bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Gut Motility in Mice Lacking Neuropilin 2 in Smooth Muscle
Authors: Bielenberg Diane R. , Doyle Claire , Vasquez Evalynn , Pelton Kristine , Cristofaro Vivian , Sullivan Maryrose P. , Adam Rosalyn M. 
Published: June 2021

Introduction/ObjectivesProfound changes in gut motility and colonic smooth muscle contraction are observed in inflammatory bowel disease states such as colitis. However, the mechanisms that contribute to altered motility and contractility under these circumstances are incompletely defined. Recent data from our group have identified the smooth muscle of the gastrointestinal tract as a major site of expression of neuropilin 2 (Nrp2) in vivo. Nrp2 and the related molecule neuropilin 1 are 130–140 kDa transmembrane receptors for the class 3 semaphorin (SEMA3) family of axonal guidance regulators and for members of the vascular endothelial growth factor (VEGF) family that regulate angiogenesis. Based on recent data from our group implicating Nrp2 as a novel regulator of bladder smooth muscle contractility, the objective of this study was to determine the functional significance of Nrp2 in gastrointestinal smooth muscle.MethodsTwo mouse models were used to explore a role for Nrp2 in gastrointestinal motility: (i) SM22alpha‐Cre; Nrp2 fl/fl mice to enable inducible smooth muscle‐specific deletion of Nrp2 in vivo under controlled conditions and (ii) wild type Balb/c mice exposed to dextran sodium sulfate (DSS) to evoke acute colitis. Gut tissues were subjected to isometric tension testing to characterize contractility. Gut transit was evaluated by charcoal meal assay. Nrp2 levels were assessed by immunohistochemical staining and immunoblot analysis of tissues and of primary colonic smooth muscle cells exposed to inflammatory cytokines.ResultsSmooth muscle‐specific deletion of Nrp2 led to an increase in force generation of colonic rings, upon exposure to electrical field stimulation or treatment with the cholinergic agonist, carbachol. Nrp2 deletion also led to elevated gut transit as assessed by charcoal meal assay. In response to colitis, Nrp2 levels were found to decrease in the distal colon, in parallel with elevated contractility of distal colon rings. In addition, treatment of primary human colonic smooth muscle cells with IL‐4, representative of the TH2 inflammatory milieu associated with DSS colitis, decreased Nrp2 levels while treatment with TNF‐a, characteristic of the TH1 response in colitis increased Nrp2 levels.ConclusionsThese observations suggest that dynamic alterations in Nrp2 under conditions of inflammation may underlie altered contractility of intestinal smooth muscle, resulting in dysmotility. Moreover, these findings suggest that Nrp2 may represent a novel therapeutic target for restoration of normal gut motility.Support or Funding InformationHarvard Digestive Diseases Center P&F Grant (RMA); R01 DK104641 (RMA, DRB, MPS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Methocinnamox: Sustained Antagonism of the Antinociceptive Effects of Morphine and Not Spiradoline in Rats
Authors: Gerak Lisa R , Latham Elizabeth A , Woods James H , Disney Alex , Husbands Stephen M , France Charles P 
Published: June 2021

