bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complex allosteric effects of amiodarone at M1 muscarinic receptors: signal sharpening
Authors: Stahl Edward , Elmslie Gwendolynne , Ellis John 
Published: June 2021

We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. At the M3 and M5 subtypes, the major effect of amiodarone is to enhance the maximal degree of response elicited by acetylcholine and other agonists, without significantly altering the potency of the agonist. The initial screening of the M1 subtype, at typical (EC20‐EC50) concentrations of agonist, revealed no effect of amiodarone. In the present study, we demonstrate that amiodarone does in fact enhance the maximal agonist effect at M1, but that a concomitant decrease in agonist potency obscures the effect at the screening concentrations of agonist that were previously used. These effects, at all three subtypes, are well‐explained as an interaction between the parameters for binding cooperativity and activation cooperativity in Hall's allosteric two‐state model (Mol Pharmacol 58:1412).Furthermore, the effects of amiodarone on M1 receptor signaling illustrate the possibility of a new form of receptor modulation; we have named this modulation “signal sharpening”. The effect of signal sharpening occurs in the sense that responses above a certain magnitude are enhanced, while responses below that magnitude are reduced. We speculate that one way this type of modulation may be useful would be in regulating the contribution of transmitter spillover to extra‐synaptic signaling.[Supported by PHS R01 05214]
The Role of Cardiorespiratory Fitness and Central Arterial Pressure in Age‐Related Reduction in Brain Volume
Authors: Tarumi Takashi , Ayaz Muhammad , Parker Rosemary , Tinajero Cynthia , Zhang Rong 
Published: June 2021

Emerging evidence suggests that vascular risk factors accelerate but physical activity attenuates age‐related decline in cognitive function which may be related to changes in brain volume.PurposeTo determine whether maximal aerobic capacity, central blood pressure and arterial stiffness moderate age‐related changes in brain volume.Methods18 young (30±1 years), 27 middle‐aged (51±1 years), and 17 older (67±1 years) adults underwent measurements of cognitive function, maximal oxygen consumption (VO2max), central blood pressure, arterial stiffness, and brain MRI.ResultsAge was significantly correlated with lower levels of memory recall (r=−0.43) and VO2max (r=−0.72) and higher levels of central systolic and pulse pressures (both r=0.57) and arterial stiffness (r=0.62) (all P<0.05). Gray matter volume of neocortex, subcortex, and cerebellum, were negatively correlated with age (r=−0.40~−0.76, all P<0.05). In middle‐aged and older subjects, multiple regression analysis adjusted for age and sex revealed that VO2max is positively associated with parietal cortical thickness (β=0.50, P<0.05) and that central systolic blood pressure is negatively associated with subcortical gray matter volume (β=−0.31, P<0.05).ConclusionGreater maximal aerobic capacity and lower central systolic blood pressure may attenuate age‐related reductions in brain tissue volume.
Intragastric ketone ester administration prevents CNS oxygen toxicity (CNS‐OT) and modulates tidal volume and respiratory frequency in rats
Authors: Pilla Raffaele , D'Agostino Dominic P , Landon Carol S. , Dean Jay B. 
Published: June 2021

In clinical and military operations, hyperbaric oxygen (HBO) can generate central nervous system oxygen toxicity (seizures). In a previous study, we demonstrated that the intragastric administration of ketone ester (KE), a non‐ionized ketone bodies precursor, has a prominent anti‐seizure effect. In this follow‐up study, we tested the anticonvulsant properties of multiple KEs, and their effects on cardio‐respiration.60 male rats were implanted with radio‐telemetry devices to record EEG, diaphragmatic electromyogram (dEMG) and ECG. Rats were orally administered with one of four KEs: beta hydroxybutyrate, R,S‐1,3‐butanediol, acetoacetate monoester (AcAc), and acetoacetate diester (AcAc2). 30 min later, rats were exposed to HBO at 5 atmosphere absolute, until the onset of CN‐SOT, and the latency to seizure (LS) was measured.Our results showed that: a) AcAc2 was found to be the most potent anticonvulsant ester, as it increased the LS of 574%, compared to controls; b) AcAc and AcAc2 administration caused a significant increase in tidal volume (VT) and thus minute ventilation c) while stabilizing respiratory frequency (fresp) between 15 min before and after seizure, compared to controls.We report that 1) KEs (notably AcAc and AcAc2) increase the animal's resistance to seizures, and 2) ventilation (VT and fresp) was significantly stimulated by the oral administration of KEs.
Intrapleural CTB‐saporin selectively kills phrenic motor neurons: a motor neuron disease model
Authors: Nichols Nicole Louise , Vinit Stephane , Mitchell Gordon S 
Published: June 2021

