bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of a novel integrin‐targeted anti‐c‐Myc nanotherapy against multiple myeloma in mice (1054.11)
Authors: Soodgupta Deepti , Pan Dipanjan , Hu Grace , Sen Pan Angana , Yang XiaoXia , Prochownik Edward , Lanza Gregory , Tomasson Michael 
Published: June 2021

The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC‐MAX dimerization is limited by poor efficacy. We first sought to test the efficacy of a novel MYC‐MAX dimerization inhibitor prodrug. Treatment of three MM cell lines (mouse and human) with a lipase‐labile prodrug inhibitor of MYC‐MAX dimerization (MI1‐PD) decreased cell viability more than parent drug MI1 on an equimolar basis and increased apoptosis. However, MI1‐PD is hydrophobic, limiting translation to in vivo use. To overcome this challenge, we next determined if the efficacy of MI1‐PD could be improved by delivery in nanoparticles targeted to MM‐specific integrins. Integrin‐targeted, MI1‐PD‐containing nanoparticles inhibited growth and induced apoptosis compared to control nanoparticles without drug, or without integrin‐targeting. Binding and efficacy of nanoparticles correlated with integrin expression in target cells. A mouse model of MM was used to assess in vivo efficacy of nanoparticle‐bound MI1‐PD, with survival used as the primary endpoint. In vivo, administration of nanoparticle‐bound MI1‐PD conferred significant survival benefit versus untreated controls (52 days vs. 29 days, p=0.001). Our results suggest the feasibility of an improved integrin‐targeted nanotherapy approach to disrupt MYC‐MAX dimerization using a lipase‐labile prodrug.Grant Funding Source: This work was supported by the Department of Defense Grant Award # W81XWH1110446
Presence of inhibitory GABA receptors on serotonin neurons in the bivalve mollusc Crassostrea virginica (1059.5)
Authors: Welsh Christopher , Saunders A.C. , Carroll Margaret , Catapane Edward 
Published: June 2021

GABA is a major inhibitory neurotransmitter in molluscs and other animals, but has not been well studied in bivalves. In several bivalves, including Crassostrea virginica, beating of gill lateral cilia is controlled by a reciprocal serotonergic‐dopaminergic innervation from their ganglia. Serotonin (HT) increases beating rates, dopamine slows it down. GABA has no direct effects on cilia beating in C. virginica, however, GABA blocked the cilio‐excitation of HT when both are applied to the cerebral ganglia. We hypothesize cerebral and visceral ganglia contain GABA neurons and the cilio‐excitatory HT neurons in the ganglia contain inhibitory GABA receptors. We used immunofluorescence histochemistry to visualize GABA receptors and HT neurons in cerebral and visceral ganglia. Tissues were dissected, snap frozen, sectioned on a cryostat, fixed with paraformaldehyde, treated with blockers, incubated with 1̊ and 2̊ antibodies and viewed with a fluorescence microscope with FITC and Texas Red filters. We found cerebral and visceral ganglia contained GABA neurons and some HT neurons had GABA receptors on their soma. This study confirms our earlier pharmacological studies indicating a role for GABA in this bivalve, working centrally as an inhibitory ganglionic neurotransmitter to inhibit cilio‐excitatory HT neurons that innervate the gill and helps to explain the ganglionic circuitry by which this could be done.Grant Funding Source: NIH‐2R25GM0600309, NYSED‐0516041071, NSF‐0622197
Oxidative stress and the impact of prenatal chronic hypoxia on ryanodine receptor generated calcium responses in fetal pulmonary arterial myocytes (1089.11)
Authors: Kaushal Shawn , Romero Monica , Osman Noah , Paez Ricardo , Francis Michael , Taylor Mark , Longo Lawrence , Wilson Sean 
Published: June 2021

