bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data‐driven prediction of therapeutic efficacy and optimization of de novo drug combinations on the human protein‐protein interaction network (842.11)
Authors: Wang Hann 
Published: June 2021

Combination therapy is a promising direction for cancer research as it is shown to eradicate drug‐resistant cancer more effectively than monotherapy. The challenge, however, in creating a successful combinatorial treatment lies in the inability to screen through a huge number of possible combinations. We introduce PROPHECY (Predictive Optimization of Pharmaceutical Efficacy), a data‐driven search engine for the selection of drugs in combination therapy. The user provides a genetic profile, e.g. mutations in cancer cell lines or primary cells, and PROPHECY will select optimal drug combinations from a comprehensive library of existing drugs to meet clinical objectives. The decision is made by comparing the efficacy of drug combinations with in silico screening, in which a predictive machine is trained with a large‐scale database of drug screening experiments to recognize high‐order target‐gene interactions in the human protein‐protein interaction network (PPI). The predictive module in the machine incorporates knowledge of information propagation in the network, so can accurately elucidate interactions of a group of drug targets and disease genes in a de novo drug combination. Unlike other approaches of reductionistic drug development, PROPHECY can fully acknowledge the synergy between multiple drugs and predict the most effective multi‐target treatment against drug resistant cancer.Grant Funding Source: Supported by NSF
Ontogeny, ryanodine receptor‐mediated calcium sparks, and BK channel clustering in basilar arterial myocytes from long‐term hypoxic sheep (853.9)
Authors: Glasgow Shane , Tao Xiaoxiao , Romero Monica , Osman Noah , Puglisi Jose , Bers Donald , Izu Leighton , Longo Lawrence , Hessinger David , Wilson Sean 
Published: June 2021

Ryanodine receptor (RyR) activity causes Ca2+ sparks in cerebral arterial myocytes by activating adjacent Ca2+‐activated K+ (BK) channels, which can dilate arteries. Previous studies show ontogeny increases Ca2+ sparks and long‐term hypoxia (LTH) increases BK channel activity. We hypothesized that BK channel activity is greater in arterial myocytes of the LTH fetus than adult due to greater spark activity, and because BK channel clustering is greater in regions where sparks occur. To address this hypothesis we examined spark activity and BK channel clustering to sites of potential spark activity. This was accomplished using line‐scan and immunofluorescence techniques, respectively, in basilar arteries from LTH fetal (FH) and adult sheep (AH) kept at 3,801 m for > 100 days. The percentage of myocytes with sparks was ~ 2‐fold greater in FH versus AH and unaffected by 30 mM K (30K). Spark amplitude was 7% greater in FH 30K versus AH 30K, while no spatial or temporal changes to sparks were observed. BK channels were 2‐3 times more clustered and ~1.5 times more co‐localized with cholera toxin B‐labeled clusters in FH. These data suggest greater BK targeting to potential sites of spark activity in FH myocytes. Elevated RyR‐dependent Ca2+ spark activity in FH and altered patterns of BK distribution shed new light on the therapeutic potential of RyRs and BKs for treatment of cerebral vascular disease in newborns and adults.Grant Funding Source: Supported by NSF MRI 0923559, NIH HD‐069746, P01HD031226, R01HD003807, LLUSOM
Association of vitamin D level, leg extensor power, and neuromuscular function in mobility‐limited older adults (863.7)
Authors: Kirn Dylan , Laussen Jonathan , Hau Cynthia , Reid Kieran , Fielding Roger 
Published: June 2021

Purpose: Low vitamin D level is associated with poor muscle strength in older adults, but little is known about its relationship with muscle power and neuromuscular function in a mobility‐limited population. This study examines the cross‐sectional relationship between vitamin D level, leg power, and neuromuscular activation in mobility‐limited older adults.Methods: Sixty‐two mobility‐limited older adults completed the study (age= 77.2±4.7 years; Short Physical Performance Battery score = 7.8±1.2). Leg extensor peak power was assessed using bilateral leg press exercise and rate of vastus lateralis neuromuscular activation was assessed using surface electromyography.Results: As vitamin D level increased, a decrease was seen in muscle power (r= ‐0.27, p= .04) and neuromuscular activation (r= ‐.45, p= .06). Neuromuscular activation was significantly higher in subjects with vitamin D <30 ng/ml compared to those 蠅30 (.24±.09 vs. .11±.14, respectively; p= .02).Conclusion: This data suggests a negative association between vitamin D level, leg power and neuromuscular function, though further analysis is needed to confirm these findings.Grant Funding Source: USDA (58‐1950‐0‐014)
Chemosensitive locus coeruleus neurons in the Savannah monitor lizard, Varanus exanthematicus (879.13)
Authors: Zena Lucas , Fonseca Elisa , Santin Joseph , Bícego Kênia , Gargaglioni Luciane , Hartzler Lynn 
Published: June 2021