The opioid epidemic continues in the US. Currently available pharmacotherapies for opioid abuse and overdose include mu opioid receptor agonists (methadone and buprenorphine) and antagonists (naltrexone and naloxone), and while each treatment can be effective, they have limitations. A novel mu opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action in blocking the abuse‐related and toxic effects of opioids, and its antagonist effects are not surmounted by subsequent administration of mu opioid receptor agonists. Consequently, MCAM might overcome the limitations of other antagonists, although other problems could emerge with long‐term blockade of mu opioid receptors (e.g. prescription opioids would be ineffective for treating pain). The current study measured antinociception using a warm water tail withdrawal procedure in rats and examined the persistence, surmountability, and selectivity of antagonism by MCAM. In 1 group of 8 rats, morphine dose‐effect curves were determined 1 day after MCAM administration and periodically thereafter, and in a different group of 8 rats, a dose‐effect curve for the kappa opioid receptor agonist spiradoline was determined 1 day after MCAM administration with morphine dose‐effect curves determined periodically thereafter. Morphine (1.78–17.8 mg/kg) and spiradoline (1–10 mg/kg) dose‐dependently increased the latency for rats to remove their tails from water maintained at 50°C. MCAM (1–10 mg/kg) attenuated the antinociceptive effects of morphine in a dose‐ and time‐dependent manner, with 10 mg/kg MCAM producing a 30‐fold rightward shift in the morphine dose‐effect curve 1 day after it was administered. For at least 37 days after administration of the largest dose of MCAM, doses of 178–560 mg/kg of morphine were needed to produce a maximal antinociceptive effect. In contrast, the spiradoline dose‐effect curve was not changed 1 day after administration of 10 mg/kg MCAM, although in the same rats the antinociceptive effects of morphine were attenuated 4 days later (i.e. 5 days after MCAM administration). Thus, MCAM produces a sustained and selective antagonism of the antinociceptive effects of mu opioid receptor agonists. Under these conditions, antagonism by MCAM was surmounted by very large doses of morphine, although it remains to be determined whether the antinociceptive effects of those doses of morphine are mediated by mu opioid receptors. Nevertheless, the selectivity of MCAM in antagonizing the effects of mu opioid receptor agonists suggests that pain could be treated through mechanisms other than mu opioid receptors in patients that are taking MCAM for opioid abuse or overdose.Support or Funding InformationSupported by NIH (R01DA005018; R01DA07315) and the Welch Foundation (AQ‐0039).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Manganese exposure augments misfolded α‐synuclein‐induced proinflammatory M1 microglial phenotype and inflammasome activation
Authors: Kondru Naveen , Manne Sireesha , Hepker Monica , Malovic Emir , Jin Huajun , Anantram Vellareddy , Kanthasamy Arthi , Kanthasamy Anumantha G 
Published: June 2021

Sustained microglial activation is a key player in the immunopathogenesis of several neurodegenerative disorders including Parkinson's disease (PD). Chronic exposure to the environmental toxicant manganese (Mn) has been implicated as a risk factor for PD. We have previously demonstrated that misfolded and aggregated human α‐synuclein (αSynPFF) induces microglial activation. Recently, we have shown that chronic Mn exposure induces neuroinflammation by impairing mitochondrial dynamics. In this study, we determined whether Mn exposure alters the specific RNA transcripts in response to the αSynPFF proteostatic challenge. We systematically characterized the transcriptome of mouse microglia in response to Mn and/or αSynPFF using RNA sequencing. Treating a mouse microglial cell model with αSynPFF significantly induced both cytokine and interferon‐g signaling pathways. In contrast, Mn treatment caused distinct changes to pathways related to cellular senescence and apoptosis. Intriguingly, co‐treatment with Mn and αSynPFF caused profound enrichment of transcripts, including IL‐6, IL‐12b, IFN‐β, IL‐1α, and IL‐1β CXCL2, CXCL3, CXCL10, CCL5‐R, and Nos2, that signify the proinflammatory M1 microglial phenotype. These targets were further validated by real‐time qRT‐PCR, immunoblotting, and immunocytochemistry. As anticipated, cotreatment with Mn and αSynPFF lead to significant upregulation of the mRNA expression of IL‐6, Nos2, IL‐1α, and IL‐1β in a synergistic manner when compared to either treatment alone. Additionally, Mn and αSynPFF co‐treatment elicited NLRP3 inflammasome activation when compared to either treatment alone or untreated control cells. Taken together, these findings identify that environmental toxicants, such as Mn, perturb microglial homeostasis, thereby leading to transformation to a pro‐inflammatory M1 microglial phenotypic state. Importantly, our study suggests that the environmental toxicant Mn can augment αSynPFF‐induced neuroinflammatory processes in microglia to accelerate neurodegeneration.Support or Funding InformationNIH grants ES026892, NS088206, and W. Eugene Linda Lloyd Endowed ChairThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
This hyperoxia mouse model using the wavelet transform analysis of flowmotion signals helps to look further into microvascular dysfunction
Authors: Rodrigues Luis Monteiro , Silva Henrique , Ferreira Hugo , Gadeau Alain‐Pierre 
Published: June 2021

