bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Circadian Control of Endothelial Function in Mice on a High Fat Diet
Authors: Pati Paramita , Allan John Miller , Colson Jackson , Young Martin , Bailey Shannon , Pollock David M. , Gamble Karen , Pollock Jennifer S. 
Published: June 2021

Both human and animal studies demonstrate that a chronic high fat diet (HFD) leads to endothelial dysfunction. Timing of feeding and fasting is known to influence risk for cardiometabolic disease. Ad libitum chronic HFD disrupts the normal circadian rhythm in metabolism and peripheral molecular clock gene rhythm in mice. However, specific circadian‐dependent mechanisms affecting endothelial function during chronic HFD are poorly understood. Thus, we hypothesized that ad libitum chronic HFD mediates endothelial dysfunction via metabolic arrhythmia and clock gene dysfunction. To test this hypothesis, we designed experiments to measure vascular function in ad libitum and restricted feeding (RF), defined as food availability only during the active phase (ZT 12 to 0 or 7 PM to 7 AM). C57BL/6J 8 week old male mice were provided HFD for 20 weeks ad libitum and separate mice were exposed to RF from weeks 20 to 22 of chronic HFD. Endothelial‐dependent relaxation to acetylcholine in aorta (wire myography) was 1.58 ±0.34 mN in mice provided ad libitum HFD. HFD+RF significantly improved endothelial‐dependent relaxation to 5.12±1.07 mN (n=5–6, p<0.01). In contrast, aortic endothelial‐independent relaxation to the exogenous NO donor, sodium nitroprusside, was similar in ad libitum HFD and HFD+RF mice. In additional experiments, male and female Period2:Luciferase (Per2:Luc) reporter mice were given a normal diet (ND) or HFD for 20 weeks ad libitum and separate groups were subjected to RF from weeks 20 to 22 of ND or HFD. Food consumption and body weight between groups did not differ with 2 weeks of RF. Chronic HFD induced a significantly shortened circadian period of Per2 in aorta (n=4, p=0.0054) compared to ND, and 2 weeks of RF restored the aortic Per2 circadian period in mice on HFD (n=3–4, p=0.0417). Circadian period was unaffected by RF in mice on ND. Interestingly, Per2 rhythm in the perivascular adipose tissue was unaffected by HFD. These findings suggest circadian control of endothelial function during chronic HFD and that HFD induces clock gene arrhythmia specifically disrupting vascular peripheral clocks.Support or Funding InformationThis research was supported by the NIH T32 DK007545 and the UAB School of Medicine AMC21 Multi‐Investigator Grant “Circadian Disruption and Susceptibility to Target Organ Damage.”This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nighttime sodium intake is associated with cardiometabolic risk and insulin resistance in night shift nurses
Authors: Speed Joshua S. , Molzov Hylton E. , Johnson Russell L. , Becker Bryan K. , Pollock David M. , Gamble Karen L. 
Published: June 2021

Night shift work and salt intake are each independent risk factors for cardiovascular disease and possibly insulin resistance. Rhythms in renal sodium excretory function are observed regardless of the time of intake suggesting that salt ingested during the typical inactive period is retained until the following active period. Thus, we hypothesized that eating more salt at night contributes to cardiometabolic disease risk in night shift workers. Day and night shift nurses were followed for 8 days total (5 days off work and 3 days on work) keeping strict food diaries. Nutrient intake was estimated using the Nutrition Data System for Research. Fasting blood draws were taken on day 9. Interestingly, 24‐hour Na+ intake was similar between day and night shift workers throughout the observation period. Both day and night shift workers had similar Na+ intake patterns during off days. As expected, night shift workers consumed significantly more Na+ during the night while day shift workers consumed significantly more Na+ during the day on workdays. The major finding of the study is that greater work‐night Na+ intake was a significant predictor of elevated homeostatic model assessment ‐ insulin resistance (HOMA‐IR), a measure of insulin resistance, for night‐shift nurses only, even after controlling for the effect of work‐night caloric intake (F(1,5)Δ = 16.4, p < 0.05; b = 0.84). In addition, nighttime Na+ intake accounted for 71% of the variance in HOMA‐IR in night shift nurses. Finally, a significant positive correlation was observed between nighttime Na+ intake and fasting total cholesterol (p<0.05, r2=0.57) and triglycerides (p<0.05, r2=0.66) in night shift nurses. These data suggest that lowering nighttime salt intake in night shift workers may improve cardiometabolic risk and insulin resistance in this population with a high prevalence of cardiovascular disease.Support or Funding InformationThis research was supported by NIH grant K99HL127178 to JSS, the UAB Center for Clinical and Translational Science (CCTS) Grant Number ULITR000165 to KLG, the UAB Department of Vision Sciences, the UAB Comprehensive Diabetes Center, and the UAB Department of Psychiatry Office of Clinical ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Drowning a frog respiratory oscillator in a wash of network excitability
Authors: Wilson Richard JA. , Baghdadwala Mufaddal 
Published: June 2021

