bluuebunny/crossref_metadata_2025_split huggingface dataset:
Countermeasure Analysis for Galactic Cosmic Radiation Induced Damage
Authors: Adams Jessica , Haran Harry , Nikisher Bridgette , Edwards John 
Published: May 2022

Galactic cosmic radiation (GCR) exposure is increased to space flight crews as travel moves beyond low Earth orbit. GCR includes high energy protons and heavy ionizing ions such as 56Fe, 28Si, and 16O and there are distinct differences in the biological response compared to low‐energy transfer events (x‐rays). Although the exposure rate is relatively low, the cumulative radiation dose is likely to have deleterious effects for long duration flight crews. The underlying mechanisms for these elevated risks are thought to include direct DNA damage as well as chronically elevated oxidant stress, and inflammation.Given the relatively low fluence rate of GCR exposure during flight operations it might be possible to manage these deleterious effects using small molecules currently available. To that end we have utilized a FDA approved drug library to perform a high throughput screen of cultured cells following exposure to GCR. H9c2 cells were exposed to a single 75 cGy dose using the 5‐ion GCRsim protocol developed by NSRL. Following GCRsim exposure, cells were treated using 10 µM for each drug. At harvest, cells were tested for protein content, oxidant stress, cellular senescence, and mitochondrial function.Of 725 drugs, more than 500 were ineffective in managing GCR exposure. Within the top 160 drugs, 33 were primarily designated as anti‐inflammatory. Significant variations within drug classes were observed. Only 10 of 46 drugs that interacted with histamine receptors were found useful and most were 5‐HT3 specific. The COX inhibitors deemed useful were all COX2 specific. Surprisingly, some anti‐diabetic medications observed to be useful including metformin.The bias of mitochondrial degradation as a central readout comes from several “omics” analyses that identified mitochondrial dysfunction as a consequence of GCR exposure. Mitochondrial dysfunction is also an antecedent event in the transformation leading to carcinogenesis. And the potential for carcinogenesis is a significant risk for long duration space missions. Separate from examining mitochondrial and cellular dysfunction as readouts, we have developed a Afp‐tdTomato expressing cell line that is responsive to different carcinogenic reagents including GCR. We have observed that some of the lead candidates will at least partially rescue the cells from GCR induced Afp driven expression. Additionally adapting cell doubling time protocols we observed that GCR exposure significantly increased cell doubling time; a finding indicative of mitotic dysfunction. We also observed that this increase was partially ameliorated by some of the lead candidates. That no one class of drug dominated the response to radiation exposure speaks to the complexity of managing GCR exposure.
Toward a Validated Metabolic Systems Thinking Framework
Authors: Barton Tyler 
Published: May 2022

Several recently reported research projects describe or measure student reasoning about biochemical pathway dynamics and regulation (BPDR). In this growing literature, a variety of approaches are taken to assess conceptual understanding in this area. While some studies have qualitatively investigated student misconceptions that arise in the context of research interviews, others have used test instruments constructed by biochemistry instructors to evaluate student learning quantitatively in the context of biochemistry course exams. In all cases, the focus has been on explicit biochemistry content with less emphasis on underlying general conceptual challenges. For both instructional and research purposes, a BPDR assessment framework based on underlying latent variables particularly informed by research in systems thinking is desirable.This project builds on the insights offered by the work cited above but takes a different approach to assess BPDR reasoning by considering the problem from the perspective of domain‐general conceptual challenges in systems thinking. Drawing on systems thinking research in the learning sciences and a variety of science education research fields, a preliminary Metabolic Systems Thinking Framework (MSTF) is proposed. This framework includes five factors – organizational levels, direct relationships, indirect relationships, parallel processes, and autoregulation. These factors are proposed to represent independent conceptual factors that influence reasoning in the context of BPDR problems.The sufficiency of the MSTF as a tool to assess student reasoning for BPDR is being evaluated through think‐aloud interviews with problems related to reasoning about glycolysis. Data from interviews with undergraduate biochemistry students has yielded evidence for the necessity of each of these factors, but whether they are jointly sufficient in this regard is currently being explored further. Additionally, a survey instrument is currently in development to establish the construct validity of the MSTF. This instrument includes multi‐item subscales for each of the factors of the MSTF. The instrument will be administered to undergraduate students enrolled in a biochemistry course covering metabolic pathways in spring 2022. Psychometric properties of the instrument will be determined to establish instrument reliability followed by confirmatory factor analysis to assess the construct validity of each factor.
Identification of Infarct Border Zone Using Late Gadolinium Enhanced MRI in Rats
Authors: Mendiola Emilio , Merchant Samer , Xiang Qian , Neelakantan Sunder , Hsu Edward , Vanderslice Peter , Avazmohammadi Reza 
Published: May 2022

