bluuebunny/crossref_metadata_2025_split huggingface dataset:
Situs Inversus Totalis in a 96‐Year‐Old Female Cadaver: Genetic Insights
Authors: Jenkins Mia , Frolov Andrey , Tan Yun , Daly Daniel , Lawson Craig , Martin John 
Published: June 2021

BackgroundSitus inversus totalis is a complete reversal of thoracic and abdominal organs. Since only 25% of individuals with situs inversus have primary ciliary dyskinesia (PCD), which is a genetically heterogeneous disorder affecting motile cilia and is thought to be one of the underlining mechanisms of situs inversus, the majority of the latter cases still await their mechanistic elucidation. The present study reports the complete reversal of internal organs in a female cadaver 96 years of age and uses state‐of‐the‐art Next Generation Sequencing (NGS) to detect novel genetic mutations associated with situs inversus totalis.ResultsOur examination of the individual's body revealed that the visceral organs of the abdomen and thorax were mirror‐imaged to normal anatomy. The apex of the heart was directed to the right with a trilobed left lung and bilobed right lung. The liver was situated on the left side of the body, while the spleen and stomach were right sided. Several abdominal vasculature anomalies were also identified. In particular, the common hepatic artery branches from the superior mesenteric artery and the cystic artery branches from the right hepatic artery. There was also a common trunk that gives off the left gastric artery and an accessory right hepatic artery. In order to gain new insights into the molecular mechanisms that govern determination of the left/right asymmetry during the internal organ development, the genetic screen was performed using DNA extracted from the cadaveric tissue and the exome sequencing on the Illumina NGS platform.ConclusionThe present case can be described as situs inversus totalis which is accompanied by abnormal development of abdominal vasculature. The respective genetic analysis could point to a novel and additional to PCD mechanism(s) responsible for the aberrant visceral organ patterning and vascular development in humans.Support or Funding InformationThis study was supported by the Center for Anatomical Science and Education, Department of Surgery, Saint Louis University School of Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in Heart Rate Response to Isometric Handgrip Exercise with Concurrent Contralateral Forearm Somatosensory Stimulation
Authors: Jacobs Kaitlyn , Woerhle Emilie , Klassen Stephen , Smith Sydney , Barker Andrea , Knestch Rachel , Shoemaker J. Kevin 
Published: June 2021

BackgroundPharmacological evidence indicates that baseline cardiovagal mechanisms determine the rapid heart rate (HR) response to the onset of moderate intensity isometric handgrip (IHG) exercise. The HR response at exercise onset expresses sex differences, being less in females. Further, somatosensory nerve stimulation (STIM) appears to affect baseline cardiovagal control in some supine participants.ObjectiveThis study explored the effect of STIM on HR and heart rate variability (HRV) during short‐duration moderate‐intensity IHG in supine healthy adults and explored whether this effect expresses sex differences.ParticipantsTwenty‐four young healthy individuals aged 23 ± 1.9 years (18 females (F): 165 ± 7.4cm, 63 ± 13kg, BMI 23 ± 2kg/m2; 6 males (M): 179 ± 2.2cm, 79 ± 11kg, BMI 25 ± 3.3kg/m2).MethodsParticipants performed six isometric handgrips with their right hand at 30 to 40% of their maximal grip strength, each lasting 20 to 30 seconds and separated by one minute of rest. Three of these IHG contractions were performed during simultaneous administration of sub‐motor STIM provided by transcutaneous electrical nerve stimulation (TENS; 100 Hz, 50 μs) on the medial contralateral forearm through anesthetized skin for the duration of the handgrip. A 3‐lead ECG provided R‐R interval data. Systolic (SBP) and diastolic blood pressure (DBP) were monitored, as well as, heart rate (HR), root mean square of successive differences in R‐R intervals (RMSSD) as a measure of HRV, and respiration. Data were analysed using two‐factor ANOVA with Bonferroni correction, and independent t‐tests.ResultsThe ΔHR from baseline to IHG without STIM was greater in males compared to females (12 ± 6bpm versus 6 ± 6bpm, respectively; d = 1.00). No differences in ΔHR were detected for either sex when STIM was added to the IHG. Of the 18 F participants, 4 provided a minimal HR response (ΔHR > 4bpm) to the IHG without STIM (F1: 77 to 79bpm; F2: 69 to 70 bpm; F3: 50 to 50bpm; F4: 62 to 62 bpm) which resolved in 3 of the 4 F participants with application of STIM (F1:73 to 83bpm; F3: 45 to 59bpm; F4: 54 to 60bpm). Further, no statistically significant differences were observed in ΔRMSSD from baseline to IHG without STIM (p = 0.0321; M: 77 ± 68ms to 30 ± 145ms; F: 74 ± 38ms to 54 ± 39ms) and with STIM (p = 0.953; M: −28 ± 61ms and F: −30 ± 21ms).ConclusionOur preliminary findings suggest that, in supine individuals, sex differences exist in the HR response at the exercise onset but these effects are not modified by concurrent sub‐motor somatosensory nerve stimulation.Support or Funding InformationSupported by Natural Science and Engineering Research Council of CanadaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
GABAergic Contribution to the Muscle Mechanoreflex‐Mediated Heart Rate Responses at the Onset of Exercise in Humans
Authors: Teixeira André L. , Ramos Plinio S. , Samora Milena , Sabino‐Carvalho Jeann L. , Ricardo Djalma R. , Colombari Eduardo , Vianna Lauro C. 
Published: June 2021

