bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to Homocysteic Acid Early in Postnatal Development Leads to a Mixed Depressive/Manic Behavioral Phenotype and Changes in NMDA Receptor Expression
Authors: Simko Stephanie , Johnson Jacob , Flores Guillermo , Barney Christopher C. , Chase Leah 
Published: November 2023

Homocysteic acid (HCA), a NMDA receptor agonist, is an endogenous metabolite formed from the oxidation of homocysteine. Since hyperhomocysteinemia is a risk factor for several neuropsychiatric disorders, including bipolar disorder and major depressive disorder (MDD), we tested the hypothesis that elevated HCA levels in developing rats may induce alterations in NMDA receptor expression and the development of behaviors associated with MDD and/or bipolar disorder. Twenty postnatal male and twenty female rats were injected daily with either HCA or saline from day P3 to P21. HCA‐treated rats displayed increased risk‐taking behavior, reduced social behavior, novelty‐induced hyper‐locomotion, anhedonia in the saccharine preference test, and reduced spatial learning in the Morris water maze, consistent with a depressive state with manic tendencies. Interestingly, female rats were more sensitive to the effects of HCA than male rats. As expected, HCA treatment had no effect on motor coordination (Rotarod) or startle behavior (paired‐pulse inhibition). In addition to these behavioral changes, we observed that HCA led to an increase in expression of the GABAergic marker, GAD‐67, in the cortex, but not the hippocampus, of both male and female rats. We also observed a significant change in the NMDAR2b:NMDAR2a subunit expression ratio in the cortex. Specifically, HCA triggers an increase in the NMDAR2b:NMDAR2a ratio in male rats, while female rats exhibit a decrease in this ratio. We also observed that HCA triggered an increase in NMDAR2a expression in the hippocampus in both males and females. Finally, HCA also led to a decrease in NMDAR2b expression in females, but an increase in NMDAR2b expression males in the hippocampus. We are currently examining the effect of HCA exposure on NMDAR1 subunit expression. Collectively, these data suggest that early postnatal exposure to HCA may lead to a mixed manic/depressive phenotype that may also be accompanied by changes in GABAergic signaling in the cortex. Given the role that NMDA receptors are proposed to play in regulating GABAergic interneuron activity and the regulation of mood, we suggest that this may serve as a novel animal model for studies of complex mood disorders such as bipolar disorder or major depressive disorder.Support or Funding InformationThis research was supported by the Hope College Neuroscience Program, Biology Department and Chemistry Department.
NPY‐Induced Stress Resilience and Downregulation of HCN1 Channels Modifies Expression of Conditioned Fear
Authors: Bompolaki Maria , Rosenkranz J. Amiel , Colmers William F. , Urban Janice H. 
Published: November 2023

The anxiolytic and stress‐buffering properties of neuropeptide Y (NPY) in the basolateral amygdala (BLA) have long been established in animal models as well as in humans. Repeated injections of NPY into the BLA promote long‐lasting resilience to restraint stress (Sadjyk et al., 2008), which is associated with downregulation of HCN1 channels. In addition to inducing stress resilience, we hypothesize that repeated injections of NPY and downregulation of HCN1 subunits in the BLA will ameliorate freezing behavior in a cued fear conditioning paradigm. Male rats received bilateral infusions of 10pmol NPY or vehicle (100nl; 0.1M PBS) into the BLA repeated daily for 5 days. Two weeks after the injections, animals underwent a cued fear conditioning protocol: On day 1, animals were placed in chamber 1 and received 4 pairings of a tone (1500Hz, 85dB) with a foot shock (0.4mA; fear acquisition). The following day the rats were placed in novel chamber 2 and received 15 trials of the tone without a foot shock at 60s intertrial intervals (fear extinction) and freezing behavior was monitored (Anymaze software). Both vehicle‐ and NPY‐treated rats displayed similar rates and amplitudes of fear acquisition on day 1. On day 2, NPY‐treated rats exhibited significantly lower freezing in the first five sessions of the extinction phase. Additionally, at the time point we performed the fear conditioning experiment, we observed an induction of LC3B expression (an autophagy marker) and downregulation of brain‐derived nerve factor (BDNF), however downregulation of the HCN1 protein is not seen until 4 weeks after the NPY treatment. Lastly, to test the involvement of HCN1 subunits in fear conditioning, HCN1 protein was knocked‐down in the BLA using lentiviral delivery of HCN1‐shRNA. Four weeks after the surgery, the rats underwent the same cued fear conditioning protocol as described above and freezing behavior was monitored. HCN1‐knockdown animals had reduced freezing on the acquisition day. This work indicates that the induction and maintenance of NPY‐induced stress resilience is associated with differential changes in protein expression. NPY‐induced resilience is correlated with BDNF downregulation and induction of autophagic pathways at early time points, while HCN1 downregulation later consolidates a new stress‐relieving baseline in NPY‐treated animals. These findings can be of great importance for the way anxiety disorders like post‐traumatic stress disorder are viewed and treated.Support or Funding InformationWork supported by MH090292 (JHU; WFC)
Passive Leg Cycling Comprehensively Restores Cerebrovascular Health After Experimental High‐thoracic Spinal Cord Injury
Authors: Jia Mengyao , Phillips Aaron A. , Matin Nusrat , Yung Andrew , Zheng Mei Mu Zi , Lee Amanda , Monga Aaron , Kozlowski Piotr , Dorrence Anne , Krassioukov Andrei V. 
Published: November 2023