BackgroundFollowing acute myocardial infarction (MI), cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW) alters the biomechanical behavior of the myocardium resulting in changes to organ‐level function. Despite significant advances in understanding LVFW remodeling in the setting of MI, the extent of tissue remodeling in the regions where infarct tissue transitions to healthy tissue, commonly called the border zone (BZ), is not well understood. Additionally, the effect of alterations in biomechanical behavior of the BZ on LV pump function remains understudied. We hypothesize that image‐based cardiac modeling can effectively address this gap. To this end, our objective was to develop an automated method to identify the infarct and BZ regions in rats using ex‐vivo late gadolinium‐enhanced magnetic resonance images (LGE‐MRI) and make use of these delineations to study regional structural remodeling in MI.MethodsAnterobasal MI was induced in Wistar‐Kyoto rats (n=2) by ligating the left anterior descending artery. Prior to sacrifice, subjects in the infarct group were given gadolinium contrast agent for MRI enhancement. Animals were sacrificed at 4 weeks post‐infarct and cardiac MRI scans were performed at an isotropic 100 µm resolution. The mean value of the voxel signal‐intensity (SI) of the posterobasal region of the heart was calculated and is hereafter referred to as the baseline SI (BSI). The image voxels were then segmented in to three regions by using the following SIs as threshold value cutoffs: i) SI of greater than 125% of BSI was considered infarcted myocardium, ii) SI between 115% and 125% of BSI was considered BZ, iii) SI of less than 115% BSI was considered remote myocardium. The geometry and dimensions of the infarct region were confirmed with measurements from the excised heart of the animal.ResultsIncreased SI was noted in the anterobasal region of the infarcted hearts (Fig 1), indicating myocyte necrosis and scar formation. Mean SI of the infarct region defined via this method was 1.6‐fold larger compared to that of the remote region. The infarct region resulting from the automated identification method closely matched the gemometry and dimensions of the infarct scar region of the excised hearts.ConclusionsThe extent of myocardial remodeling in LVFW during the post‐infarct healing process determines the contractile behavior in the LVFW and influences long‐term outcomes. Automated identification of infarct, BZ, and remote myocardium regions using LGE‐MRI is a step towards image‐based characterization of the heterogenous remodeling in the LVFW. Additionally, our algorithm enables the simple definition of a BZ of varied size and could allow us to better understand the influence of distinct regional remodeling events on organ‐level function as MI proceeds from early‐stage scarring to late‐stage remodeling.
MitoQ supplementation improves oxygen uptake kinetic by reduced reactive oxygen species levels and altered expression of miR‐155 and miR‐181b
Authors: Park Yoonjung , Aminizadeh Soheil , Lee Junghoon , Zarezadehmehrizi Aliasghar , Najafipour Hamid , Amiri‐Deh Ahmadi Maedeh , Moflehi Daruosh , Rashidzadeh Hamed 
Published: May 2022