Savannah monitor lizards, Varanus exanthematicus, are unusual among air‐breathing, ectothermic vertebrates by maintaining arterial pH nearly constant during changes in body temperature (‐0.003 U °C‐1) in contrast to the typical α‐stat regulating strategy (‐0.015 to ‐0.017 U °C‐1) of most other ectotherms. Given the importance of pH in the control of ventilation, we examined the CO2/H+ sensitivity of neurons from the locus coeruleus (LC) region of Savannah monitor lizard brainstems. Whole‐cell patch clamp electrophysiology was used to record membrane voltage (Vm) in neurons within the LC region in brainstem slices; changes in firing rate of LC neurons were calculated from action potential recordings. Upon exposure to hypercapnic acidosis (HA) at 20°C, 60% of neurons significantly decreased firing rate (1.8±0.3 vs. 0.6±0.1 Hz; P<0.05). The percentage of LC neurons inhibited by HA is high at 20°C compared with published percentages from bullfrogs and rats. Increasing temperature to 30°C abolished the inhibited response to HA (2.4±0.9 Hz vs. 2.6±1.0 Hz; P=1.0). The large proportion of neurons inhibited by HA at 20°C may provide a mechanism whereby retention of whole body CO2 stores with cooling enables the pH‐stat regulation strategy of Varanus exanthematicus.Grant Funding Source: Supported by NSF IOS 1257338
Dose dependent effects of intramuscular administered atropine on heart rate in Trachemys scripta (879.16)
Authors: Cruz Carissa Nicole , Williams Cassondra , Hicks James 
Published: June 2021

Atropine sulfate is a common anticholingeric drug that is used in human medicine and veterinary medicine, as well as in scientific research. At doses less than 0.1mg/kg, it is used to treat bradycardia, ptyalism, and as an antidote for organophosphate poisoning. Although the effects of atropine have not been thoroughly examined in reptiles, previous studies utilized atropine, 1‐5mg/kg doses, to abolish shunting in reptiles, including snakes, crocodilians, and chelonians . In the present study, we investigated the influence of intramuscular administered atropine on heart rate in freshwater turtles, Trachemys scripta. To achieve this objective, an untethered electrocardiogram device recorded continuously in healthy female adult turtles (n=5, m=1‐2kg) before, during, and after the injections of veterinary grade atropine (0.01‐5mg/kg I.M.) with minimal observer interference. Heart rate was then derived from these measurements. Turtles showed a rapid increase to the peak heart rate less than ten minutes after the injection of atropine, except after the 0.01mg/kg dose, then gradually returned to the resting heart rate. In all doses above 0.01mg/kg, the length of the peak elevated heart rate constitutes about 1/5 of the total time atropine has an effect on heart rate. As a result, the extent of the elevated heart rates in the turtles increased exponentially as the dose of atropine also increased. Thus, we conclude that the lasting consequence of atropine on elevated heart rate is dose‐related. These results suggest that scientists can effectively eliminate shunting in turtles at lower atropine doses without subjecting the animal to prolonged tachycardia and associated cardiovascular adjustments.Grant Funding Source: Supported by NSF (1121324‐IOS)
Cardiorespiratory and metabolic changes during hypoxic flight in bar‐headed geese (879.20)
Authors: York Julia , Meir Jessica , Willy Jardine , Chua Beverly , Hawkes Lucy , Bishop Charles , Butler Patrick , Frappell Peter , Milsom William 
Published: June 2021