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and ultimately, ventilatory failure. In a rodent model of ALS (SOD1G93Arats), ventilatory capacity is preserved despite >;50% loss of phrenic and intercostal motor neurons (i.e. compensatory respiratory plasticity preserves breathing capacity). Here, our intent was to develop an experimental model to study compensatory plasticity without many of the complications attendant to ALS. Thus, we tested the hypothesis that intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB‐SAP) selectively kill respiratory motor neurons to mimic motor neuron death in ALS. Phrenic motor output was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 3–28 days following bilateral intrapleural injections of: 1) CTB‐SAP (25–50μg), or 2) un‐conjugated CTB and SAP (control). CTB‐SAP elicited dose‐dependent phrenic motor neuron death; 25μg CTB‐SAP (7 days) most closely resembled cell death in end‐stage (ES) ALS rats (36±7% survival; n=9; p<0.05 vs. controls); CTB‐SAP diminished phrenic motor output (CTB‐SAP: 0.3±0.07 volts vs. Control: 1.5±0.3; n=9; p<0.05) to a level resembling ES ALSrats (0.4 volts). Intrapleural CTB‐SAP injections represent a novel inducible and repeatable model to study the impact of respiratory motor neuron death on breathing.[Supported by NIH NS057778 and HL080209 and the Francis Families Foundation]
Selective contribution of inflammation and oxidative stress to the cardiorespiratory and carotid body alterations following intermittent hypoxia
Authors: Del Rio Rodrigo , Moya Esteban A , Iturriaga Rodrigo 
Published: June 2021

Chronic intermittent hypoxia (CIH), a main feature of obstructive sleep apnea, potentiates carotid body (CB) chemosensory and ventilatory hypoxic responses, and induces hypertension. These alterations are attributed to oxidative stress, since antioxidants prevent the enhanced chemosensory and ventilatory hypoxic responses and the hypertension. We tested if oxidative stressinduced upregulation of pro‐inflammatory cytokines TNF‐α and IL‐1β are involved in the CB and cardiorespiratory alterations during CIH. We studied the effects of ibuprofen (40 mg/Kg day) on TNF‐α, IL‐1β and 3‐nitrotyrosine (3‐NT) CB levels, chemosensory and ventilatory hypoxic responses, and blood pressure in male Sprague‐Dawley rats exposed to CIH (5%O2, 12 times/h for 8 h/day) for 21 days. CIH increased CB TNF‐α, IL‐1β and 3‐NT, enhanced chemosensory and ventilatory hypoxic responses, and led to hypertension. Ibuprofen prevented the increased TNF‐α and IL‐1β CB levels and cardioventilatory alterations, but not the enhanced chemosensory hypoxic response and 3‐NT accumulation. Contrarily, ascorbic acid prevented the increased CB cytokines and 3‐NT expression, the chemosensory and ventilatory potentiation, and the hypertension. Thus, present results show that CIH‐induced potentiation of CB chemosensory responses to hypoxia depends critically on the oxidative stress, but not on the increased TNF‐α and IL‐1β in the CB. Thus, we provide new evidence suggesting a plausible role for pro‐inflammatory cytokines in the control of breathing and arterial pressure during CIH acting through a CB independent pathway.Supported by FONDECYT 1100405
Estradiol increases plasma membrane insertion of αENaC in the lung
Authors: Greenlee Megan M. , Mitzelfelt Jeremiah D. , Yue Qiang , Duke Billie Jeanne , Eaton Douglas C. 
Published: June 2021

Sodium reabsorption through alveolar epithelial sodium channels (ENaC) is the major driving force for lung fluid clearance. Recent evidence shows greater rates of lung fluid clearance in females than males suggesting that female sex hormones might regulate ENaC function. Using cell‐attached patch clamp, we have previously shown that β‐estradiol (E2) activates both highly‐selective and non‐selective ENaC in rat alveolar cells (L2). To extend that study, we examined possible mechanisms by which E2 increases ENaC activity. We first investigated whether E2 (200 pg/mL) altered αENaC gene expression in alveolar (L2) cells. E2 did not affect mRNA or protein levels of αENaC. Using cell surface biotinylation, we also examined differences in apical plasma membrane abundance of αENaC in vehicle and E2‐treated cells. There was ~3 fold increase in αENaC (60kDa) abundance with E2 treatment. Finally, we examined plasma membrane abundance of αENaC in lungs from female rats at the diestrus, proestrus, and estrus phases of the estrous cycle. Consistent with an effect of E2, we observed ~3 fold greater abundance of αENaC (60–75kDa) in lungs from proestrus rats. These results suggest that greater insertion of αENaC into the plasma membrane is one mechanism by which E2 increases alveolar ENaC activity. Future studies will focus on which estrogen receptor mediates this effect.Funding: NIH R37DK037963, K12GM000680 and T32HL076118
Influence of Early Growth Response 1 (Egr1) and Tenascin C (Tnc) on compensatory lung growth
Authors: Rauschkolb Peter Michael , Wolff Jens Christian , Morty Rory , Seeger Werner , Voswinckel Robert 
Published: June 2021