BackgroundMitochondrial antioxidant (MitoQ) has been developed as a pharmaceutical for diseases. Few studies have investigated the role of MitoQ in enhancing athletic performance. Thus, the purpose of the study was to determine the effects of MitoQ supplementation to exercise training (EX) on the oxygen uptake kinetic, oxidative stress, and MicroRNAs (miRNAs) regulating vascular inflammation and reactive oxygen species (ROS) generation.Methods32 healthy young cyclists (25.6±3.8yr) were randomly divided into 4 groups (n=8); 1) Placebo, 2) EX (Cycle ergometer, moderate intensity), 3) MitoQ (20 mg/day, oral), and 4) EX+MitoQ. Oxygen uptake kinetics during low, moderate, and severe intensity cycling were measured before and after two weeks of interventions. Serum levels of ROS, glutathione peroxidase (GPx), and superoxide dismutases (SOD) were measured. miR‐19b, miR‐155, miR‐181b, and miRNA‐146a were measured by RT‐qPCR.ResultsEX+MitoQ accelerated the phase Ⅱ of oxygen uptake kinetic (moderate intensity) compared to EX (P<0.05). Both EX+MitoQ and MitoQ reduced ROS levels but there was no change in EX (P<0.05). GPx was increased in EX, MitoQ, and EX+MitoQ (P<0.05) whereas SOD levels in all groups were not different. miR‐155 and miR‐19b expressions were decreased in EX+MitoQ compared to EX (P<0.05). miR‐146a was increased in EX+MitoQ compared to EX only (P<0.05). There was no difference of miR‐181b between EX and Mito+Q. Placebo effects were not found.ConclusionsA short‐term MitoQ supplementation to aerobic training enhanced oxygen utilization during a moderate performance in cyclists compared to training alone by reduced ROS levels and altered expression of miR‐155 and miR‐181b mediating vascular endothelial inflammation and ROS generation.
Biomechanical consequences of alveolar cleft defect
Authors: Smith Amanda L. , Nicholas Christina , Bakhsh Nora , Patankar Sayali , Ledogar Justin A. , Moreno‐Uribe Lina 
Published: May 2022

Cleft palate is a common birth defect, requiring interventions that must be timed according to maxillary growth and patients often require multiple procedures to repair an alveolar cleft defect. Mechanical variables, such as pre‐surgical defect shape and size, have been suggested to affect the success of surgical repair, but the biomechanical consequences of these variables are not well understood. We hypothesize that mechanical performance of bony craniofacial structures will vary with cleft morphology.3D surface models of alveolar cleft defects were created from cone‐bean (CB) CT scans of adolescent and young adult patients (n=36; IRB: 201601711). Surface semilandmarks were used to conduct a cluster analysis, identifying common axes of variation which broadly differentiated between defects that are mediolaterally wider from those that are superoinferiorly taller.The centroid cleft defect shape from Cluster I was selected for preliminary biomechanical analysis. To isolate the mechanical effects of a defect of this shape/size, we used a previously published human cranial finite element model (FEM) as a baseline for model construction and comparison of performance. Patient CBCT was scaled and registered to the FEM and used to reconstruct the defect in the maxilla of the baseline model. Identical boundary conditions (material properties, muscle forces and joint and bite constraints) were applied to the cleft and non‐cleft FE models, to simulate biting on different teeth.Our results reveal notable and unexpected differences in deformation and strain regimes of the cleft and non‐cleft models. Although both models show characteristic regions of elevated strain on the biting‐side, the cleft‐model experiences a marked reduction (50‐90%) in strain on the balancing (non‐biting) side, due to the cleft disrupting the transmission of internal forces across the maxilla and palate from the biting to the balancing side. Importantly, regions that experience diffuse low‐level shear strains in our baseline model drop to nearly undetectable levels in the cleft model.We conclude that it is possible that the reduction of strain below this critical threshold could impede osteogenic mechanical signaling. This has important clinical implications for alveolar cleft defect repair and the development of novel scaffold‐based methods that both survive in vivo and restore functional orofacial load paths.
Do Adolescents With Insulin Resistance Demonstrate Impaired Heart Rate Recovery From Exercise?
Authors: Spaude Katie , Ward Aaron T. , Brubaker Justin M. , Zevin Erika L. , Livett Timothy A. , Carrel Aaron M. , Schrage William G. 
Published: May 2022