Individuals living with chronic spinal cord injury exhibit a 3–4 fold increased risk of stroke. Reduced cerebral blood flow following is associated with cognitive decline, increased risk of stroke, and development of white matter irregularities. Previously, we have reported impairment in cerebrovascular health following experimental high‐thoracic spinal cord injury, including cerebrovascular reactivity declines, as well as inward remodelling and profibrosis of the middle cerebral artery. Passive hind‐limb exercise after spinal cord injury has been shown to restore systemic cardiovascular function, however it has never been explored for improving cerebrovascular health.ObjectiveTo preclinically investigate the effect of passive hind‐limb exercise in preventing cerebrovascular decline following high‐thoracic spinal cord injury.Design/MethodMale Wistar rats (n=45) were uninjured, T3‐level complete transected or T3‐transected with passive exercise. Six days after surgery, the hind‐limb passive cycling intervention was initiated and lasted for five weeks. Six weeks after surgery, Magnetic resonance imaging was performed to evaluate baseline cerebral blood flow. Middle cerebral arteries were then harvested for functional and structural assessments, including in vitro pressure myography and immunohistochemistry.ConclusionThere was a 44% reduction in global cerebral blood flow (p=0.001) after spinal cord injury, which was restored with passive exercise (Figure 1). Passive exercise also prevented the endothelial dysfunction seen after spinal cord injury (p=0.046). Profibrotic remodelling of middle cerebral arteries demonstrated by increased collagen (95%, p=0.004), was also reversed by passive exercise. As such, passive hind‐limb cycling is effective in restoring healthy brain blood flow, endothelial function, and preventing profibrosis in the cerebral vasculature. Clearly, passive exercise is a promising pre‐clinical therapy to restore cardiovascular health after spinal cord injury, and the present data extend these benefits even to the brain.Support or Funding InformationSupport: AAP: Killam Trust, Craig H. Neilsen Foundation Postdoctoral Fellowship 337427, Heart and Stroke Foundation of Canada Research Fellowship, Michael Smith Foundation for Health Research Postdoctoral Fellowship AVK: Canadian Institute of Health Research, Craig H. Neilsen Foundation.
Aortic Augmentation Index and Age in Persons with SCI and Intact Controls
Authors: Katzelnick Caitlyn G , Weir Joseph P , Chiaravalloti Nancy , Bauman William A , Wylie Glenn R , Dyson‐Hudson Trevor A , Wecht Jill M 
Published: November 2023