It is well stablished that the cardiovascular response to exercise is governed by both central and peripheral mechanisms. However the possible neurotransmitters involved in the autonomic responses during exercise are not fully understood. During exercise, Potts et al. (Neuroscience 2003;119:201–14) showed that electrically evoked muscular contraction inhibits arterial baroreceptors signaling within the nucleus of the tractus solitaries (NTS) via activation of GABAergic receptors in rats, suggesting that skeletal muscle afferents are a potential source synaptic drive to GABAergic neurons within the NTS. However, the extent to which these findings can be extrapolated to humans remains unclear. We reasoned that the GABAergic mechanisms involved in the heart rate (HR) responses at the onset of dynamic exercise is primarily mediated by muscle mechanoreceptors afferents. Therefore, in this study we sought to determine if central GABA mechanisms are involved in the muscle mechanoreflex‐mediated HR responses at the onset of exercise in humans. Twenty‐eight healthy subjects (14 men) aged between 18 to 35 years randomly performed three bouts of 5‐s of passive and active cycling under placebo and following oral administration of diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. Beat‐to‐beat HR (electrocardiography) and arterial blood pressure (BP ‐ finger photopletysmography) were continuously measured. Electromyography of vastus lateralis was obtained to confirm no electrical activity during passive trials. HR increased from rest under placebo and further increased following administration of diazepam in both passive (Δ12 ± 1 beats min−1 vs. Δ17 ± 1 beats min−1, P < 0.01) and active (Δ14 ± 1 beats min−1 vs. Δ18 ± 1 beats min−1, P < 0.01) cycling. Arterial BP increased from rest similarly during all conditions. Importantly, no sex‐related differences were found in any variables during all experiments. These findings demonstrate for the first time that the central GABAergic mechanisms significantly contribute to the muscle mechanoreflex‐mediated cardiac vagal withdrawal at the onset of exercise in humans.Support or Funding InformationBrazilian National Council of Scientific and Technological Development (CNPq)Foundation for Research Support of Federal District (FAPDF)Brazilian Federal Agency for Support and Evaluation of Graduate Education (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.
Beta Adrenergic Induced Pulmonary Arterial Vasodilation Following Long Term Hypoxia in Fetal and Adult Sheep
Authors: Vazquez Ashley , Amen Marvin , Painter Brandon , Jalota Raveena , Blood Quinton , Zhang Lubo , Wilson Sean M. 
Published: June 2021