Ryanodine receptors (RyRs) are sensitive to reactive oxygen species in that this stress increases leak of Ca2+ through the channels. Our recent work shows RyR‐generated Ca2+ sparks are aberrant following prenatal chronic hypoxia (CH) in pulmonary arterial myocytes of fetal sheep. Other evidence suggests that the enhanced Ca2+ leak due to oxidative stress can cause loss of Ca2+ from the sarcoplasmic reticulum (SR); our Ca2+ spark data are consistent with such a loss in SR Ca2+ and CH can cause oxidative stress. To address potential Ca2+ loss we quantified 10 mM caffeine (CAF) elicited Ca2+ release from the SR, as RyR activation provides an index of Ca2+ storage. This was performed in pulmonary arterial myocytes of intact arteries using Fluo‐4 and confocal imaging approaches of fetal sheep that lived in normoxia at low altitude (FN) or fetal sheep that lived in CH at (3,801 m) for >100 days (FH). Using customized analysis software, the data show that under control conditions prenatal CH does not impact the area under the curve (AUC) due to CAF. Thus, the changes in spark activity previously observed likely arise from something other than alterations in SR Ca2+ storage. Pretreating PA with 1 mM tert‐butyl H2O2 resulted in a ~ 31% decrease in CAF‐elicited AUC in FN and a 6% increase in FH. These data suggest that sheep exposed to prenatal CH may adapt, which limits decrements in total SR Ca2+ storage in an attempt to preserve SR function.Grant Funding Source: NSF MRI 0923559, NIH HD‐069746, P01HD031226, R01HD003807, 5P20 MD‐006988, LLUSOM
Gravitational stress and the evolution of relative tail‐length in arboreal snakes (1100.10)
Authors: Sheehy Coleman , Lillywhite Harvey 
Published: June 2021

Gravity imposes potentially important constraints on blood circulation in elongate animals during upright posture or climbing. We test the hypothesis that arboreal snakes have longer tails than non‐scansorial species and interpret the results in context of adaptation to gravity stress. Length data for 226 species in 15 snake families were divided among three gravitational habitats (G‐habitats: stenotopically arboreal, eurytopically arboreal/terrestrial, and non‐scansorial) to categorize climbing habits. We analyzed data using conventional statistics and phylogenetically independent contrasts by constructing a composite tree. Mean relative tail length (RTL) increased and mean relative snout‐vent length decreased with increasing arboreality among the three G‐habitats, independent of phylogeny. Mean total body length (TL) was not different between the two arboreal G‐habitats. Snakes with longer RTLs have a larger percentage of elongate blood vessels contained within relatively tight integument of the tail, which theoretically mitigates postural blood pooling. TL may be constrained in adult female arboreal snakes, and this could be driving an evolutionary tradeoff between longer RTL and lower female fecundity. Our results complement previous studies and suggest that elongated RTLs of arboreal snakes function, at least in part, as an adaptive response to gravity stress.Grant Funding Source: Supported by the U.S. National Science Foundation grant IOS–0926802 to HBL
Thermoregulatory plasticity in Northern Cardinals (1100.13)
Authors: Komer Maria , Corder Keely , Schaeffer Paul 
Published: June 2021

Northern cardinals (Cardinalis cardinalis) are able to endure drastic seasonal variations by physiologically adapting to their environment using thermoregulatory techniques. By examining whole‐animal function, we ask whether decreased metabolic activity during winter nights were a result of decreased activity or an induced state of torpor. We measured body weight, percent fat content, metabolic rate (VO2) across a range of temperatures and body temperature (Tb) using data loggers during both summer (August to early September) and winter (December to January) conditions. We hypothesize that: (1) daily winter Tb fluctuations will be depressed compared to summer displaying an induced torpor, and (2) insulation will play a significant role in thermoregulation. We found a slight depression in circadian temperature rhythms for the winter animals compared to summer animals. Metabolic rate measurements did not differ between summer and winter animals. Fat percentage was significantly increased in the winter birds compared to summer. Our findings suggest that thermoregulatory mechanisms are not as fixed as previously thought and while fat deposits may function to increase insulation, they are more likely important for fuel storage. These data identify subtle changes in seasonal thermoregulation are present, and suggest that mechanisms behind these slight alterations in thermoregulatory states should be further assessed.Grant Funding Source: Supported by NSF # IOS‐1257455 to PJS
Heat shock proteins protect skeletal muscle against frostbite injury (1102.43)
Authors: Mestril Ruben , Batey Jason , Liskutin Tomas , Schweigert Colin 
Published: June 2021

Backgound: Frostbite injury results in serious skeletal muscle damage. Potentially the inflammatory response due to frostbite causes local muscle degeneration. Previous studies have shown that the heat shock proteins (hsp) are able to protect against oxidative stress and inflammation.Results: In the present study we examined the effects of the heat shock protein inducer, 17‐Dimethylaminoethylamino‐17‐demethoxygeldanamycin (17‐DMAG) which was administered within 45 minutes following frostbite injury. Our results show that rat hind‐limb muscles injected with 17‐DMAG following frostbite injury exhibit less inflammatory cell infiltration as compared to control rat hind‐limb muscles. In agreement with this observation, we found that the increased heat shock protein expression results in a decrease in inflammatory cytokine expression. We also found that administration of 17‐DMAG after frostbite injury is able to preserve muscle function. Our results therefore suggest that 17‐DMAG protects skeletal muscle if administered shortly after frostbite injury.Conclusion: We conclude that compounds such as 17‐DMAG that induce heat shock proteins are able to preserve skeletal muscle function and structure if injected within 45 minutes after frostbite injury. Our studies provide the basis for the development of a potential therapeutic strategy to treat injury caused by frostbite.Grant Funding Source: This research was supported by an award from the USAMRMC.
Hemodynamic responses to severe heat stress in rats: implications for blood pressure regulation (1104.20)
Authors: Charkoudian Nisha , Quinn Carrie , Duran Rocio , Leon Lisa 
Published: June 2021

