222 ± 66%, n=2), but not amplitude (147 ± 26%, n=2. In the absence of depolarization, the NE‐induced increase of mEPSC frequency also recovered more rapidly, returning to baseline with 15–20 min of washout. Blockade of α1‐adrenergic receptors with prazosin (20 μM) prevented the increase of mEPSC frequency (127 ± 21%; P<0.05, n=3) and amplitude (108 ± 8%; P<0.05, n=3) following bath application of NE (100 μM; Vm = −20 mV). Interestingly, effects of NE on mEPSCs were not consistently observed in neurons not retrogradely labelled from the NTS. Although the resting membrane potential (−57.8 ± 0.6 mV, n=9) and membrane capacitance values (−42.9 ± 4.4 pF, n=9) of PVN‐NTS neurons was consistent with PVN parvocellular neurons, the majority (7 of 9) had a membrane input resistance (400–600 MΩ) lower than that typical of parvocellular neurons. These data provide insight into the possible regulation of poorly understood population of autonomic‐regulatory PVN neurons by noradrenergic inputs and indicate that α1‐adrenergic receptors can elicit a large amplitude and prolonged increase of glutamatergic signaling through AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptors.

Support or Funding Information

NIH T32‐HL007446, HL088052 and AHA 25710176 (GMT)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Working memory testing reveals neuroplasticity acutely and longitudinally after mild traumatic brain injury (mTBI)
Authors: Arakaki Xianghong , Lee Ryan , Fonteh Alfred N. , Goldweber Robert T. , Harrington Michael G.
Published: June 2021

Background and Objectives

There are increasing concerns about mild traumatic brain injury (mTBI) because of its effects in later life. However, objective markers that help physicians quantify the injury are still understudied. We aim to investigate the underlying neuroplasticity reflected by working memory processing after mTBI.

Methods

We used cognitive brain challenges to explore neuroplasticity in acute mTBI. Brain activities during the N□back working memory (WM) test was investigated using quantitative electroencephalography (qEEG) in an acute and longitudinal mild traumatic brain injury study. mTBI patients (n=22) and controls (n=9) (trauma patients without head injury), 18–50 years of age, were recruited from the emergency department of Huntington Memorial Hospital in Pasadena, CA. Brain challenges were administered using E‐prime software. Data were collected from 21 recording head sensors at four visits: within 1 week, 14 days, 30 days, and 6–12 months after injury (with some missing visits). Behavioral performance as well as spectral power were analyzed to compare the two groups. Brain WM processing were also evaluated by event‐related potentials (ERPs) P300, and corresponding EEG signal (ir)regularity or “noise” level measured by spectral entropy (SE). High SE means signal is more irregular and “noisier”.

Results & Discussion

Behavioral performance during 0‐back challenge was similar between the two groups, though mTBI patients had significantly lower accuracy than controls during 2‐back at the first visit. qEEG analysis revealed altered brain activities in mTBI group during 0‐back: alpha and beta power were lower in mTBI patients than controls at the second and third visit. Further, theta power during 2‐back at second visit were significantly higher (P=0.0099 and 0.0018) in controls (0.73+/−0.37 and 0.96+/−0.46) compared to mTBI (0.21+/−0.41 and 0.09+/−0.55) patients at the left and right temporal regions. When comparing regional theta power from first visit to second visit, controls were increased (p<0.005), indicating a learning mechanism, while mTBIs were not changed (p>0.10). SE analysis of the EEG signals during the P300 time window demonstrated more irregular or noisier brain signals in mTBI patients. These changes indicate neuroplasticity acutely and longitudinally after mTBI, consistent with learning impairment and “noisier” brain after mTBI. The spectral power and SE under WM challenge are sensitive measures of neuroplasticity after injury, and could be potential objective mTBI markers to help diagnosis, prognosis, or treatment management.