Mice that underwent a unilateral pneumonectomy (PNX) show complete restoration of pulmonary function through a rapid and complete compensatory growth of the remaining lung. Currently there is still little known about the nature, initiation and modulation of such growth. Microarray studies showed an upregulated expression of the immediate early gene Egr1 and the matricellular protein Tnc after PNX. In this study we assess the role of Egr1 and Tnc in early stages of compensatory lung growth.Stereology analysis of tissue sections showed that lungs of Egr−/− mice have the same surface area but less alveoli and a larger lung volume compared to wild type mice. During compensatory lung growth the loss of Egr1 seems to lead to a delayed regeneration of alveolar surface area whereas lung volume increases faster. Stereological analysis of Tnc−/− mice showed that these mice also have a larger lung volume compared to wild type mice. After PNX regeneration of alveolar number and lung volume is impaired.The results indicate that Egr1 and Tnc seem to have an influential role in the initial phases of compensatory lung growth. Additional experiments will be done to clarify how these genes are regulated after PNX. German research foundation.
Influence of Lung Volume, Fluid and Capillary Recruitment during Positional Changes and Exercise on Thoracic Impedance in Heart Failure
Authors: Kim Chul‐Ho , Fuglestad Matthew A. , Richert Malie L Ceridon , Shen Win‐Kuang , Johnson Bruce D 
Published: June 2021

IntroductionOptivol (Medtronic Inc.) thoracic impedance (ZT) provides preemptive disease status information in heart failure (HF). It remains unclear how pulmonary‐capillary blood volume (Vc), lung volume (Lvol), and interstitial fluid influence ZT.HypothesisPositional change and exercise result in increased Vc and/or lung interstitial fluid and ZT tracks fluctuation in these variables.Methods12 HF patients (age 63±8yr, LVEF 41±14%) were recruited. Measures were taken at rest, exercise, recovery. This included: spirometry, ZT, diffusing capacity of the lungs for CO and NO (DLCO, DLNO), alveolar‐capillary conductance (Dm, interstitial fluid index), and Vc. Inspiratory capacity was obtained to provide consistent lung volumes for assessing ZT.ResultsPositional change (upright‐supine) resulted in an increased ZT (5±4%, p<0.01), while the change in Lvol (RV‐TLC) resulted in a 7±2 ohm swing in ZT (0.2±0.1ohm change/100ml change in Lvol). After 30min supine, Vc increased 28±39% (p<0.05) while Dm/Vc and Lvol decreased (29±11% and 17±3%, p<0.05). During exercise compared to baseline, Vc increased 56±44% (p<0.01), DmCO/Vc decreased 25±7% (p<0.05), and ZT did not change. During recovery measures normalized except DmCO/Vc.ConclusionPositional changes and fluctuations in Lvol influence ZT yet measures of lung fluid minimally impact this measure despite significant fluctuations.
Terms that move us: Striding through the intersection of anatomy and biomechanics
Authors: Greiner Thomas M. 
Published: June 2021

Terminologia Anatomica provides an incomplete list of terms used to describe movements (A03.0.00.055 ‐ A03.0.00.063). These terms are generally thought to be well understood. Yet, they have no standardized definitions. Descriptions of movement are based more on linguistic tradition than upon anatomical or kinematic convention. Although this may seem trivial, it can lead to several unintended contraindications and miscommunications in clinical, biomechanical and functional anatomical applications. This presentation will provide examples of some problems that occur when applying these terms to movements of the foot and ankle.The foot is constructed with a series of ligaments that link adjacent bones. This insures that no foot joint moves in isolation. Similarly, there are no foot muscles that cross and act upon a single joint. Therefore, every motion of the foot is a complex multi‐joint motion. But, the available terms of movement do not account for this complexity. Instead, the same term is frequently used to describe motion for a single joint and for whole foot movements. This creates a conundrum. A term that describes the movement of the whole foot should not similarly describe the complex and varied movements that occur in several joints simultaneously. We have no way to clearly describe and communicate individual joint or whole foot movements.
The influence of locomotion and modularity on craniocaudal patterns of vertebral growth
Authors: Jones Katrina E , German Rebecca 
Published: June 2021