Long term high altitude exposure is known to cause tissue hypoxia and exposure of fetuses as well as adults to rarefied environments increases morbidity and mortality. In particular, hypoxia can cause developmental abnormalities in the fetal pulmonary vasculature and contribute to pulmonary arterial hypertension in the adult. β2 adrenergic receptor (β‐AR) agonists are a major treatment for asthma, however far less is known about their role in pulmonary arterial function. Even still, previous evidence illustrates that β‐AR stimulation holds promise for the treatment of pulmonary arterial hypertension. Other evidence illustrates that β‐AR stimulation modulates the activity of Ca2+‐activated K+ channels (KCa), which are important mediators of pulmonary vasorelaxation. Dysregulation of KCa may contribute to chronic hypoxia induced pulmonary hypertension and β‐AR signaling may be involved in the process. In these studies we tested the hypothesis that β‐AR ‐ mediated pulmonary arterial vasodilation may be preserved following long term high altitude hypoxia due to dependency on KCa channels. This hypothesis was addressed in isolated pulmonary arteries from adult or fetal sheep that gestated at 700 meters (normoxic) or 3,801 meters for 110+ days (hypoxic). Myography was performed on pulmonary arterial rings to evaluate the vasorelaxation in response to the β‐AR agonist isoproterenol (ISO) and the methylxanthine phosphodiesterase inhibitor, IBMX. ISO‐mediated relaxation was preserved following hypoxia in fetal sheep and relaxation was greater in arteries from adult hypoxic animals relative to fetuses. Inhibition of BKCa with TEA blunted ISO‐mediated vasorelaxation in fetal normoxic and adult hypoxic arteries. IBMX caused a dose dependent relaxation in arteries from all groups and TEA did not influence this effect. Overall, these studies provide evidence that β‐AR stimulated pathways cause pulmonary arterial vasodilation, but with varying reliance on BKCa activation. Targeting β‐AR signaling pathways could therefore be therapeutically significant and functional alterations in the pathways may contribute to the development of disease.Support or Funding InformationThis material is based upon work supported by NIH HD‐069746, P01HD083132, and P20MD006988. MA and BP were Walter E Macpherson Medical Student Summer Research Fellows while AV was an Undergraduate Summer Research Fellow through the Center for Health Disparities and Molecular Mechanisms at Loma Linda University.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 Long Non‐Coding RNA XIST Is Decreased in Lungs and Plasma Exosomes of Sickle Cell Mice and in Hemin‐Treated Human Pulmonary Artery Endothelial Cells
Authors: Kang Bum‐Yong , Chang Sarah S. , Bedi Brahmchetna , Sutliff Roy L. , Archer David R. , Hart C. Michael , Sadikot Ruxana T. 
Published: June 2021

RationalePulmonaryhypertension (PH), a serious complication of sicklecell disease (SCD), causes significant morbidity andmortality. The release ofhemoglobin and free heme during hemolysis triggers endothelial dysfunction andcontributes to PH pathogenesis. Emerging evidence indicates that longnon‐coding RNAs (lncRNAs) play a pivotal role in cellular proliferation,differentiation, and apoptosis. Circulating exosomes, which are nano‐sized extracellular vesicles, contain lncRNAs and play an important role in intercellular communication. However, the role of lncRNAs released from lungs and plasmaexosomes in SCD‐PH pathogenesis has not been defined. We hypothesized that lncRNAs are differentially expressed in SSmouse lungs and plasma exosomes and in hemin‐treated human pulmonary artery endothelialcells (HPAECs).Methods and ResultslncRNAs were isolated from lungs and plasma exosomes of sicklecell (SS) mice and littermate control (AA) mice at age 15–17 weeks. Isolated plasma exosomes were characterized forlevels of exosomal markers (CD9, CD45, and CD63), following which exosomes andlung samples were subjected to determine theexpression profiles of 90 lncRNAs using the LncProfiler™ lncRNA qPCR array(System Bioscienes). 5 lncRNAs were increased and10 lncRNAs were decreased in the lungs and plasma exosomes of SS mice compared to AA mice. One of thelncRNAs found to be decreased in SS samples was X‐inactivespecific transcript (XIST). To further examinewhether hemin reduces lncRNA XIST expression, HPAECs were treated with DMSO or hemin (5 uM) for 72 hours. XIST expression was decreased in hemin‐treatedHPAECs. Hemin also stimulated dose (0–10 μM)− and time (0–72hours)‐dependent increases in HPAEC monocyteadhesion and proliferation (BrdU assays). Because PPAR gamma (PPARg) levels were reduced in the lungs of SS mice,and pharmacological PPARg activation attenuated SCD‐PH, we examined the impactof PPARg activation on XIST levels in SS mouse lungs and found that PPARgactivation attenuates reductions in XIST expression.ConclusionsTheseresults suggest that sickle cell disease can impact lncRNAs and these effectsmay be reversed by treatment with PPARg agonists. Therefore, characterizationof lncRNAs are impacted in SCD may provide new insights into SCD pulmonaryvascular dysfunction and PH pathogenesis and identify novel targets fortherapeutic intervention.Support or Funding InformationSupported by NIH HL102167 (RLS and CMH) and NIH HL133053‐01A1 (BYK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increasing or decreasing the excitability of V2a neurons activates accessory respiratory muscles
Authors: Jensen Victoria N. , Seedle Kari , Turner Sarah M. , Crone Steven A. 
Published: June 2021