Support or Funding Information

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Quantitative EEG during memory testing indicates pre‐symptomatic Alzheimer's disease and correlation with MRI
Authors: Arakaki Xianghong , King Kevin S. , Lee Ryan , Wei Ke , Tran Thao , Fonteh Alfred N. , Harrington Michael G.
Published: June 2021

Background and Objectives

Increasing attention for Alzheimer's disease (AD) have been focused on pre‐symptomatic stage for potential effective treatment. We aim to explore the quantitative electroencephalography (qEEG) during memory testing and evaluate qEEG correlations with MRI volumetric data to investigate the underlying events of pre‐symptomatic AD.

Methods

We employed qEEG test to investigate brain activity during working memory processing (N‐back) in a pre‐symptomatic AD study. Study participants, age 60–100 years, with normal cognition were recruited from the local community, consisting of two subdivisions from cerebrospinal fluid proteins: cognitively healthy with normal amyloid/tau ratio (CH‐NAT, n=10) or pathological amyloid/tau ratio (CH‐PAT, n=14). Behavioral performance and spectral power from 21 recording head sensors were collected during testing. EEG signal (ir)regularity or “noise” levels were measured by spectral entropy (SE). To assess brain anatomical structures, MRI was collected from the same individuals. We analyzed the EEG data for all channels, and explored the spectral power correlations with MRI total gray matter and hippocampal volumes.

Results & Discussion

The behavioral performance was similar between the two groups during lower memory load, and CH‐PATs had significantly less accuracy of performance than CH‐NATs during higher memory load. The qEEG from several sensors were significantly different (p<0.01) between CH‐NAT and CH‐PAT groups during the lower load memory testing when behavioral performances did not differ. The CH‐PAT brain signals were “noisier” compared to CH‐NATs. We interpret the altered brain activity in the CH‐PAT group to indicate a compensation mechanism for the CH‐PATs. qEEG measures from specific sensors correlated with total gray matter volume (p<0.001) and hippocampal volumes (p<0.001); these unexpected results suggest neuroplasticity occurs in the pre‐symptomatic AD stage to compensate for reduction in brain regional volumes. We propose that intervention at the pre‐symptomatic phase of AD using strategies that improve cognitive efficiency may attenuate neurodegeneration.

Support or Funding Information

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Diet‐Induced Obesity Increases H‐Reflex Excitability in Adult Mice of Both Sexes
Authors: Nguyen Gerard , Putnam Shea , Haile Mulatwa , Wilkinson Katherine A.
Published: June 2021

Obesity is a metabolic condition characterized by excess adipose tissue and chronic inflammation. It is associated with deficits in balance and motor control leading to an increased risk of falling and fall‐related injuries. These balance deficits may be partially due to alterations in the muscle stretch reflex, which helps correct motor movements and adapt to uncertain terrain. Muscle stretch is sensed by muscle spindle afferents, which then excite alpha motor neurons to cause a reflex contraction. We tested the hypothesis that spinal cord integration of sensory information from muscle spindle afferents is altered in a mouse model of diet‐induced obesity. Changes in spinal cord integration were measured using the Hoffman's or H‐reflex, the electrical analog of the muscle stretch reflex. Following electrical stimulation of the sciatic nerve, two waves of muscle contraction were recorded: the M wave caused by direct excitation of motor neuron axons and the longer latency H wave caused by reflex activation of motor neurons by muscle spindle afferents. Adult mice of both sexes were fed either a control diet (CD, 10% kcal fat; n=16 M, 8 F) or high‐fat diet (HFD, 60% kcal fat; n=15 M, 9 F) for 10 weeks. We measured three properties of the H‐reflex as indicators of excitability: (1) H latency, the time from stimulus to the peak of the H wave; (2) Hmax/Mmax, the percentage of motor neurons recruited from the stimulus of Group Ia afferents; and (3) rate‐dependent depression (RDD), the decrease in H‐reflex amplitude following high‐frequency stimulation (20 stimuli, 5 Hz). After 10 weeks, there were no significant differences in H latency (p=0.558) between groups. However, the 10‐week HFD group showed a significant increase in Hmax/Mmax (p=0.013; sex x diet p=0.570). 10 weeks of high‐fat feeding also decreased the degree of RDD (p=0.001; sex x diet p=0.797). These results suggest that obesity increases spinal cord sensitivity to sensory input from the muscle spindle afferents. A preliminary sample of male mice fed the HFD for 5‐weeks showed similar decreases in RDD (n=6 per group, p=0.033), but no changes in Hmax/Mmax (p=0.485). We are currently increasing this sample size and testing whether more severe increases in excitability are seen following longer exposures to the HFD. Future studies will also determine whether these changes in spinal cord excitability translate into changes in the strength of the muscle stretch reflex and/or balance.