The bar‐headed goose (Anser indicus) undergoes a biannual migration over the Himalayas, sustaining aerobic flight above 6,000 meters. The goal of our study was to collect cardiorespiratory and metabolic data during flight from geese flying in a wind tunnel in normoxia and two levels of hypoxia simulating altitude. In birds at rest, metabolic rate fell from 26.6 ± 1.3 mL min‐1 kg‐1 to 10.0 ± 0.9 mL min‐1 kg‐1 and 10.7 ± 4.8 mL min‐1 kg‐1 in normoxia, 10.5% O2 and 7% O2 respectively. It rose to 209.8 ± 5.2 mL min‐1 kg‐1 during flight in normoxia but decreased to 181.7 ± 5.0 mL min‐1 kg‐1 in 10.5% O2 and to 131.7 ± 7.1 mL min‐1 kg‐1 in birds during flight in 7% O2. We found no change in heart rate across oxygen levels at rest or in flight. Heart rate at rest averaged 116.3 ± 35.4. While in flight, for any given metabolic rate we found a large range of heart rates in some individuals (184.5 to 457.0) and a very small range of heart rates in other individuals (256.8 to 375.7). There was, however, a strong positive correlation between metabolic rate and O2 pulse (stroke volume x arterial‐venous O2 content difference) at rest (slope=109.71; R2=0.57635) and in flight (slope=187.27; R2=0.65285) independent of the level of inspired O2 in all birds. It appears that the bar‐heads increase metabolic efficiency during hypoxic flight and match O2 supply to O2 demand by a general increase in heart rate and specific increases in O2 pulse.Grant Funding Source: NSERC of Canada; NSF, USA
Effects of age and lifetime flight behavior on senescence and reproduction in Drosophila (880.2)
Authors: Roberts Stephen , Mancinelli Georgina , Lane Steven , Elekonich Michelle 
Published: June 2021

The effects of aerobic activity on physiology and senescence may be profound in variably active species such as flying insects, which attain among the highest metabolic rates ever measured. Flight capacity in insects decreases with age, although limiting flight behavior extends lifespan, slows the age‐related loss of antioxidant capacity and accumulation of oxidative damage, and potentially allows for greater energy investment in non‐locomotor traits such as reproduction. We tested the effects of age and lifetime flight behavior on flight capacity, longevity and reproduction in Drosophila. Specifically, 5 day‐old adult flies were separated into three life‐long treatments: (A) those not allowed to fly (no flight or NF), (B) those allowed ‐ but not forced ‐ to fly (voluntary flight or VF), and (C) those mechanically stimulated to fly (induced flight or IF). Longevity was in the order NF>VF>IF, although the ability to fly and attain high metabolic rates persisted the longest in VF flies. Age‐specific fecundity did not vary among the groups, although NF flies had the greatest lifetime fecundity due to their longer lifespans. These results indicate that aerobic locomotor behavior can accelerate physiological senescence and trade‐off against other traits.Grant Funding Source: National Science Foundation IOS‐0725030
Epigenetic modification of gene expression during human acclimatization to hypobaric hypoxia (885.4)
Authors: Julian Colleen , Subudhi Andrew , Evero Oghenero , Pedersen Brent , Dvorkin Daniel , Lovering Andrew , Roach Robert 
Published: June 2021

Epigenetic processes and hypoxia‐inducible transcription factors work in coordination to regulate transcriptional responses to hypoxia. Our aim was to determine the role of epigenetics and associated changes to gene transcription for human acclimatization to high altitude. We performed genome‐wide methylation (Infinium HumanMethylation450 BeadChip, Illumina) and expression (Affymetrix Human Gene 1.0 ST Array) studies in peripheral blood mononuclear cells obtained from 21 healthy individuals at sea level and on three occasions during acclimatization to 5260m. Acute hypoxia minimally affected DNA methylation status. After 16 days of acclimatization, we identified 183 differentially methylated sites, including several that are associated with genes known to be involved in hypoxic response (e.g., eukaryotic translation initiation factor 2C subunit 2 [EIF2C], heat shock protein [HSP] 27, DNA (cytosine‐5)‐methyltransferase 3A). Indicating the potential functional importance of these epigenetic modifications, using methQTL we found that methylation status altered the transcriptional activity of hypoxia‐related genes considered central to human acclimatization to hypoxia (e.g., HIF1AN, EIFs, HSPs). Our findings support the possibility that epigenetic modification of gene expression contributes to acclimatization to high altitude.Grant Funding Source: Supported by: W81XWH‐11‐2‐0040 (DoD), NIH‐CCTSI UL1 TR000154 (NIH‐CCTSI), & 5 K12 HD057022‐07 (NIH)
AltitudeOmics: hemoglobin mass and blood volume changes during early acclimatization to and de‐acclimatization from 5260m (885.5)
Authors: Ryan Benjamin , Wachsmuth Nadine , Schmidt Walter , Byrnes William , Lovering Andrew , Subudhi Andrew , Roach Robert 
Published: June 2021