Increases in heart rate (HR) and cardiac output, and redistribution of blood flow to the periphery are key cardiovascular responses to heat exposure. We previously observed hysteresis in the HR response to heating in rats, whereby HR was higher for a given core temperature (Tc) during cooling/recovery compared to during heating. In the present study, we evaluated whether this hysteresis was associated with dehydration, and whether specific cardiovascular response patterns were associated with more negative outcomes. Tc, HR and arterial pressure were measured via radiotelemetry in conscious male Fischer 344 rats (n=22; 272.4 ± 4.7 g) during exposure to 37°C (heating phase) and during recovery at 20°C (cooling phase). HR increased substantially during heating. At Tc = 39.5°C, HR was 386 ± 5 bpm during the heating phase and 490 ± 14 bpm during the cooling phase (P< 0.001). HR hysteresis in recovery was coincident with substantial dehydration (7‐8%BW), but returned to baseline after ~20 min despite continued dehydration, suggesting these events were not linked. Independent of hysteresis, rats with the worst outcomes demonstrated a drop‐off in HR at end of heating. These findings provide further insight into multiple simultaneous stressors placed on integrative cardiovascular regulation during and immediately following heat stress.Research supported by USAMRMC. Author views not official US Army or DoD policy.
Polar bear body temperatures and behavior in the changing Arctic summer (1104.25)
Authors: Whiteman John , Harlow Henry , Ben‐David Merav , Durner George 
Published: June 2021

In the Arctic summer, extent and duration of sea ice melt is increasing, displacing Alaskan polar bears from ice in productive near‐shore waters to deep‐water ice or to land. In these habitats, seal prey is likely at low availability. Additionally, extensive open water may increase long‐distance swimming. It is unknown how these changes affect metabolic rates and thermoregulation of polar bears. We recorded body temperature (Tb) with loggers implanted adjacent to the abdominal peritoneum, ventral to the linea alba, in 4 bears on deep‐water ice (May–Oct) and 5 bears on shore (Aug–Oct) in the Beaufort Sea. Tb of ice bears declined from a weekly mean of 37.2–37.5°C (May 23–Jun 03) to 34.7–36.6°C (Sep 21–Oct 09). Bears had unexpected, rapid bouts of Tb decline and recovery. In Aug–Oct, ice bears averaged 0.65 bouts per day (95% were 蠄 12 hours) that reached a mean minimum Tb of 33.6°C; shore bears averaged 1.06 bouts per day (94% were 蠄 12 hours) that reached a mean minimum Tb of 28.6°C. The cause of these bouts and why they were more frequent and reached a lower Tb for bears on shore is not clear. Pending analyses contrast Tb to data collected from loggers implanted in the rump; relationships between bouts of low Tb and swimming behavior; and implications of these patterns for polar bears in the changing Arctic summer.Grant Funding Source: National Science Foundation 0732713
Characterization of changes in muscle afferent response to stretch following inflammation in male and female mice (1128.1)
Authors: Allawala Anusha , Behnke Stephanie , Zaytseva Dasha , Wilkinson Katherine 
Published: June 2021

Chronic pain and musculoskeletal disorders are a leading cause of disability and are more likely to affect females than males. Inflammatory factors can alter the activity of muscle sensory afferents and may contribute to the development of chronic pain or other sensory disorders. We hypothesized that muscle afferent population responses to stretch will be altered following systemic inflammation caused by a Lipopolysaccharide injection (7.5 x 10^5 EU/kg; controls 200 µL saline) 18 hrs prior to the experiment. The extensor digitorum longus muscle and deep peroneal nerve from adult male and female C57BL/6 mice were placed into an in vitro bath and muscle afferent activity recorded with a suction electrode in response to a battery of physiological ramp and hold stretches. The muscle afferent response to stretch was altered by inflammation, but the response in females was opposite of that in males (Multivariate ANOVA, drug x sex interaction, p < .05). Inflamed females showed an increase in muscle afferent firing frequency normalized to baseline frequency during both the ramp and hold phases of stretch, while males showed a blunted response in both. This suggests that inflammation alters the muscle sensory information reaching the central nervous system. As we only measured population responses, future studies will determine the proprioceptor and nociceptor responses to inflammation by measuring the responses in identified individual afferents.Grant Funding Source: Supported by NSF # DBI 1262832 (AA) and a CSUPERB New Investigator Award (KAW).
Ehs‐1 is required for the expulsion step of the Caenorhabditis elegans defecation motor program (1129.5)
Authors: Freeburg Nelson , Peters Maureen 
Published: June 2021