Support or Funding Information

This work was supported by SJSU RSCA funds and NIGMS Grant# 4T34GM008253‐30 (MH).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Posture Modifies Neuro‐Cardiac Heart Rate Responses at the Onset of Moderate Intensity Isometric Handgrip Exercise
Authors: Woehrle Emilie , Jacobs Kaitlyn G. , Shoemaker J. Kevin
Published: June 2021

Background

The heart rate (HR) response at the onset of moderate intensity isometric handgrip (IHG) exercise is related to neural control of the heart, primarily vagal withdrawal. If so, modest modifications in neuro‐cardiac function by postural shifts should modify the HR response to exercise.

Objective

This study examined the effect of supine versus seated postures on the changes in HR and heart rate variability (HRV) at the onset of IHG.

Methods

13 healthy adults (24±3 years; 6 females) performed IHG at 35% and 50% of maximal voluntary contraction strength (MVC), each lasting 30 seconds and separated by at least one minute of rest. HR (electrocardiogram) and root mean square of successive differences (RMSSD) were recorded from the last 30 seconds of the 1 minute baseline prior to handgrip, and the last 10 seconds of each 30 second handgrip.

Results

Baseline HR increased from 68bpm to 76bpm (p<0.001; d=1) and RMSSD decreased from 56ms to 44ms (p=0.25; d=0.4) when shifting from supine to seated positions. Compared to the supine position, the ΔHR with 35% IHG decreased in the seated position (7bpm to 3bpm; p=0.01; d=0.71). Similarly, the ΔRMSSD with 35% IHG tended to be less in the seated versus supine positions (−31ms to −16ms; p=0.07; d=0.7). During 50% MVC work, the seated position exerted only a modest effect on the IHG‐induced ΔHR compared to supine (18bpm to 13bpm; p=0.06; d=0.47) whereas the ΔRMSSD from baseline to IHG was diminished in seated versus supine positions (−47ms to −22ms; p=0.001; d=0.78).

Conclusion

With RMSSD as an indicator of changes in cardiovagal influence, these preliminary results indicate that small changes in posture modify parasympathetic modulation of HR responses at the onset of moderate‐intensity isometric handgrip.

Support or Funding Information

Supported by the Natural Sciences and Engineering Research Council of Canada.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blunted Blood Pressure to Hand Grip Exercise in Individuals with Intellectual Disabilities: Preliminary Results
Authors: Hilgenkamp Thessa , Schroeder Elizabeth C. , White Daniel W. , Baynard Tracy , Fernhall Bo
Published: June 2021

Individuals with intellectual disabilities (ID) have limited work capacity. In individuals with Down syndrome, this has been previously linked to autonomic dysfunction. Previous research suggests autonomic dysfunction and altered hemodynamics may also be present in individuals with ID without Down syndrome but this has not been tested.

PURPOSE

To compare the autonomic and hemodynamic response to isometric handgrip (HG) exercise in individuals with ID to a control group without ID.