The use of animal models still presents many difficulties mostly because (a) no single model accurately recreates one disease, (b) the use of so many models impair comparison of results and (c) extrapolation to human is very limited. We have been dedicated to develop the potential use of oxygen as a challenger to study microcirculatory function and regulatory mechanisms. In the present study we show how this hyperoxia mouse model helps to identify different events associated to angiogenesis, following an hindlimb ischemia procedure, and test its discriminative capacities in detecting relevant differences in microvascular function between healthy and non‐healthy mice. Animals (n=66) were divided in three groups ‐ Control (C) with 33 C57/BL6 non‐transgenic male mice, part of which (9) submitted to a hindlimb ischemia (HLI) procedure, a genetically modified diabetic group (DB) including 8 transgenic C57BLKsJ‐db/db obese diabetic mice and the corresponding internal control of 8 age‐matched C57BLKsJ‐db/+ mice, and a transgenic cardiac hypertrophy group (CH) with 9 BALB/c mice prone to develop cardiac failure and 8corresponding age‐matched internal controls. Animals were anesthetized with a ketamine ‐ xylazine mixture and perfusion data collect by Laser Doppler Flowmetry during baseline rest (Phase 1), while breathing a 100% oxygen atmosphere (Phase2) and during recovery (Phase 3) and compared. Laser Doppler (LD) imaging and flowmetry were used as assessment instruments allowing to follow up all the processes regarding the HLI recovery. The wavelet transform (WT) component's analysis was allowed to further distinct between groups. Hyperoxia by itself revealled that new vessels are not functionally equivalent to those in the non‐operated limb but that recovery, also involves this limb, suggesting a cooperation mechanism probably centrally mediated. The WT analysis suggests that cardiorespiratory, myogenic and endothelial components act as main markers. In DB group db/+ animals behave as the Control group, as expected, but WT analysis shown significant differences for myogenic and the endothelial components. Noteworthy was the increase of the sympathetic components in the db/db set, as in the NHE1‐OE animals, in both cases reported as a main component of these pathophysiological processes. In conclusion, this hyperoxia‐mouse model, including the WT component analysis of LDF signal, seems to be reproducible, robust and discriminative, providing a deeper look into these different expressions of microcirculatoru pathophysiology in different experimental conditionsSupport or Funding InformationThis work was supported by national funds from FCT I.P, within the project UID/DTP/04567/2016.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Limitations of Pulse Transit Time to Estimate Blood Pressure
Authors: Sklarsky Amanda , Garvin Nathan M , Pawelczyk James A 
Published: June 2021

INTRODUCTIONPulse transit time (PTT) is inversely related to blood pressure. Because PTT can be measured non‐invasively and with relative ease, it has received attention as a method to estimate blood pressure in mobile health applications. However, both vessel diameter and distensibility affect pulse wave velocity and PTT independent of blood pressure. In question is the utility of a simplified form of the Moens‐Korteweg equation when these factors are ignored.OBJECTIVEWe tested whether or not PTT alone would be sufficient to overcome between‐subject and within‐subject variation in vascular tone to derive estimations of blood pressure that are sufficiently accurate for health monitoring.METHODSBoth systolic BP (Finapres) and PTT (time between the R‐wave of the ECG and SBP peak) were determined in 17 healthy, college age men and women during three conditions that elicit large changes in sympathetic activity and blood pressure: static handgrip exercise (3 min at 30% maximum voluntary contraction), 2 min of post‐exercise circulatory arrest of the exercising limb, and cold nociception (3 min of hand immersion in an ice water slurry). HR, BP and PTT were recorded beat‐to‐beat and averaged in 30 second epochs. Regression analysis was used to relate SBP to PTT. Subject ID, autonomic test and the phase of testing (e.g., rest, intervention and recovery) were included as categorical predictors of BP to test the sensitivity of SBP estimation to individual variation, test specificity, and autonomic state, respectively.RESULTSCompared to resting conditions, SBP increased by an average of 47.1 ± 4.5 mmHg during SHG, 34.6 ± 4.4 mmHg during PECA, and 32.9 ± 4.1 mmHg during CPT (mean ± SE). The regression model accounted for 73% of the BP variance (P<0.0001); the SE of the intercept was 3.3% (8.5 mmHg). Autonomic state and intra‐individual variance accounted for more of the variance in the model than PTT and type of autonomic test.CONCLUSIONIndividual calibration reduces the error associated with PTT estimation of blood pressure. Changes in autonomic state can be sufficient to affect blood pressure estimations by more than 10 mmHg. This finding raises questions about simplifying the Moens‐Korteweg equation to estimate BP in mobile health applications, and suggests that autonomic state and its effect on vascular tone must be considered.Support or Funding InformationHuck Institutes of the Life SciencesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Potential Link between Glycine Metabolism, Glutathione and Diabetes
Authors: Jog Ruta , Chen Guohua , Wang Jian , Leff Todd 
Published: June 2021