The early time course of changes in hemoglobin mass (Hbmass) and red cell volume (RCV) following ascent to and descent from altitudes greater than 5000m has not been previously determined in humans. We examined Hbmass and blood volume (BV) compartments in healthy men (n = 12) and women (n = 9) at sea level (SL) and 5260m following 1, 7, and 16 days of altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260m following descent to 1525m of either 7 or 21 days. Hbmass was assessed using the optimized CO rebreathing method. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7 ± 5.8% (n = 20; p < 0.01) at ALT7 and 7.6 ± 6.6% (n = 21; p < 0.001) at ALT16. Following descent to 1525m, Hbmass was reduced compared to ALT16 (‐6.0 ± 3.7%; n = 20; p = 0.001) and not different from SL, with no difference in the loss in Hbmass between groups that descended for 7 vs. 21 days. There was a large correlation between the loss in Hbmass and increase in serum ferritin following 7 days at 1525m (r = ‐0.64; n = 13; p < 0.05), suggesting increased red blood cell destruction. We found significant reductions in absolute and relative plasma volume (PV) of ~9‐12% at ALT7 and ALT16 compared to SL; PV returned to SL values following descent to 1525m. Relative BV was not different from SL at any time point due to opposing changes in PV and RCV. Our results demonstrate that large changes in Hbmass can occur within 1‐2 weeks in lowlanders during acclimatization to and de‐acclimatization from altitudes greater than 5000m.Grant Funding Source: Supported in part by DOD grants W81XWH‐11‐2‐0040 and W81XWH‐10‐2‐0114
Morphometry and fabric orientation of trabecular bone in human craniofacial regions (918.17)
Authors: Pryor Smith Leslie , Dechow Paul , Yardley Thomas 
Published: June 2021

Variation in primate craniofacial form has been attributed to orofacial function. Strain gage experiments show that during orofacial function the zygoma is subjected to high strain relative to the browridge. Trabecular bone morphometry and orientation are reflective of function, but trabecular bone in these regions has been unexplored. This study uses µCT to quantify the morphometric properties of trabecular bone, anisotropy, and fabric orientation in the human browridge and zygoma. We hypothesize that zygomatic trabecular bone will have significantly greater bone volume fraction and anisotropy relative to the browridge as an adaption to larger, more unidirectional loads. Primary orientations of trabecular bone will differ by region consistent with their function.No significant differences were found between the browridge and zygoma in BVF (0.38 vs. 0.31), and DA (1.65 vs. 1.85), but SMI was significantly lower in the browridge (0.075; honeycomb‐like vs. SMI=1.0752; ideal plate‐like, p<0.034). Orientation was highly significantly different between regions. The zygoma is made up of mediolaterally oriented plates with a slight inferosuperior tilt, while trabecular bone in the browridge is made of denser sagittally oriented plates.Both regions may be more similar in overall elasticity than predicted, but further analysis needs to test the combined effects of differences in individual features. Orientation of trabeculae in the zygoma appears to be consistent with what would be predicted based on orofacial strain patterns.Grant Funding Source: NSF BCS 0725141
Can morphological variables be used to predict hip joint function? An examination of the anthropoid proximal femur and range of abduction (919.10)
Authors: Hammond Ashley , Plavcan J. , Ward Carol 
Published: June 2021

Femoral morphology is often been used to make inferences about hip mobility in fossil anthropoids, abduction ability in particular. However, no study has shown that variation in hip morphology is actually related to hip mobility. If hip joint mobility is predicted by morphological variation, this would provide a new tool to more specifically evaluate locomotor adaptation in fossils.We present results of an in silico model of anthropoid hip joint mobility that has been validated on a large sample of extant taxa (hominoids, cercopithecids, Ateles, Cebus). Pelves and femora of the same taxa were laser scanned and polygonal models were digitally articulated. Maximum hip abduction was modeled using PolyWorks software using strict morphological criteria for joint movement. Several morphologies of the femur that are hypothesized to relate to hip mobility were quantified from the laser scan data using PolyWorks. Regression was used to assess the relationship between morphologies and functional abilities.Neck‐shaft angle and femoral head orientation were significantly related to degree of abduction. However, the majority of morphologies quantified were not significant predictors of hip abduction ability, suggesting that many of the morphologies attributed to high joint mobility may not relate to increased abduction ability. This work has applications to reconstructing locomotor abilities in fossil anthropoids.Grant Funding Source: Study supported by NSF (BCS 1232393, 0647557, 0716244), Wenner Gren Foundation, LSB Leakey Foundatio
How do the bone elastic properties vary through different layers of the skull? (920.1)
Authors: Zapata Uriel , Wang Qian 
Published: June 2021