METHODS

Nine individuals with ID and 19 individuals without ID had heart rate and blood pressure continuously recorded via an ECG‐lead and finger‐photoplethysmography in the seated position. Isometric HG was performed at 30% of maximal voluntary contraction for 2 min. Recordings were acquired for the last 2 min of quiet rest, HG, and the first 2 min of recovery.

RESULTS

Individuals with ID showed smaller increases compared to individuals without ID for systolic and diastolic blood pressure, mean arterial pressure and pulse pressure during HG (p<0.001; Table).

CONCLUSION

Despite no HRV differences, these preliminary results suggest a blunted blood pressure response to isometric HG in individuals with ID, which may help explain low fitness levels observed in this population.

Support or Funding Information

The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no 625455.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Influence of Total Load on Cardiac Autonomic Recovery Following Resistance Exercise in Young and older adults
Authors: Sardeli Amanda Veiga , Fernandes Gáspari Arthur F. , Ferreira Marina Lívia Venturini , do Carmo Santos Lucas , Rosenberg Alexander J. , Fernhall Bo J. , Cavaglieri Cláudia Regina , Chacon‐Mikahil Mara Patrícia Traina
Published: June 2021

Introduction

The delay in cardiac autonomic recovery (CAR) following physical activity is associated with increased risk of cardiovascular events. Aging is a major risk factor for cardiovascular disease, and older adults have altered resting cardiac autonomic modulation than young individuals. The intensity of exercise also influences autonomic recovery in young individuals.

Objective

To compare the CAR following resistance exercise (RE) in young (Y) and older (O) men, using high and low intensity RE.

Methods

The two groups (Y: n=9, age=26.3±4y, BMI=22.3±1.5Kg/m2 and O: n=9, age=64.3±4y, BMI=26.2±1.8 Kg/m2) performed 4 sets of RE, using leg press equipment, until failure. Subjects performed two different protocols; RE at 80% of 1RM (RE80) and at 30% of 1RM (RE30) in a random sequence. Heart rate was measured via a heart rate monitor and CAR was obtained through heart rate variability analysis pre and 30‐min post‐RE. The change values for heart rate variability (post 30‐min – pre) were assessed by root mean square (RMSSD) of successive RR intervals (iRR), high and low frequency in normalized units (HF and LF, respectively) and analyzed by 2‐way ANOVA (group*load).

Results

The table shows a greater reduction of iRR, RMSSD and HF and a greater increase of LF in Y compared to O. Since the total load was higher in Y compared to O in RE80 and RE30 (Y RE30: 13767 ± 4738 kg vs. O RE30: 7812 ± 2094 kg, p < 0.05, and Y RE80: 10921 ± 4201 kg vs. O RE80: 7488 ± 2040 kg, p < 0.05), we evaluated the change in heart rate variability as a function of TL. This correction eliminated differences between Y and O for iRR and RMSSD (p > 0.05), while HF and LF remained different between Y and O (p < 0.05).

Conclusion

Y showed delayed CAR in protocols with both RE80 and RE30. The higher TL in Y did not explain the delayed CAR in this group, thus other factors are involved. It is possible the lower heart rate variability adjustments of O is associated with limiting increases in sympathetic and reductions in parasympathetic modulation during RE but this needs further investigation.

Support or Funding Information

We thanks the support of CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), FAEPEX (Fundo de Apoio ao Ensino, à Pesquisa e Extensão da Universidade Estadual de Campinas) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Rho Kinase and Na+/H+ Exchanger Mediate Endothelin‐1 Induced Pulmonary Arterial Smooth Muscle Cell Proliferation and Migration
Authors: Huetsch John Christian , Yun Xin , Jiang Haiyang , Shimoda Larissa
Published: June 2021

Objective

Remodeling of the pulmonary vasculature, involving increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a key component of the pathology underlying pulmonary hypertension (PH). Endothelin‐1 (ET‐1) is known to be an important contributor to both pulmonary vasoconstriction and remodeling in PH. We aimed to determine whether ET‐1 modulates PASMC function via a pathway involving Rho kinase (ROCK) and the Na+/H+ exchanger (NHE).