Type 2 diabetes (T2D) is accompanied by alterations in amino acid metabolism. Interestingly, in both humans and rodents, circulating glycine levels are significantly reduced in obesity, glucose intolerance and T2D identifying glycine as a biomarker of T2D and raising the possibility that altered glycine metabolism plays an active role in the etiology of the disease. The goals of our study are to determine if altered glycine metabolism plays a functional role in the development of diabetes. The glycine cleavage system (GCS) is the only biochemical route that degrades glycine in humans and loss‐of‐function mutations of GCS cause hyperglycinemia. Here, we show that the expression of the rate‐limiting enzyme of GCS, Glycine Decarboxylase (GLDC), is upregulated in livers of hyperinsulinemic mouse models of diabetes, and in hepatoma cell lines insulin stimulates transcription of the GLDC gene. We identified the insulin responsive transcription factor Sterol regulatory element binding protein 1c (SREBP‐1c) as the primary mediator of this insulin stimulatory effect. We also observed that altering GLDC expression levels strongly affected intracellular glutathione levels and levels of reactive oxygen species (ROS). Our findings suggest a working model in which Srebp1c‐mediated regulation of GLDC is responsible for the reduction of glycine levels seen in insulin resistant states and may play function as a compensatory mechanism to increase glutathione production as a defense against diabetes‐induced oxidative stress.Support or Funding InformationThis work is supported by NIH R21AG050741, and the Michigan Diabetes Research and Training 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.
Lactobacillus rhamnosus GG improves skeletal muscle fatigability in a mouse model of hyperhomocysteinemia
Authors: Majumder Avisek , Singh Mahavir , George Akash K , Homme Rubens P , Metreveli Naira , Tyagi Suresh C 
Published: June 2021

Hyperhomocysteinemia (HHcy) can occur due to insufficiency in cystathionine‐β‐synthase (CBS), activity causing skeletal muscle fatigability however it is still unclear whether this effect is mediated via reduced intracellular calcium release or lower ATP production or both. Consumption of Lactobacillus rhamnosus GG (LGG) as a probiotic supplementation has been shown to improve overall exercise performance and the physical strength. Based on this understanding, we hypothesized that LGG administration might improve the muscle functions in a mouse model of HHcy via improving the calcium release from the sarcoplasmic reticulum (SR) compartment and thus inducing the ATP production in the muscle tissue. To study this we used 4 experimental groups of mice as follows: Group‐I: WT mice (C57BL/6J); Group‐II: genetically heterozygous CBS deficient mice (CBS+/−) + High Methionine Diet (HMD), Group‐III: CBS+/− + HMD + LGG (orally @ 2.5x105 CFU/d for 12 weeks), and Group‐IV: WT + LGG. Data revealed that CBS mice had significantly high tHcy levels, and lower body weight in comparison to the age‐matched WT mice, unlike the LGG treated CBS+/− mice. Whole animal muscle fatigability measurements (by swim‐test performance and grip strength test) showed that HHcy induced muscle fatigability in CBS+/− mice compared to WT mice and it was noticed that LGG supplementation was able to improve this effect. Moreover, when we measured the excitation‐contraction coupling via muscle myobath experiment, we found that the soleus muscle of CBS mice produced lower contraction force and showed longer relaxation duration as compared to the WT mice, and these effects were also seemed to be mitigated via LGG consumption. Finally, we found reduced ATP production and calcium release were also improved in the CBS mice group by LGG supplementation. In conclusion, this work highlights the therapeutic potential of LGG towards reversing the harmful metabolic effects of HHcy mediated skeletal muscle dysfunction.Support or Funding InformationNIH (HL‐74815, HL‐139047, AR071789)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Patterns of Dental Morphology and Disparity in the Eocene Herbivore Lineage Esthonyx (Mammalia, Tillodontia)
Authors: Luongo Ricki A , Cozart Hannah K , Ahrens Heather E 
Published: June 2021