Heterochrony (i.e., changes in the rate or timing of growth) is important in evolution of the adult phenotype. However, very little is known about the growth of the vertebral column. The objective of this project is to quantify craniocaudal growth patterns in the thoracolumbar spine using longitudinal data. We examine the influence of locomotion by comparing growth between generalist, quadrupedal mammals and those with a convergently‐acquired, half‐bound gait that emphasizes sagittal extensions of the spine. Lateral x‐rays of 38 specimens from two specialized (Oryctolagus cuniculus and Chinchilla lanigera) and two non‐specialized (Cavia porcellus and Monodelphys domestica) species of similar size were the source of centrum length measurements on individual vertebrae. The same individuals were radiographed soon after birth and again at adult size using a repeated measurements design. Data show a craniocaudal increase in both absolute growth and interspecific variability that coincides with developmental and functional modules of the spine. Half bounders have increased lumbar growth relative to non‐specialists, resulting in a larger craniocaudal growth gradient in these taxa. These results indicate that growth patterns are correlated with locomotor behavior resulting in both intra‐ (serial) and interspecific heterochronies in the vertebral column.Grant Funding Source: NA
Form, function, and evolution of archosaur mandibular symphyses
Authors: Holliday Casey M 
Published: June 2021

Archosaurs radiated into numerous trophic niches during their evolution, resulting in a diversity of cranial adaptations and feeding behaviors. The mandibular symphysis is a poorly understood cranial joint which may offer significant insight into cranial development and function, feeding ecology, and evolution in these vertebrates. We investigated the anatomy and evolution of archosaur symphyses with a focus on Alligator mississippiensis and crocodyliforms. Character complexes of extant and fossil species were identified and their evolution was traced using a current phylogeny of archosauriforms. During ontogeny, alligators rapidly develop a complex, interdigitated, Class III symphysis coupled with fused Meckel's cartilages. Major iterative transitions from plesiomorphic Class I to derived, rigid Class II–IV symphyses and beaks occurred along the lines to phytosaurs, aetosaurs, poposauroids, crocodyliforms, pterosaurs, ornithischians, and birds. These transitions in symphyseal morphology appear to correlate with changes in function, the origin of beaks, and potentially inferred diet.Grant Funding Source: n/a
Sphingolipid metabolism modulates motor neuron degeneration in Drosophila
Authors: Sahoo Ishtapran , Hebbar Sarita , Osborne Kathleen Amy , Schwudke Dominik , Kraut Rachel Susan 
Published: June 2021

We are interested in the involvement of sphingolipids in neurodegeneration in Drosophila. To look at this, we study animals deficient in Blue cheese, a BEACH domain protein involved in autophagy and lysosomal transport, and highly expressed in the nervous system. Blue cheese mutants exhibit shortened life span, extensive neuronal loss and accumulation of ubiquitinated proteins in the brain (Finley et al, 2003). The role of BEACH domain in the FAN protein, which triggers neutral sphingomyelinase activity (Segui et al, 1999), and the involvement of sphingolipids in various human neurodegenerative conditions (Cutler et al, 2002, 2004; Han et al, 2004), led us to hypothesize that blue cheese mutation could lead to degeneration by altering sphingolipid balance. We introduced mutations in the sphingolipid‐biosynthetic pathway into the blue cheese background to look for modification of the phenotype (motorneuron count). Lace (SPT) and slab (CDase) mutants and overexpressors in the background of the blue cheese mutation indeed modulated neuronal survival, in a way that suggests that ceramide availability in the brain is critical. Mass spectrometric quantification of sphingolipid levels in mutant larval brains show dysregulation of ceramides and changes in activation of putative ceramide‐regulated MAPK signaling pathway targets P‐Akt, P‐JNK and P‐MKK4, which may affect neuronal survival. Based on these sphingolipid changes and genetic interactions, we propose a possible mechanism whereby blue cheese may regulate sphingomyelinase and SPT, and act synergistically with ceramidase.Research Grant: Biomedical Research Council (BMRC), A‐star, Singapore
Stromal galektin‐1 and myofibroblasts are reponsible for invasive behavior of the head and neck squamous cell carcinoma
Authors: Fik Zdenek , Valach Jarolsav , Smetana Karel , Strnad Hynek , Chovanec Martin , Gabius Hans Joachim 
Published: June 2021