The Caenorhabditis elegans digestive motor program occurs at approximately 50 second intervals and consists of three contractions. The first contraction occurs in the posterior body wall muscle and is followed by a contraction of the anterior body wall muscle approximately 4 seconds later. Finally, waste is expelled via contraction of the enteric muscles. The later contractions are controlled by the release of neuropeptides from the intestine, which activate two GABAergic neurons. A genome‐wide RNA interference (RNAi) screen identified EPS‐15 homologous sequence 1 (ehs‐1) as a candidate gene involved in defecation. Ehs‐1 knockdown does not affect the first contraction or the timekeeping mechanisms. However, the expulsion step occurs in only 10.9% percent of cycles. Ehs‐1 has previously been implicated in synaptic vesicle recycling in neurons, suggesting that the expulsion defect is due to defective GABA release from DVB. However, intestine‐specific knockdown of ehs‐1 results in a 92.3% reduction in expulsion, matching the expulsion frequency following systemic knockdown. Our findings suggest that intestinal expression of ehs‐1 is also required for expulsion. We hypothesize that ehs‐1 is needed for recycling of vesicles in both neurons and intestines.Grant Funding Source: Supported by a National Science Foundation grant: NSF‐RUI0842830
Assessment of organic and heavy metal contaminants as a function of urban development near rivers of Puerto Rico (1143.9)
Authors: Ortiz Ana , Piñero Luis , Rivera Nilsa , Sosa Maria 
Published: June 2021

Anthropogenic activities, such as urbanization, manufacture, agriculture and transportation, often lead to contamination of water resources through runoff from sewer systems or illegal dumping. We wish to determine if urbanization near rivers in Puerto Rico results in increased levels of organic and metal contaminants of anthropogenic origin, to then test how these may affect behavior and nervous system function of river fauna. Water samples from two urban rivers with differing hydrological flow characteristics, Rio Piedras and La Plata, and a control non‐urban river, Rio Mameyes, were analyzed with Gas Chromatography‐Mass Spectrometry and Atomic Absorption Spectroscopy. A wide range screening of organic compounds (OC) identified 35 contaminants in the urban rivers, including esters, phthalates, pharmaceuticals and ingredients in personal care products. Dibutyl phthalate, commonly used in plastics and cosmetics, was found in La Plata at a concentration five times higher than the limit allowed by the EPA for drinking water. Copper, chromium and cadmium in the urban rivers are within EPA standards, although copper in the Río Piedras increased consistently from its origin to its lower reach, while remaining constant throughout the length of La Plata. Further experiments to measure other heavy metals and OCs from pharmaceuticals and personal care products are being conducted.Grant Funding Source: Supported by: NSF HRD‐1137725; NIH NIGMS R25GM061838; NIH NIGMS 5SC3GM084763
Proteomic investigation of human α7‐nicotinic acetylcholine receptor interacting proteins (1147.5)
Authors: Mulcahy Matthew , Lukas Ronald , Barrantes Francisco , Hawrot Edward 
Published: June 2021

The α7‐nicotinic acetylcholine receptor (α7‐nAChR) is a ligand‐gated ion channel widely expressed in the mammalian CNS that is associated with numerous physiological functions. α7‐nAChRs are also the principal high‐affinity α‐bungarotoxin (bgtx) binding proteins in the mammalian brain. There is evidence that α7‐nAChRs are involved in a number of protein‐protein signaling cascades. SH‐SY5Y and SH‐EP1 human clonal cell lines have been utilized extensively to characterize nAChRs. SH‐SY5Y cells naturally express α7‐nAChRs. SH‐EP1‐hα7 and SH‐EP1‐hα7‐Ric‐3 cells have been engineered to stably and heterologously express human α7‐nAChRs alone or along with human Resistance to Inhibitors of Cholinesterase 3 (Ric‐3). Bgtx‐sensitive protein complexes were isolated from each cell line using bgtx affinity immobilization. Bound protein was eluted, reduced and alkylated prior to digestion with trypsin in‐solution. The resulting peptides were analyzed with an LTQ‐Orbitrap mass spectrometer and data analyzed using ProteoIQ™. 216 total proteins (1% peptide FDR; 90‐100% probability) that were not present in controls were identified from multiple preparations of the three cell lines. Identified interacting proteins will serve as a foundation for further investigations in human‐derived cells lines and primary human tissue.Grant Funding Source: Supported by NIH 1R21AG038774, 1S10RR027027, NSF EPS‐1004057 (EH); PIP 2012 and PICT 2011‐0604 (FJB)
Mitochondrial dynamics in the type 2 diabetic heart (1159.6)
Authors: Gonzalez Eileen , Brito Alfonso , Peltekian Lila , Lopez Vanessa , Delgado Daniel , Yamazaki Katrina 
Published: June 2021