Heart rate recovery (HRR) following maximal aerobic exercise can serve as a noninvasive method of analyzing the risk for cardiovascular diseases. Inability to recover heart rate to pre‐exercise values can indicate parasympathetic nervous system dysfunction. Poor HRR could also be an indicator of early mortality, as decreased ability to recover heart rate is linked to decreases in vagal tone. Insulin resistance (IR) has also been linked to diabetes, obesity, and parasympathic nervous system dysfunction in adults, through an increased ratio of sympathetic to parasympathetic nerve activity. However, it remains unknown if adolescents with IR exhibit similar parasympathetic dysfunction. Therefore, it was hypothesized that increased IR would be associated with decreased HRR in adolescents.Data were collected from adolescents aged 12‐18. Insulin resistance was quantified as HOMA‐IR using fasting glucose and insulin. Subjects underwent maximal aerobic exercise testing on a cycle ergometer pedaling at 60‐70 RPM, starting at 25 W and increasing 25 W every two minutes. The test was terminated when subjects could no longer maintain the pedaling cadence for 5 consecutive seconds. Following cessation of exercise, subjects remained seated without movement for a two‐minute recovery period. Heart rate (HR) was collected via three lead ECG. Data was filtered and resampled to 1 Hz. A linear regression model was applied to the first 30s of HRR data for each subject, with the resulting slope used as the output variable in a subsequent linear regression model with HOMA‐IR as the predictor. Significance was set p<0.05.Subjects were 15 ± 2 years old with a HOMA‐IR 2.08 ± 1.92. The average HRR slope was ‐0.63 ± 0.13 BPM (r=‐0.91). The slope of HRR vs. HOMA‐IR was ‐0.02 ± 0.02 (r=‐0.32, p=0.18). The slope of HRR vs. fasting glucose was ‐0.001 ± 0.003 (r=‐0.07, p=0.8). The slope of HRR vs. fasting insulin was ‐0.008 ± 0.004 (r=‐0.42, p=0.08).Poor HRR has been linked to early mortality, and insulin resistance causes diabetes. However, IR and HRR were not found to have a statistically significant relationship. The relationships between HRR and fasting glucose and insulin levels were also not statistically significant. These data suggest there is no relationship between HRR and IR post exercise in adolescents.
Mitochondrial PKD Activates Mitochondrial Fission and Proliferative Signaling in Cardiac Fibroblasts
Authors: Zhou Xiaoxu , Adhikari Neeta , Cypress Michael W. , Polina Iuliia , Landherr Maria , Chaput Isabel , Suckow Mark A. , Choudhary Gaurav , O‐Uchi Jin , Jhun Bong Sook 
Published: May 2022

IntroductionCardiac fibrosis, characterized by wall stiffening, reduced contractility, and impaired overall heart performance, is a self‐reinforcing process in response to injury (e.g., myocardial infarction) and pressure overload (e.g., systemic hypertension and pulmonary arterial hypertension [PAH]). The severity of cardiac fibrosis is associated with cardiac dysfunction, increased risk of arrhythmia, and mortality. However, there is a lack of effective therapies designed to inhibit or reverse cardiac fibrosis. Hyperproliferation of cardiac fibroblasts (CFs) and their differentiation into myofibroblasts are the key contributors to cardiac fibrosis. We previously showed that mitochondrial reactive oxygen species (mROS) are one of the regulators for activating proliferative signaling in rat neonatal CFs. Moreover, we reported that phosphorylation of dynamin‐related protein 1 (DRP1) by a stress‐responsive protein kinase D (PKD) at the outer mitochondrial membrane (OMM) promotes mROS generation via increased mitochondrial fission in H9c2 cardiac myoblasts.HypothesisMitochondrial PKD‐DRP1 signaling increases mitochondrial fission leading to increased mROS levels, which activates proliferative signaling.MethodsPrimary adult CFs from human ventricles and the right ventricles (RVs) of a SU5415/hypoxia‐induced rat PAH model were used. Mitochondrial morphology and mROS levels were measured by confocal microscopy.ResultsOverexpression of PKD1 increased DRP1 phosphorylation at Ser637, and activates proliferative signaling pathways including ERK1/2 and p38 in human CFs, but did not promote their differentiation into myofibroblasts, assessed by the amount of a‐smooth muscle actin. To specifically identify the involvement of OMM‐localized PKD activity in these processes, we generated an OMM‐targeted dominant‐negative PKD1 (termed mt‐PKD‐DN) by adding an OMM‐target sequence (amino acid 1‐33 from human TOM20) at the N‐terminus of PKD1‐K612W. Importantly, mt‐PKD‐DN was able to inhibit mitochondrial fission, decrease mROS, hyperpolarize mitochondrial membrane potential, and ultimately decrease proliferation in human CFs. To further understand the role of PKD‐DRP1 signaling in vivo, we employed a preclinical PAH animal model. Immunofluorescence staining of RVs from PAH rats revealed that PKD activity and DRP1 phosphorylation increased only in CFs, but not in ventricular myocytes. RV‐CFs isolated from PAH rats exhibited increased mitochondrial fission, mROS levels, and proliferative signaling compared to RV‐CFs from control rats, and these changes were abolished by adenoviral expression of mt‐PKD‐DN.ConclusionMitochondrial mROS elevation via PKD‐DRP1‐dependent mitochondrial fission promotes CF proliferation. Targeting mitochondrial PKD may be a potential therapeutic strategy to reduce cardiac fibrosis under pathological conditions such as PAH.
Rapid Onset Vasodilation: Impact of Cardiorespiratory Fitness
Authors: Sherman Sara R. , Hibner Brooks A. , DeJonge Sydney R. , Rosenberg Alexander J. , Lima Natalia S. , Baynard Tracy , Fernhall Bo 
Published: May 2022