To be part of a respiratory rhythm generating circuit, a brainstem nuclei must (1) have phasic activity timed to the rhythm (correlation), (2) be able to speed the rhythm when excited (sufficiency), and (3) be able to slow the rhythm or terminate it when inhibited (necessity). A discrete brainstem nucleus passing these tests is currently considered a critical site for respiratory rhythm generation (an oscillator) if the nuclei continues to be rhythmic when physically isolated.Compelling and accumulating evidence in support of oscillators has been found in many vertebrates including lampreys, bullfrogs, turtles, birds, mice and rats. In bullfrogs and rodents, three putative oscillators have been discovered: the lung power stroke, lung priming and buccal oscillators in frogs; and in mammals the para Facial Respiratory Group (pFRG), Post‐Inspiratory Complex (PICO), and the PreBötzinger Complex (PreBötC). As the buccal oscillator in frogs and the PreBötC in mammals are located in the same brainstem rhombomere, r7, they may be homologous. Identification of multiple ‐‐ possibly homomogous ‐‐ oscillators in different species has led to the Oscillator Hypothesis which, in its strongest form, posits that respiratory rhythm is produced solely by brainstem oscillators and phase of motor bursts is determine by their interaction.However, almost complete (90%) destruction of the putative PreBötC in goats over several days was insufficient to terminate breathing. One explanations for this observation is a network architecture in which respiratory oscillators are no more than isolatable units in a much larger rhythmogenic network. To test if this is the case in frogs, we (a) located the frog buccal oscillator using necessity and sufficiency tests in an isolated hemisected brainstem preparation; (b) increased the excitability of the hemisection which increases the frequency and amplitude of the buccal motor pattern; and (c) again tested for necessity. We found that with network excitation, the necessity of the buccal oscillator disappeared, replaced by distributed rhythmogenesis in the surrounding premotor network.These data suggest that the Oscillator Hypothesis may need to be revised in frogs and possibly other vertebrates; the existence of the buccal oscillator as a discrete site of rhythm generation appears to be state dependent and may only be demonstrable in some conditions.Support or Funding InformationThis work was supported by NSERCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Viral‐genetic Mapping of Neural Circuit Organization of Nociceptive Neurons in the Thalamus
Authors: Umorin Mikhail 
Published: June 2021

There is a critical need to determine the location, connections and neurochemical identities of neurons participating in the transmission and modulation of pain in the CNS so that these circuits can be precisely targeted for pain intervention. Without such knowledge the development of effective, low side‐effect pain treatments will be difficult. In this talk I will report our progress using recent technological advancements to determine detailed neural activation patterns and synaptic circuit organization of neurons related to pain sensation and modulation in the thalamus. We have identified and visualized thalamic nociceptive neurons activated by chronic pain, using a strategy of genetic capture of active neurons on the basis of activity dependent c‐fos gene expression. Specifically, pain‐activated neurons are captured using Fos‐CreER mice with tamoxifen‐dependent recombinase CreERT2 under the promoter of the immediate early gene c‐fos. These mice are crossed with Cre reporter Ai9 mice to express tdTomato fluorescent proteins. A noxious stimulus is evoked by injection of complete Freund's adjuvant (CFA) into the hind paw; only neurons that are functionally active within a limited time window of 4‐OHT administration are genetically labeled. Then we build on this technical development to combine the Fos‐CreER based strategy with new viral tracing of circuit connections to nociceptive neurons in the ventral posterolateral (VPL) nucleus. Genetically modified rabies is used to trace global direct synaptic connections to pain activated neurons in VPL. These studies allow us to map molecular and neurochemical identities (e.g., excitatory versus inhibitory) of whole brain‐wide presynaptic neurons that are directly connected to thalamic nociceptive neurons. We foresee that this new research can address the critical barrier in the field and will advance our understanding of thalamic nociceptive neuron circuits and pain modulating processes.Support or Funding InformationStart‐up funds from Texas A&M UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Expanding the Horizon of Recombination Repair in Mycobacteria: Identification and Characterization of Novel Proteins
Authors: Singh Amandeep 
Published: June 2021