Cancer‐associated fibroblasts (CAFs) play a significant role in the cross‐talk between tumor storma and the tumor cells. CAFs frequently express smooth muscle actin and are capable to support the developement of invasive cancer cells, which are responsible for establishing of metastases.We set the immunohistochemical presence of smooth muscle actin‐positive (SMA) CAFs in relation to galectin‐1. To pinpoint further correlations on the molecular level, microarray analyses was applied to the transcription profiles of the corresponding tumors, focusing on genes, representing poor prognosis for patient.In the squamous cell carcinomas of head and neck, upregulation of galectin‐1 was significantly correlated to presence of SMA‐positive CAFs in the tumor. Significant correlations of several transcripts were detected in the tumor epithelium with the protein level of galectin‐1 in the CAFs (MAP3K2, SPIN1, etc.).These results provide new insights into the significance of presence of myofibroblasts in squamous cell carcinoma and shows relationship between stromal reactivity and gene expression, associated with cancer progression directly in the samples of head and neck squamous carcinomas.This work was supported by the project PRVOUK No. 27–1 and GAUK No. 291811 of the Charles university.
Local concepts of infant illness among Mam‐Mayan women and impact on feeding practices: a qualitative study in the Western Highlands of Guatemala
Authors: Kincaid Mariah , Bermudez Odilia I. , Chomat Anne Marie , Escobar Marta , Garcia Maria , Garcia Rosario , Scott Marilyn E. , Koski Kristine G. , Solomons Noel W. 
Published: June 2021

ObjectivesTo examine maternal beliefs regarding etiology, presentation and treatment of prevalent child illnesses in rural Mam‐Mayan Guatemalan communities.Methods9 pregnant and 9 early‐lactating women already enrolled in a concurrent maternal‐infant health study participated in semi‐structured, in‐depth interviews. Two focus groups were conducted with community women. All interviews were audio recorded, transcribed and analyzed with HyperResearch.FindingsMost women ascribe infant parasitic, diarrheal and respiratory illnesses to a mix of local/culture‐bound and biomedical concepts of illness. Traditional herbs are routinely used to treat or prevent these conditions. Compliance with food requests made by the infant was mentioned as being protective against parasites, including during the first 6mo of life. Whereas “cold air” was associated with respiratory illness, specific foods considered “cold” in local narratives (fruits, chicken, avocado, potatoes) were associated with gastrointestinal illness.ConclusionsMaternal beliefs about childhood illness influence infant feeding practices and may determine both exclusivity of breastfeeding during lactation and infant diet variety. Better comprehension is needed of how socio‐cultural realities impact health‐related behaviors and feeding practice outcomes.Funding: TUSM, IDSA, ASTMH
Sodium and Potassium Intake among US Infants and Preschool Children, 2003–2010
Authors: Tian Niu , Zhang Zefeng , Loustalot Fleetwood , Yang Quanhe , Cogswell Mary E. 
Published: June 2021

To estimate sodium and potassium intakes among U.S. infants and preschoolers, and to compare these estimates by race/ethnicity and breastfeeding status, we analyzed cross‐sectional survey data on 699 infants (7–11 months) and 4271 preschoolers (1–3 and 4–5 years) from the National Health and Nutrition Examination Survey 2003–2010. We assessed mean intakes and the prevalence of excess sodium and inadequate potassium intakes relative to the Institute of Medicine Dietary Reference Intakes, Tolerable Upper Intake Levels (UL) or Adequate Intake (AI), respectively, adjusting for sociodemographic and other characteristics. Overall, 79% (95% CI: 76.5%–81.5%) of preschoolers aged 1–3 years and 87% (95% CI: 84.3%–89.7%) aged 4–5 years exceeded the UL for sodium. Among non‐Hispanic blacks, 84% (95% CI: 79.7%–88.3%) and 97% (95% CI: 94.1%–99.9%) exceeded the UL, respectively. Non‐Hispanic black infants and preschoolers had the highest mean sodium intakes than all other groups. Only 1% to 5% of preschoolers met the AI for potassium and mean potassium intake was highest among Mexican‐American preschoolers. Non‐breastfed infants and preschoolers had significantly higher mean sodium intake than those breastfed (p<0.05).ConclusionMost U.S. preschoolers consume excessive sodium, and consumption is highest among non‐Hispanic blacks. Very few preschoolers consume enough potassium. Support: No external funding.