The extinct clade Tillodontia includes numerous species representing relatively common, specialized herbivores of the Paleogene. The Eocene (56 – 33.8 mya) fossil record of the Bighorn Basin, Wyoming contains abundant fossils of the tillodont lineage, Esthonyx. Due to the abundance of specimens and their specialized diet, Esthonyx provides a valuable case study in phenotypic variation during climatic change over an extended temporal scale. Our objective was to quantify morphological disparity along the tooth row and assess variation between species and through time. To evaluate patterns of dental variation within Esthonyx, we used landmark‐based geometric morphometrics. Twelve landmarks representing prominent cusps and additional anatomical features in occlusal view of the lower fourth premolar and three molars were digitized for analysis. Principal components analysis indicated that the majority of shape variation, though very slight, occurred within the trigonid. Along the tooth row, p4 and m3 possessed greater disparity than m1 and m2; however, those differences were not significant. When dental loci were examined by both species and temporal unit, distinct species groupings and temporal shifts were difficult to distinguish because of the well‐conserved dental morphology within the lineage. In total, these results indicate that the lower dentition of Esthonyx is relatively conservative both along the tooth row, as well as between species and through time. The lack of evidence for morphologic change during significant climatic events may indicate low capacity for evolution and could have ultimately led to the extinction of this lineage.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Influence of Gravitational Gradients on American Alligators (Alligator Mississippiensis)
Authors: Knoche Lucas , Young Bruce , Kondrashova Tatyana 
Published: June 2021

BackgroundCranial fluids of vertebrae mammals are composed of arterial blood, venous blood, and cerebrospinal fluid that can be altered by orthostatic pressures; head‐down postures can elevate intracranial pressure and carotid/jugular luminal area while head up postures produce opposite effects. Previous studies on aquatic and terrestrial snakes showed cardiovascular variation while arboreal snakes showed little cardiovascular variation during orthostatic transitions. Little experimental work regarding orthostatic transitions has been done on alligators. Alligators are known to have unique blood flow patterns due to active regulation of blood flow. The purpose of this study is to investigate the effects of gravitational tilt on vessel luminal diameter and ICP in alligators.MethodsLive adult alligators (n = 5, 165 – 183 cm total length) were subjected to gravitational tilts between 45° head‐up to 45° head‐down in 15° increments. Short (30 s) and long (120 s) duration tilts were performed to assess barostatic reflex and ICP using ocular ultrasonography, respectively. Vascular ultrasonography was also used to assess luminal diameter of the carotid artery and jugular vein. Instantaneous heart rate was inferred from EKG recordings throughout tilts.ResultsThroughout orthostatic transitions, ocular ultrasonography revealed an increase in optic nerve sheath diameter (head down tilts) and a decrease in optic nerve sheath diameter (head up tilts). Head down tilts resulted in jugular and carotid dilation while head up tilts resulted in various jugular luminal diameters and minimal change in carotid diameter. Heart rate increased at the onset of all orthostatic transitions. There was no evidence for a barostatic response.ConclusionsOcular ultrasonography was used to non‐invasively assess intracranial pressure of reptiles. There was a linear relationship between orthostatic transitions and intracranial pressure due to redistribution of CSF. Compared to previous studies, orthostatic transitions produced similar results on vessel flow and diameter. Variations of vessel flow and diameter may be attributed to unusual patters of heart rate or blood shunts in the cephalic venous system. Increases in heart rate in all rotations may be due to a fear response. Additional studies are needed to further understand the underlying regulatory mechanisms that give rise to the alligator's heart rate and blood flow patterns.Support or Funding InformationFunding: The Influence of Gravitational Gradients on American Alligators (Alligator Mississippiensis) project has been funded by A.T. Still University's Masters in Biomedical Sciences program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.