ObjectiveArterial stiffness (AS) has been identified as an independent risk factor for cardiovascular disease (CVD) progression. Increases in AS are associated with advancing age and resting blood pressure (BP) in the general population; however, these associations have not been described in the spinal cord injury (SCI) population. The objective of this investigation was to quantify the impact of age and seated systolic BP (SBP) on AS in persons with SCI by estimating aortic augmentation index (AI) compared to healthy controls.Participants/methodsThree groups of age‐matched subjects (25–48 years) were recruited for study; 29 individuals with HIGH‐SCI (C3‐T5), 17 LOW‐SCI (T7–T12), and 27 age‐matched controls (CONT).DesignParticipants were asked to remain seated for instrumentation and five minutes of beat‐to‐beat SBP was assessed at the finger arteriolar using photoplethysmography (Finometer PRO, Finapres Medical Systems B.V., Netherlands). After the seated data collection, participants transferred to supine position and radial artery pulse wave analysis (SphymoCor, AtCor Medical) was used to estimate aortic AI, which was normalized to a heart rate of 75 bpm (AI@75). ANOVA models were used to determine group differences in AI@75, age and SBP and multiple regression models were constructed to determine the influence of age and seated SBP on aortic AI@75 among the groups.ResultsThe groups did not differ for age; however the group main effect for AI@75 was significant (F=11.618; p<0.0001) suggesting that AI@75 was significantly increased in the HIGH‐SCI (19.6±9.3%) compared to the CONT (6.2±11.0%; p<0.0001) and the LOW‐SCI group (9.8±12.2%; p<0.001). The group by age interaction effect was statistically significant (F=3.188; p<0.05); follow‐up procedures using separate bivariate regressions between AI@75 and age were performed for each group. Age was directly related to AI@75 in CONT (F=67.46, r2=0.60; p<0.0001), but did not contribute to AI@75 in either the HIGH‐SCI (r2 <0.01) or LOW‐SCI groups (r2 <0.06). Seated SBP was significantly lower in the HIGH‐SCI (97.2±16.9 mmHg) compared to the CONT and LOW‐SCI groups (122.1±14.3 and 119.0±18.7 mmHg, respectively; p<0.0001), and there was a significant inverse association between AI@75 and SBP in the HIGH‐SCI group (F=5.703, r2=0.174; p<0.05).ConclusionThese preliminary data suggest that, although age does not contribute to AS in individuals with SCI, level of lesion appears to influence vascular stiffness, which may be dependent on resting SBP. We speculate that the inverse association between AI and SBP in the HIGH‐SCI group may relate to an increased dependency on the renin‐angiotensin‐aldosterone system for orthostatic BP maintenance.Support or Funding InformationSupported by the New Jersey Commission for Spinal Cord Research [Grant # CSCR13IRG018]
Heart Rate and Heart Rate Variability during the Cold Pressor Test in Recently Concussed Patients
Authors: O'Leary Morgan C , Sackett James R , Schlader Zachary J , Leddy John J , Johnson Blair D 
Published: November 2023

IntroductionAutonomic function appears to be altered in concussed patients, especially when a physiological stressor is present. Heart rate variability (HRV) during whole body exercise is attenuated in concussed patients compared to healthy controls. However, HRV during isometric handgrip exercise has been shown to have a similar response between concussed patients and healthy controls. The cold pressor test (CPT) is an exercise‐independent test that could be used to identify shifts in autonomic function in concussed patients. The root mean squared of successive differences (RMSSD) is a metric of HRV that can be used during the CPT to assess the degree of parasympathetic control of heart rate.PurposeWe tested the hypothesis that heart rate and RMSSD during the CPT in concussed patients is impaired versus healthy controls.MethodsFour concussed patients who were symptomatic and within 7 days of injury (age: 19 ± 1 years, 2 men) and four healthy controls (age: 27 ± 4 years, 4 men) completed a CPT. The CPT consisted of submerging a hand up to the wrist in an agitated ice/water slurry mixture (~1°C) for 120 seconds. We continuously measured heart rate (ECG) throughout the CPT. Heart rate and RMSSD were analyzed in 60‐second increments at baseline, 60 seconds and 120 seconds during the CPT, and 60 seconds post CPT.ResultsHeart rate in the concussed patients did not change from baseline (67 ± 17 bpm) to 60 seconds (73 ± 20 bpm, P = 0.192), 120 seconds (74 ± 16 bpm, P = 0.187), or post CPT (70 ± 15 bpm, P = 0.412). However, heart rate in the healthy controls increased from baseline (59 ± 8 bpm) to 60 seconds (78 ± 8 bpm, P < 0.001) and 120 seconds (68 ± 10 bpm, P = 0.046) of the CPT and returned to baseline post CPT (55 ± 2 bpm, P = 0.300). RMSSD in the concussed patients did not change from baseline (87 ± 74 ms) to 60 seconds (86 ± 114 ms, P = 0.979), 120 seconds (91 ± 127 ms, P = 0.979), or post CPT (100 ± 134 ms, P = 0.902). RMSSD in the healthy controls also did not change from baseline (71 ± 26 ms) to 60 seconds (48 ± 23 ms, P = 0.325), 120 seconds (41 ± 11 ms, P = 0. 325), or post CPT (104 ± 36 ms, P = 0. 325).ConclusionsThese preliminary data indicate that parasympathetic control of heart rate, represented by RMSSD, is not altered during the CPT in recently concussed patients or healthy controls. However, the blunted heart rate response during the CPT does indicate that cardiac autonomic control is impaired in recently concussed patients.
Local Delivery of β‐Aminopropionitrile Improves Arteriovenous Fistula Maturation and Remodeling
Authors: Hernandez Diana Rosa , Wei Yuntao , Andreopoulos Fotios , Vazquez‐Padron Roberto 
Published: November 2023