Type 2 Diabetes (T2D) mitochondrial effects include imbalanced dynamic events of fusion, fission, and autophagy. The flavanol epicatechin has been previously observed to provide cardioprotection in the setting of ischemia‐reperfusion by reducing inflammation and ROS production. Our objectives are to observe the protective effects of epicatechin in the T2D setting via in vitro and in vivo models. In vitro, C2C12 myoblasts were cultured in glucolipotoxicity treatment (GLT) for 3 days in high glucose (~33 mM) and high fatty acids (0.6 mM) media, ± epicatechin. Our in vivo rat model included controls, sham ± epicatechin (1 mg/kg/day), and diabetes ± epicatechin (1 mg/kg/day). T2D was induced in vivo by high‐energy diet (HED) of 20% lard and 10% glucose. Low dose streptozotocin (30 mg/kg) injection was given at four weeks to decrease insulin secretion, after which epicatechin treatment began with maintained HED. In vitro results thus far show GLT average cell counts of 7.54E+04, which show significant increase in cell death compared to control (3.56E+05). Cells maintained in GLT setting with 100 nM epicatechin yielded an average cell count of 1.78E+0, thus demonstrating a reduction in cell death. Western analysis show enhanced mitochondrial proteins with epicatechin treatment compared to diabetic controls. We predict further data analysis will show a positive correlation between epicatechin and the restoration of normal mitochondrial dynamics in the T2D setting. As the incidence of T2D rises, further investigation into possible therapies and treatments is warranted.Grant Funding Source: Supported by CSU‐LSAMP fund from the National Science Foundation under Grant No. HRD‐0802628
The role of cerebral oxygenation on tolerance to central hypovolemia (1183.12)
Authors: Kay Victoria , Rickards Caroline 
Published: June 2021

Background: Tolerance to central hypovolemia varies between individuals, and recent studies have shown that protection of absolute cerebral blood flow is not an underlying mechanism. We hypothesized that subjects with high tolerance (HT) to central hypovolemia maintain cerebral oxygenation(ScO2) at higher levels of lower body negative pressure (LBNP) compared to their low tolerant (LT) counterparts, despite similar reductions in absolute flow. Methods: 15 healthy human subjects (10 male; 5 female) were instrumented for assessment of ScO2 (via near‐infrared spectroscopy, NIRS) and mean middle cerebral artery velocity (MCAv; via transcranial Doppler, TCD). All subjects completed a presyncopal‐limited lower body negative pressure (LBNP) protocol with an onset rate of 3 mmHg/min. Subjects who made it to 蠅80mmHg LBNP were classified as HT, and subjects who made it to 蠄70 mmHg LBNP were classified as LT. Results: The minimum difference in LBNP tolerance between the HT (N=6) and LT (N=9) group was 206 s (LT=1400±104 s vs. HT=2080±65 s; P=0.0003). Up to ‐45 mmHg LBNP, ScO2 was maintained in HT subjects (P蠅0.538), while the LT (N=9) subjects had a progressive decrease in ScO2 (P蠄0.016) from baseline. MCAv decreased from baseline in both HT and LT subjects (P蠄0.022). There was a strong linear relationship between %∆ MCAv and %∆ ScO2 within the LT group (R2=0.98; P=0.013), whereas a weaker association between perfusion and oxygenation (R2=0.53; P=0.271) was observed in the HT group. Conclusion: In support of our hypothesis, higher tolerance to progressive central hypovolemia was associated with the protection of ScO2, despite an early and significant reduction in cerebral blood flow. This may have important clinical implications for the monitoring of cerebral perfusion and oxygenation in trauma patients.Grant Funding Source: US Army Medical Research and Materiel Command