Methods

PASMCs were isolated from distal pulmonary arteries of male C57/B6 mice as well as male Wistar rats and expanded in culture. To measure NHE activity, cells were incubated with pH‐sensitive fluorescent dye and the Na+‐dependent recovery of intracellular pH (pHi) following acidification by ammonium pulse challenge was measured via fluorescence microscopy. NHE1 mRNA expression was measured via qRT‐PCR and protein expression was measured via immunoblot. Proliferation was assessed via ELISA for BrdU incorporation over 24 hr. Migration was measured over 24 hr using Transwell filters with 8 μm pores. Cells were treated with 10−8 M ET‐1 versus vehicle for 24–48 hr. NHE was pharmacologically inhibited with 10 μM ethyl‐isopropyl amiloride. ROCK was inhibited with 10 μM Y‐27632.

Results

ET‐1 treatment, compared to vehicle, resulted in increased resting pHi and NHE activity in PASMCs. ET‐1 did not result in increased NHE1 mRNA or protein expression. ROCK inhibition prevented ET‐1‐induced NHE activation. PASMC proliferation and migration were both increased by ET‐1 treatment, compared to vehicle. ROCK inhibition attenuated PASMC proliferation and migration in the presence of ET‐1. Similarly, NHE inhibition also attenuated ET‐1‐induced PASMC proliferation and migration.

Conclusions

ET‐1 results in increased PASMC proliferation and migration via a pathway involving ROCK and NHE activation. This suggests a novel pathway which may contribute to vascular remodeling in PH.

Support or Funding Information

NIH K08HL133475 & R01HL073859

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Involvement of medullary raphe on active expiration.
Authors: DO NASCIMENTO SILVA JOSIANE , dos Santos Moreira Thiago , Takakura Ana Carolina
Published: June 2021

Introduction

In rodents, the parafacial respiratory group (pFRG), located in the ventral lateral medulla, has been described as a conditional expiratory oscillator that emerges mainly in conditions of metabolic challenges to increase ventilation. However the mechanisms required to stimulate pFRG and generate active expiration have not been fully elucidated. Because the raphe region has long been described to be involved in breathing activity, we decided to investigate whether there were projections from raphe to pFRG and to analyze the effect of raphe inhibition on the active expiration generated by hypercapnia.

Objective

Investigate the possible involvement of the medullary raphe in active expiration mediated by hypercapnia.

Methods

Male Wistar rats weighing 250–350g (CEUA: 80/13) were used. For anatomical experiments, animals received retrograde tracer FluorGold (FG) injections in the pFRG (n=4). Seven to ten days after the injections, immuhistochemistry for tryptophan hydroxylase (TrOH) was performed. For physiological experiments, urethane‐anesthetized rats received bilateral injection of the GABA‐A agonist muscimol (60 pmol/60 nl) in the Raphe Magnus (RMg) or Obscurus (ROb) regions, the electromyography of diaphragm (DiaEMG) and abdominal (AbdEMG) muscles were recorded.

Results

The anatomical experiments showed that there were projections from serotonergic and non‐serotonergic neurons of RMg and ROb to pFRG region. The injection of muscimol in RMg or ROb did not significantly alter the frequency and amplitude of DiaEMG and did not generate active expiration. In these animals, hypercapnia after raphe inhibition did not produce significant changes on DiaEMG amplitude and frequency. However, inhibition of RMg or ROb produced an increase in the AbdEMG amplitude during hypercapnia.

Conclusion

Our results demonstrated that RMg and ROb project directly to pFRG and may be involved in active expiration. We propose that RMg and ROb may be modulating the activity of pFRG during hypercapnia.

Support or Funding Information

Financial support: FAPESP, CNPq and CAPES

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.