IntroductionArteriovenous fistula (AVF) is the preferred vascular access to provide hemodialysis in patients with end stage renal disease (ESRD). The failure of AVF due to improper remodeling is a serious condition that affects not only its prevalence but also the possibility of achieving long‐term patency. β‐aminopropionitrile (BAPN) is an irreversible inhibitor of lysyl oxidase (LOX), the main enzyme responsible for collagen crosslinking. Herein, we hypothesize that inhibition of LOX by local delivery of BAPN improves biomechanical performance in experimental AVF and prevents excessive crosslinking of collagen and other extracellular matrix proteins.MethodsPoly Lactic‐co‐Glycolic Acid (PLGA) is an FDA‐approved biodegradable highly biocompatible polymer frequently used on deliveries systems. The scaffolds were grown by electrospinning PLGA/BAPN (15:1.5) in hexafluoroisopropanol at 20 keV and 13 cm away from the target with a flow of 2 mL/h. In vitro degradation as well as BAPN release profile was studied during 60 days at 37°C. BAPN concentration was assessed with a Triversa NanoMate® electrospray ionization with direct infusion through triple quadrupole LC‐MS. Two groups of Sprague Dawley rats of both sex received local delivery of scaffold containing BAPN (0.27 mg) or vehicle around the venous limb of the newly created AVF. The rat AVF was created by surgically anastomosing the left epigastric vein to the nearby femoral artery. Pressure myograph (110 P; Danish Myo Technology, Aarhus, Denmark) was used for assessment of the AVF mechanical properties.ResultsIn‐vitro release assessment showed that the drug inclusion in the scaffolds affects degradation rate with a maximum difference of 70% at 40 days. LC‐MS showed an excellent sensitivity for the quantification of BAPN with a lower limit of quantification of 30 ng/mL. Both treated and control AVF increased its size more than double that of the contralateral epigastric vein (p<0.05). However, local delivery of BAPN increased lumen volume in treated AVF with respect to control vessels (p=0.0078), Figure 1.ConclusionOur results demonstrate that inhibition of collagen cross‐linking by BAPN significantly improved vascular compliance and biomechanical properties of AVF.Support or Funding InformationThis research it is support as a Research Supplements to Promote Diversity in Health under parent award R01DK098511.
Effect of an angiotensin II type 2 receptor agonist on myocardial hypertrophy and fibrosis induced by high salt diet
Authors: Dopona Ellen Priscila Brito , Rocha Veronica Favoni , de Oliveira Ivone Braga , Furukawa Luzia Naoko Shinohara , Heimann Joel Claudio 
Published: November 2023

ObjectiveTo evaluated the role of compound 21 (C21), an AT2 receptor agonist, in a model of left (LV) and right (RV) ventricular hypertrophy and fibrosis in response to dietary salt overload.MethodsMale Wistar rats were fed normal (NS ‐ NaCl = 1,27%, n=15;) or high (HS ‐ NaCl = 8%; n=15) salt diet from weaning up to 18 weeks of age. From the 7th week of age, two subgroups (NS+C21; n=15 or HS+C21; n=13) received compound 21 (1mg/kg per day by gavage). Body weight (BW), tail‐cuf blood pressure (BP), cardiac mass to tibia length ratio (CM/TL), cardiomyocyte transverse diameter (TD), percentage of cardiac fibrosis (FI) were measured.Results(mean ± standard error):At the 8th week of age, BW was lower in HS than in the other groups. BW in HS+C21 did not differ from NS from the 10th week to the 16th week of age. BP in HS+C21 was higher than in NS and lower that in HS from the 7th week to the 18th week of age.ConclusionIn Wistars rats, compound 21 prevented both left and right ventricular hypetrophy and fibrosis and the increased blood pressure in response to high salt intake.Support or Funding InformationSupported by FAPESP.