In prokaryotes, repair by homologous recombination provides a major means to reinstate the genetic information lost in DNA damage. Recent research on recombination repair in mycobacteria has led to significant revision of the understanding of this system. A comparative analysis of the system, carried out in 43 mycobacterial genomes, lead to identification of novel proteins. To substantiate the predictions, biochemical and structural investigations on probable roles of two proteins, namely, SSBb and RecGwed, were carried out. The structure of M. smegmatis SSBb (MsSSBb), was determined at 2.5 □ resolution. Solution studies indicate that the canonical SSB (MsSSBa) is more stable towards thermal and chemical denaturation than MsSSBb. Also, MsSSBa has a two‐fold higher DNA binding affinity than MsSSBb. A direct physical interaction between MsSSBb and MsRecA was established, suggesting a role during recombination. The expression levels of ssbB gene increased by approximately two‐ and sevenfold in UV and hypoxic stress, respectively, while concurrently the levels of ssbA expression declined. These results indicate a role of MsSSBb in recombination repair during stress. MsRecGwed binds a variety of branched DNA structures in vitro, while it does not bind ss‐ or dsDNA. The up‐regulation of recGwed during UV damage, and down‐regulation during H2O2/MMS stress, in M. smegmatis indicated a possible role in post‐replicative recombination events that proceed though branched DNA intermediates. Taken together, this work augments the understanding of the repertoire of proteins known to be involved in DNA repair pathways in mycobacteria.Support or Funding InformationDepartment of Biotechnology, IndiaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
REVERSAL OF PERIPHERAL AND CNS MEDIATED A1 ADENOSINE RECEPTOR HYPOTENSION
Authors: Laughlin Bernard W , Baily Isaac , Tagaban Sierra , Drew Kelly 
Published: June 2021

IntroductionA1 adenosine receptor (A1AR) agonists such as N6‐cyclohexyladenosine (CHA) are known for their neuroprotective and anti‐convulsant properties and for modulation of thermogenesis. We have demonstrated a neuroprotective, thermolytic effect following systemic administration of CHA combined with the peripherally acting adenosine receptor antagonist, 8‐(p‐sulfophenyl)theophylline (8‐SPT). However, A1AR‐mediated cardiovascular side effects limit the translation of this drug class, and clear understanding of the effects of this drug combination on hypotension and bradycardia are lacking. CHA delivered into the CNS increases para‐sympathetic influence on the heart to produce bradycardia similar to what is seen during onset of hibernation. Systemic administration of A1AR agonist produces bradycardia via direct negative chronotropic and inotropic effects. Evidence also supports other mechanisms of A1AR agonist modulation of blood pressure including indirect activation of peripheral β2 adrenergic receptors and central H1 receptors.HypothesisWe test the hypothesis that CHA lowers blood pressure via increased para‐sympathetic tone to the heart and direct effects on the heart.MethodsRats were implanted with telemetry transmitters to monitor Tb, heart rate (HR), mean arterial pressure (MAP) and administered drugs IP as follows, CHA (1.0mg/kg), 8‐SPT (25.0mg/kg), Atropine (1.0mg/kg), diphenhydramine (4.0mg/kg), or pro‐pranolol (4.0mg/kg), 15min prior to CHA. Cage surface temperature was initially cooled to 4°C and adjusted to maintain Tb at 32°C.Results8‐SPT with atropine reversed hypotension. 8‐SPT alone increased rate of resolution in MAP to baseline value. Pre‐treatment with propranolol, atropine, or diphenhydramine alone did not influence MAP. Diphenhydramine with 8‐SPT reduced the magnitude of hypotension (− 24% average one hour baseline change after CHA) compared to pre‐treatment with 8‐SPT (− 36%) alone.ConclusionsOur results suggest that A1AR induced hypotension is mediated through increased parasympathetic tone to the heart in addition to direct effect on the heart. Histamine receptor activation may also play a role, although the resolution of MAP seen may have been due to the anticholinergic effect of diphenhydramine instead of H1 receptor antagonism. Reversing hypotension necessitates addressing both mechanism with atropine and 8‐SPTSupport or Funding InformationNIH U54GM115371, NIH R15 NS070779, NIH: RL5GM118900, TL4 GM 18992, 1UL1GN118991This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Calmodulin Binds to and Inhibits H‐Ras Activation of PI3K: A Single Molecule Study
Authors: Buckles Thomas , Ziemba Brian , Masson Glenn , Williams Roger , Falke Joseph 
Published: June 2021