One of the major roles of the skull is to protect the brain from physical injuries. To accomplish this critical condition, the cranial vault functions as a dome‐shaped structure composed of both inner and outer tables of cortical bone and diploe in between, suggesting independent biomechanical purposes for every stratum. However, questions regarding how the combination of the external and internal mechanical properties of these components in the cranial vault would maximize its capabilities to undertake functional loadings and minimize the employment of bone mass have not been systematically studied. We hypothesized that bone mass and elastic properties are different between two cortical layers. In this study, twelve pairs of the cortical samples from the parietal bone of a female baboon were collected, with each inner‐outer cortical paired sample from the same site. Cortical thicknesses and densities were measured, and elastic properties were assessed using ultrasonic technique. Results demonstrated remarkable difference in both thickness (F= 1.131, p 蠄0.05) and density (F=0.274, p= 0.015) between inner and outer paired samples. Differences in orthotropic elastic behavior (E1 and E3) were found between two cortical layers as well. How these differences are linked to the stress environments of the inner and outer cranial cortical layers awaits further studies.Grant Funding Source: Supported by NSF BCS‐0725183, and COLCIENCIAS (Bogotá, Colombia).
Fetal developmental anatomy of the human cardiovascular and central nervous systems using Lugol’s iodine staining and micro‐computed tomography (923.6)
Authors: Spaw Alexandra , Witmer Lawrence 
Published: June 2021

Iodine staining with Lugol’s solution is a fast‐developing technique that is revolutionizing imaging studies, because it provides the opportunity to distinguish between soft tissues through soaking of the specimen followed by computed tomography (CT scanning). Earlier protocols that resulted in marked tissue shrinkage have been modified by treating specimens with a buffered sucrose solution prior to staining with isotonic Lugol’s, yielding excellent results. This technique was used to compare the cardiovascular and central nervous systems of a series of human fetal specimens ranging from six weeks to 28 weeks (ages approximated by crown‐rump measurements). Anatomical structures were analyzed and segmented using the computer program Avizo, providing the basis for the generation of labeled images, 3D reconstructions, 3D interactive PDFs, movies, and other forms of digital representations of the information provided in the CT scan data. Results include all representations which lead to a catalog of developing anatomy from the late embryonic stage well into the fetal stage of gestation. The catalog created provides students and educators with multiple forms of media to study the fetal anatomy of these two systems and allows professionals to better visualize and interact with the reconstructed versions of key organ systems. The study of both normal and teratological anatomy will lead to greater knowledge of any defects and could potentially lead to improved treatment and surgical plans.Grant Funding Source: Supported by a grant to AS from the Ohio University Honors Tutorial College and to LMW from NSF
The architecture of Tetrahymena telomerase (926.2)
Authors: Feigon Juli 
Published: June 2021

Telomerase is an RNA‐protein complex that extends the ends of linear chromosomes, and is a highly regulated determinant of cellular aging, stem cell renewal, and tumorigenesis. We have obtained the 3D structure of endogenously assembled Tetrahymena thermophila telomerase holoenzyme at 25 Å resolution using electron microscopy (EM). The 7 protein subunits and the stem‐loop 2 region of TER have been localized in the 3D structure by affinity labeling. Fitting with the available high‐resolution structures, including a p65‐TER complex, reveals the organization of TERT, TER, and p65 in the RNP catalytic core. Among the other holoenzyme proteins, p50 has an unanticipated role as a hub between the RNP catalytic core, p75‐p19‐p45 subcomplex, and the DNA‐binding Teb1. A complete in vitro holoenzyme reconstitution correlates activity with structure. This first physical and functional network architecture of a telomerase holoenzyme provides unprecedented detail about the structure of the RNP catalytic core and reveals the organization of holoenzyme subunits that confer processivity and bridge telomerase to telomeres.J. Jiang, E.J. Miracco, K. Hong, B. Eckert, H. Chan, D.D. Cash, B. Min, Z. H. Zhou, K. Collins, and J. Feigon, “The architecture of Tetrahymena telomerase holoenzyme”, Nature, 496, 187‐182 (2013).K. Hong, H. Upton, E.J. Miracco, J. Jiang, Z.H. Zhou, J. Feigon, and K. Collins, “Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub”, Mol Cell Biol. 33, 3962‐3971 (2013).M. Singh, Z. Wang, B.‐K. Koo, A. Patel, D. Cascio, K. Collins, and J. Feigon: “Structural basis for telomerase RNA recognition and RNP assembly by the holoenzyme La family protein p65”, Mol Cell 47, 16‐26 (2012).Grant Funding Source: NSF MCB1022379, NIH GM48123