IntroductionHigher cardiorespiratory fitness is associated with greater vascular function that leads to improved regulation of skeletal muscle blood flow during exercise. Rapid onset vasodilation (ROV) describes the immediate increase in blood flow following a single contraction, which is integral to support greater blood flow during exercise. As such, blood flow regulation during exercise hyperemia is important. However, it is unclear if cardiorespiratory fitness plays a role in ROV of small muscle mass in young, healthy individuals.PurposeTo investigate the relationship of cardiorespiratory fitness on ROV following a single handgrip (HG) contraction in young, healthy adults.MethodsCardiorespiratory fitness (VO2peak) was assessed during a maximal cycle ergometer test in 14 volunteers (M/F, 6/8; 28 ± 5yrs; 24.8 ± 4.1kg/m2). Brachial velocity and diameter were measured using duplex Doppler ultrasound for 10 cardiac cycles prior to and 20 cardiac cycles following the first cardiac cycle after a single 30% of maximal voluntary handgrip contraction. Brachial artery blood flow (FBF) was calculated for each cardiac cycle: (diameter2/2)*π*velocity*60. Peak forearm (brachial) blood flow (FBFpeak) was determined as the maximal FBF from baseline following the first cardiac cycle after the single HG contraction. Time to peak blood flow response was determined as the time to reach FBFpeak and heart rate was measured using a three‐lead ECG. The relationship between FBFpeak and time to peak blood flow was tested using a multivariate regression analysis with cardiorespiratory fitness and sex as independent variables.ResultsCardiorespiratory fitness (VO2peak: 30.6 ± 8.0mL/kg/min); β for VO2peak= 0.162 [0.003, 0.327]) was the only predictor of time to peak blood flow response, F(1,12)= 4.602, p= 0.05, R2= 0.217, r= 0.526, while sex (β for time to peak= ‐106.5 [‐156.9, ‐56.2]) was the only predictor of FBFpeak, F(1,12)= 21.245, p<0.001, R2= 0.609, r= 0.799, indicating that females had a lower FBFpeakoverall.ConclusionOur data suggests blood flow responsiveness (e.g., time to peak) is positively associated with cardiorespiratory fitness and these data contribute to our understanding of potential mechanisms between improved blood flow regulation commonly associated with greater cardiorespiratory fitness. More research is necessary to fully elucidate the role biological sex has on these relationships, but our data suggest there may be sex differences in certain blood flow responses.
The characteristics of metformin nanoliposomes
Authors: Fan Baochan , Zu Yujiao 
Published: May 2022

ObjectivesMetformin is an FDA‐approved anti‐diabetic drug. The oral bioavailability of metformin is low. After oral intake of metformin at 0.5‐3 g/day, blood metformin levels are less than 40 μM in human subjects. We successfully synthesized biocompatible and biodegradable metformin nanoliposomes. The objectives of this study are to measure the characteristics of metformin nanoliposomes and to determine their stability at three different temperatures.MethodsThe particle size and polydispersity index of metformin nanoliposomes were measured using a dynamic light scattering technique, and their surface charges were measured using a zeta potential analyzer. The metformin nanoliposomes were stored at 4°C, 22°C and 37°C for 5 days, and their stability was measured every day.ResultsThe mean particle size of metformin nanoliposomes was around 100 nm. The polydispersity index value was less than 0.3. Moreover, the zeta potential of metformin nanoliposomes was around −20 mV. The particle size, polydispersity index and zeta potential of metformin nanoliposomes were stable at 4°C for 24 hours, but were increased at 22°C and 37°C after 24 hours.ConclusionsMetformin can be encapsulated into biocompatible and biodegradable nanoliposomes. They are stable at 4°C for 24 hours.