Parameter
Age (weeks)

NS
HS
HS+C21
NS+C21

Body Weigh (g)
3

57.9±2.9
55.6±3.5
60.9±2.99
77.4±1.35

18
571.1±11.2
497.8±12.7*
542.0±12.3
583.8±11.8

BP (mmHg)
6
112.3±3.0
114.0±4.2
111.9±3.4
108±7.9

18
115.6±2.5
143.5±1.2*
135.1±1.8*#
107.7±4.4

CM/TL (g/cm).
18
Total
0.53±0.04
0.51±0.03
0.52±0.05
0.51±0.02

RV
0.08±0.0
0.08±0.00
0.08±0.00
0.07±0.01

LV
0.33±0.02
0.32±0.02
0.35±0.03
0.34±0.01

TD (μm)
18
RV
9.82±0.21
13.80±0.29*
9.79±0.21
8.52±0.19

LV
10.17±0.2
15.60±0.9*
10.41±0.09
9.32±0.5

FI (% area)
18
RV
0.54±0.19
0.74±0.13*
0.43±0.11
0.20±0.06

LV
0.30±0.06
0.64±0.05*
0.45±0.04
0.27±0.06*

p<0.05 vs. NS;
p<0.001 vs. HS.
Regulation of Twist1 and Snail1 Gene Expression in Cardiac Fibroblasts by Scleraxis
Authors: Safi Hamza A , Al‐Hattab Danah S , Nagalingam Raghu S , Czubryt Michael Paul 
Published: November 2023

Cardiac fibrosis causes progressive cardiac stiffening due to abnormal deposition of extracellular matrix (ECM) and alters electrical conduction of the action potential, resulting in heart failure and death. Cardiac fibroblasts largely arise from epithelial precursors during development via epithelial‐to‐mesenchymal transition (EMT), and upon injury or stress, are further converted to an activated state – myofibroblasts – which express a variety of pro‐fibrotic genes responsible for ECM synthesis and deposition. Our previous data suggested that the transcription factor scleraxis plays a key role in regulating cardiac fibroblast cell fate, including EMT and myofibroblast conversion. Here, we examined the role of scleraxis in transactivating expression of genes encoding key EMT regulators including the basic helix‐loop‐helix transcription factor Twist1 and the zinc finger transcription factor Snail1. Over‐expression of scleraxis in NIH3T3 fibroblasts up‐regulated Twist1 and Snail1 expression. Using luciferase reporter assays coupled with point mutagenesis, we found that scleraxis is sufficient to directly transactivate the Twist1 and Snail1 gene promoters, and identified the responsible scleraxis binding sites in each promoter. Loss of scleraxis conversely attenuated expression of these genes. Together, our data indicates that scleraxis controls EMT via direct upstream regulation of these key EMT regulatory genes.Support or Funding InformationSupported by the Canadian Institutes of Health Research (MOP136862 to MPC), Research Manitoba (RSN) and the University of Manitoba GETS Program (HAS, DSA, RSN).
Correlation of Nucleosomes, MMP‐9, and IL‐1α with Relation to Neutrophil Activation in Patients with Atrial Fibrillation
Authors: Liles Jeffrey , Wanderling Christopher , Statz Stephen , Rowe Timothy , Bontekoe Jack , Jabati Sallu , Syed Mushabbar , Hoppensteadt Debra , Fareed Jawed 
Published: November 2023

IntroductionAtrial fibrillation (AF) is currently the most common cardiac arrhythmia encountered in clinical practice and a major cause of morbidity and mortality among adults. It is estimated that atrial fibrillation affects approximately 2.7 million people in the United States. Extracellular nucleosomes in plasma (PNs) are complexes of DNA and histones that are released during cell death. Histones have been shown to activate neutrophils by functioning as DAMPs when they are translocated from the nucleus to the extranuclear space. These nucleosomes mediate inflammatory and thrombotic responses and could serve as biomarkers in AF. MMP‐9 degrades type IV collagen and acts as a chemotactic agent for neutrophilic migration. IL‐1α is an acute phase cytokine released by neutrophils that promotes inflammation.ObjectiveTo examine the relationships of circulating levels of PNs, MMP‐9 and IL‐1α in patients with AF.MethodsIn a prospective study, plasma samples were collected from 50 patients prior to ablation surgery for AF at Loyola University Medical Center. ELISAs kits were used as per kit instructions for PNs, MMP‐9 and IL‐1α.ResultsCirculating levels of PNs were positively correlated with levels of MMP‐9 (p=0.006, r=0.49) and IL‐1α (p=0.008, r=0.50) in patients with AF. Additionally, a positive correlation was seen between circulating levels of MMP‐9 and IL‐1α (p=0.02, r=0.41).DiscussionExtracellular nucleosomes function as DAMPs by binding to receptors and triggering the activation of multiple signal pathways. Due to the involvement of inflammation and thrombosis in the pathology of atrial fibrillation, the positive correlation of nucleosome levels with the levels of MMP‐9 and IL‐1α in atrial fibrillation imply PNs may activate the immune system and generate the inflammatory response. These results may provide insight into a novel mechanism of thrombogenesis in patients with AF.