The lipid‐anchored GTPase Ras is well known for its role in oncogenesis, with around 25% of human tumors showing mutations in a Ras family member. One of the best characterized Ras effectors is the highly oncogenic lipid kinase phosphatidylinositol 3‐kinase (PI3K). PI3K phosphorylates the constitutive plasma membrane lipid PIP2, yielding the vital second messenger lipid PIP3. This PIP3 signal regulates many cell processes including migration and growth. Calmodulin also activates PI3K by tightly binding MARCKS, a PIP2 sequestering protein, freeing the lipid. The enhanced free PIP2 population serves as additional substrate for PI3K, increasing its activity. The findings presented here reveal that surprisingly, Ras activation of PI3K is blocked by the presence of calmodulin, with important implications for PIP3 signaling. We are observing these mechanisms using single molecule TIRF microscopy to probe the interactions and activities of single proteins on a supported target membrane surface. Preliminary evidence monitoring PI3K binding and lipid kinase activity at the single molecule level reveals that biologically relevant concentrations of calmodulin strongly inhibit Ras activation of PI3K. These results imply a new and additional level of control for an important and oncogenic signaling pathway.Support or Funding InformationFunding for this work was provided by the National Institutes of Health ( R01 GM063235 to J.J.F.), the Medical Research Council ( MC U105184308 to R.L.W.), the AstraZeneca/LMB Blue Skies Initiative ( MC A024‐5PF9G to R.L.W.), and St. Catharine's College (G.R.M.).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 Psycho ‐ Neuro – Immuno Axis of Cancer
Authors: Zillow Anna L , Tulp Orien L , Einstein George P 
Published: June 2021

The bio‐psycho‐social model of medicine suggests that the mind affects the brain, and which affects the body. In this manner we suggest a psycho‐neuro‐immuno axis of disease that may be found in the relationship between emotional stress and cancer.Psychological tension causes a dysregulation of the hormonal stress response resulting in an increase in the circulating levels of the stress hormone cortisol. The physiological mechanism follows that emotional stress causes the brain's hypothalamus to secrete corticotropin releasing hormone. This hormone increases the amount of adrenocorticotropin hormone flowing from the anterior pituitary gland, which ultimately magnifies the amount of cortisol released from the adrenal gland.Cortisol increase has been shown to rapidly decrease the marginalization and exit of the immunological cells known as neutrophils from the blood into tissues(1). Marginalization is an early‐phase inflammatory response during which cells move from the axial circulation in the center of the blood flow to the periphery of the cross‐sectional lumen. Therefore, despite the increased number of neutrophils, the decreased tissue deployment may have the effect of blunting the immune response. This proposed immune‐incompetence in and of itself may predispose the body to cancer via the upregulation of inflammatory markers and the simultaneous down‐regulation of anti‐inflammatory cytokines. Specifically, the multiplication of pro‐inflammatory cytokines, such as IL‐6 and tumor necrosis factor (2) are likely candidates for involvement in the carcinogenic process.Moreover, the mere abundance of neutrophils, marginalized or not, may be correlated with increased cancer risk (3). Of course, such findings don't verify a direct causal relationship between emotional stress and cancer, since other mediating variables might influence both variables. However, if with future studies, the prospective nature of the data prove consistent and the relationship holds even when other standard prognostic variables are controlled may suggest, we would consider this more convincing evidence.Septon et al assert interestingly that “associations of cortisol profiles with psychological stress suggest that rhythm dysregulation may be a marker or mediator of psychosocial effects on cancer progression” (4). Accordingly, we propose that this statement is instructive in our making the assertion that our Psycho ‐ Neuro – Immuno axis operates on a feedback loop. That is to say psychology affects neurology affects immunology and that immunological pathology can cause even more psychological stress – thereby starting the cycle all over again.Support or Funding InformationSupportde by Institutional Resources of the University of Science Arts & Technology, Montserrat, and the Einstein Medical Institute.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 Platelet Syntaxins in Endocytosis
Authors: Tichacek Laura , Whiteheart Sidney W. 
Published: June 2021

In healthy patients, platelets serve as the first line of defense in forming a hemostatic plug when damage to the vasculature is detected. Hemostasis is a balancing act, however, where hyperactive platelets can cause unwanted blood clots which may lead to heart attack or stroke, while hypoactive platelets can cause excessive bleeding. For this reason, examining the proteins critical to platelet function and understanding the bleeding phenotype when these proteins are knocked out can provide potential drug targets and help explain and diagnose platelet disorders. In addition to their role in hemostasis, platelets act as vascular “sentries,” patrolling the vasculature for damage and endocytosing small molecules and viral particles they encounter [1]. While the exact purpose of platelet endocytosis of viral particles is unknown, studies have shown that AIDS patients have increased chances of experiencing a thrombotic event [2], which implies that the uptake of the HIV virus by platelets could be implicated in this disparity, perhaps by altering platelet function. Platelets contain SNARE (soluble N‐ethylmaleimide sensitive fusion protein attachment protein receptor) proteins which are known to control trafficking in most cells [3] but this trafficking role has not been established in platelets, making them an attractive target of study. To this end, we created Syntaxin 2, Syntaxin 4 (two t‐SNARE proteins) and double knock out mice to study the endocytic capabilities of their platelets. Platelets from the Syntaxin 4 and double knock out mice showed a defect in the uptake of total fibrinogen while Syntaxin 4 knockouts did not show a defect in uptake of transferrin.Support or Funding InformationThis work is supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL56652 and HL138179), and a Veterans Affairs Merit Award to SWW.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.