Accessory respiratory muscles (ARMs) can be recruited to maintain respiration when the diaphragm is impaired or weakened, such as patients with Amyotrophic Lateral Sclerosis (ALS) or spinal cord injury. We chronically record mouse diaphragm electromyography (EMG), ARM EMG, and whole body plethysmography to assess the effect of activating and silencing V2a neurons with DREADDs on respiratory muscle activity and ventilation. Increasing the excitability of glutamatergic V2a neurons in the brainstem and/or the spinal cord recruits ARMs and enhances ventilation. Interestingly, silencing V2a neurons also activates ARMs. We hypothesize that V2a neurons participate in both excitatory and inhibitory pathways controlling activation of ARMs for breathing.Support or Funding InformationUniversity of Cincinnati T32 Training Grant 2016–2017This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Preliminary Phenotypic Cluster Analysis of Cardiorespiratory Modulated Neuronal Discharge Patterns with Dynamic Visualizations
Authors: MORRIS KENDALL F. , O'Connor Russell , Segers Lauren S. , Nuding Sarah C. , Horton Kofi‐Kermit , Alencar P. Ashley , Bolser Donald C. , Dick Thomas E. , Baekey David M. , Lindsey Bruce G. , Shuman H. Dale 
Published: June 2021

Multi‐dimensional cluster analysis has been applied successfully to many taxonomy problems. Building on previous work (see Carroll et al., 2013 & Zuperku et al., 2015), we have developed a quantitative, reproducible clustering classification of respiratory neuron phenotypes based upon activity. We displayed the results with a multi‐factorial visualization tool.We curated 100‐bin, normalized, cycle triggered histograms of spike trains with significant respiratory modulation (n=573 from a library of 1,373), recorded in lateral respiratory column (ventral respiratory group, pre‐Bötzinger, Bötzinger), pons, raphé, and dorsal lateral medulla. Initial analysis by Ward clustering with Cartesian distance in 100‐space differentiated three groups: predominantly inspiratory, predominantly expiratory and low respiratory modulation.Subsequent application of the same clustering paradigm to each of these 3 groups yielded a preliminary set of 24 archetypes, the averaged histograms of the elements of each cluster. We used those archetypes as clustering centroids on naïve recordings of 229 spike trains; all were clustered, with 20 of the archetypes. A 3‐D brainstem atlas displayed neuronal firing rates during periods of control and/or stimulated activity such as chemoreception, cough, swallow and vagotomy; cell activity was colored by type (cluster), illuminated in proportion to firing rate, and could be displayed in stereo or as a side‐by‐side or differential comparisons of stimulated vs. control activity.The data do not support a continuum of phenotypes based on discharge identity but instead are consistent with definable phenotypes.Support or Funding InformationOT2OD023854, HL109025This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lethal Avian Influenza A (H5N1) Virus Infects Pontomedullary Nuclei Containing Chemo‐sensitive Neurons to Induce Depressed Hypercapnic Ventilatory Response (dHCVR) in Mice
Authors: Zhuang Jianguo , Ye Chunyan , Xu Fadi 
Published: June 2021

Highly pathogenic H5N1 (HK483) virus is neurotropic and lethal (~60% mortality in patients) mainly due to respiratory failure, but the relevant mechanisms are not fully understood. Our previous studies have shown that HK483 viral infection produces dHCVR 2–3 days and death 7 days post‐infection (dpi) in mice. This study aimed to determine the development of dHCVR from 2 – 6 dpi and the viral impact (6 dpi) on pontomedullary respiratory‐related neurons that potentially possess CO2‐chemoreception in the nucleus of solitary tract (NTS), the retrotrapzoid nucleus (RTN), raphe (ROb, RPa, and RMg), C1/2, A1 areas, and locus coeruleus (LC). Body temperature, weight, ventilation, and HCVR (7% CO2 for 5 min) were measured at 0, 2, 4, and 6 dpi in Ctrl and HK483 viral infected awake mice followed by collecting arterial blood after anesthesia. Subsequently, the brainstem sections were immunohistochemically processed to detect the nucleoprotein of H5N1 influenza A (NP) coupled with immunoreactivity (IR) of SP, NK1R, tyrosine hydroxylase (TH, a marker of catecholaminergic neuron), or tryptophan hydroxylase (TPH, a marker of serotonergic neuron). HK483, compared to Ctrl, mice showed gradually aggravated body weight loss, hypothermia, and dHCVR. HK483 viral infection strikingly enhanced SP‐IR expression in the NTS. Among the neurons expressing: 1) NK1R in the NTS and RTN; 2) TH‐IR in C1/2, A1 areas, the NTS, and the LC; and 3) TPH in raphe, co‐labeling with NP was found up to 50%, 30%, and <10%, respectively. Moreover, the NK1R and TPH‐IR in these regions were significantly lower in HK384 than Ctrl mice. We conclude that HK483 virus is capable of invading the pontomedullary respiratory nuclei, particularly those neurons expressing NK1R or TPH to suppress their expressions, which likely contributes to dHCVR and the subsequent death.Support or Funding InformationHL119683This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fractones and basement membranes for the mathematical modeling of tissue growth and regeneration.
Authors: Fronville Alexandra , Ballet Pascal , Beros Achilles , Chyba Monique , Mercier Frederic 
Published: June 2021

Biological growth can be defined as a set of processes that cause tissues or organs to develop and maintain. When simulating this growth in DynCell, a C++ virtual reality simulator, questions arise about how the shape is controlled and maintained in a stable state whilst cells renew. In order to understand tissue growth, we elaborated a mathematical model based on viability theory and morphological analysis. In our model, each cell is defined as a control system. Moreover, each cell includes the same genetic information, which can lead to differentiated cell types. Cells interact with each other during the growth process and take decisions on their fate (cell division, differentiation, migration or apoptosis) according to the genetic information, the position of the other cells and the micro‐environmental cues provided by the extra cellular matrix. From a mathematical point of view, cellular division implies a multi‐valued dynamic. To formalize this dynamic, we have used mutational equations instead of differential equations usually utilized for classic dynamical systems. Cells successively divide according to a controlled topology, and ultimately generate the shape of the organism. This shape reaches a morphological equilibrium, up to a time horizon. To attain a defined topology, it is essential to control cell polarization and cell division. In biological organisms, this control is performed by fractones, extra‐cellular matrix structures anchored near the surface of the cells. Fractones contains heparan sulfate proteoglycans (HSPG) that bind, concentrate and dispatch growth factors to the target cells to ultimatly control cell proliferation and differentiation. Fractones constantly change their HSPG motives to bind different growth factors that either promote or inhibit stem cell proliferation and differentiation. The role of fractones as captors or activators of growth factors ultimately permits biological construction in a much finer mode than with simple reaction‐diffusion models. Using our fractone model, it is possible to generate and renew shapes throughout the tissue except at the interface of tissue layers. Indeed, we have found that our model is not sufficient for cells bordering tissue layers. Therefore, we hypothesize that basement membranes, i.e. specialized coats of extracellular matrix, chemically similar to fractones, become the leading components that control cell proliferation and the layout interface between organized tissues. In conclusion, our model strongly suggests that basement membranes and fractones are essential for the proper control of development and maintenance of biological organisms.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.