bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate Cancer Aggressiveness is Positively Associated with Oxidative Stress and Inversely Associated with Plasma Total Antioxidant Capacity (LB371)
Authors: Vance Terrence M. , Lee Sang Gil , Azabdaftari Gissou , Su L. Joseph , Fontham Elizabeth T. H. , Bensen Jeannette T. , Mohler James L. , Chen Ming‐Hui , Koo Sung I. , Chun Ock K. 
Published: June 2021

Prostate cancer (PCa) is the most common non‐cutaneous cancer in men in the US. Although the causes for PCa have yet to be determined, oxidative stress (OS) may be involved. In this study, urinary 8‐isoprostane and plasma total antioxidant capacity (TAC) were measured in a subsample of research subjects (n = 261 plasma, 279 urine) in the North Carolina‐Louisiana Prostate Cancer Project to determine the association between OS, TAC, and PCa aggressiveness. Compared with low and intermediate aggressive cases of PCa, high aggressive cases were found to have lower plasma TAC (mean: 366 vs 610 mM Trolox, n = 22 vs. 239; Wilcoxon rank test, P = 0.05) and higher urinary 8‐isoprostane levels (mean: 177 vs. 147 ng/mmol creatinine, n = 27 vs. 252; log transformed, t‐test, P < 0.05). Plasma TAC was negatively correlated with urinary 8‐isoprostane levels (ρ = ‐0.15; P < 0.05). In simple logistic regression models of high vs. low and intermediate aggressive cases, PCa aggressiveness was negatively associated with TAC, T3 vs. T1 OR=0.19 (95% CI, 0.04, 0.88; P < 0.05), and positively associated with urinary 8‐isoprostanes, T3 vs. T1 OR=3.16 (95% CI, 0.97, 10.30; P = 0.06). These findings suggest that the body’s compromised antioxidant defense and oxidative stress may contribute to PCa aggressiveness.Acknowledgement: The authors thank the staff, advisory committees and research subjects participating in the North Carolina‐Louisiana Prostate Cancer Project (PCaP) study for their important contributions.Grant Funding Source: Funded by NIH Cancer Epidemiology Small Grant #1R03CA159421‐01A1 and Department of Defense contract DAMD 17‐03‐2‐0052
Obesity is associated with increased red blood cell folate despite lower intake and serum levels of this vitamin among adults in the United States (LB411)
Authors: Bird Julia , Liu Zhenhua 
Published: June 2021

Background: Folates are essential cofactors in various metabolic pathways. Limited evidence has investigated how obesity affects folate metabolism. We investigated the association between body mass index (BMI) and obesity‐related metabolic factors with blood folate status.Methods: A representative study population of 3829 US adults was derived from the National Health and Nutrition Examination Survey (2003‐2006). Regression analyses were performed to examine the association between BMI and obesity‐related metabolic factors with serum folate and red blood cell (RBC) folate.Results: Serum folate levels were lowest in both the underweight and obese groups, closely paralleling with the lower dietary folate intakes in these two groups. In contrast, RBC folate incrementally increased with BMI. Regression analyses demonstrated a negative relationship between BMI and serum folate, but a positive relationship for RBC folate. These relationships were significant for 19‐50 year old individuals, but not for elders (蠅 51 yrs).Conclusion: Obesity is associated with decreased serum folate, and concurs with lower total intake among the obese. In contrast, obesity is positively associated with increased RBC folate. These relationships are significant for young and middle‐aged adults, but not for elders. RBC folate appears to be a better biomarker of cellular folate status in obese individuals.Grant Funding Source: Supported in part by the USDA/NIFA grant (2014‐67017‐21762, ZL), the USDA Hatch grant (MAS00454, ZL) and the funding from Rays of Hope Center of Breast Cancer Research, Baystate Medical Center (ZL)
Household food security and consumption of a traditional medicinal tincture, sraa tenam, among Cambodian women in Massachusetts (LB480)
Authors: Cordeiro Lorraine , Peterman Jerusha 
Published: June 2021

Background: Use of alcohol‐based tinctures is common during pregnancy and the postpartum period among Cambodians and other Southeast Asian populations. The consumption of alcohol‐based tinctures among Cambodians living in the U.S. has not been widely examined. This study investigates the association between household food security status and the consumption of a specific alcohol‐based medicinal tincture, sraa tenam, among Cambodian young women in Massachusetts.Method: Cambodian women aged 15‐30 years (n=127) were surveyed in this cross‐sectional study. Household food security was assessed using the U.S. Household Food Security 6‐item module. Participants provided data on their knowledge, attitudes, and practices of alcohol‐based medicinal tinctures. Multivariate logistic regression tested the association between the consumption of sraa tenam, an alcohol‐based medicinal tincture, and household food security scores, after adjusting for age, country of birth, and insurance coverage.Results: Approximately one‐fourth (25.6%) of the sample lived in low/very low food secure households. Forty‐two percent (42%) reported that they had consumed sraa tenam. Women with higher household food security scores were more likely to report consuming this alcohol‐based medicinal tincture compared to those with lower scores (β 0.423; 95% CI: 1.00, 2.33; p<0.05), after controlling for covariates.Conclusion: Consumption of an alcohol‐based medicinal tincture, sraa tenam, was associated with household food security status among Cambodian women in Massachusetts. Household food insecurity status may be an indicator of low utilization of conventional health care, leading to greater use of traditional medicine as a coping mechanism. Alcohol‐based tinctures have both risks and benefits: the use of alcohol in tinctures may contribute to nutritional deficiencies, and yet, alcohol‐based fermented tinctures may also have potential health benefits with levels of alcohol that may be too low to pose a risk to maternal and infant health. The overall risks and benefits of alcohol‐based medicinal tinctures need to be carefully investigated to support optimal maternal and child health. Raising awareness of traditional practices among health practitioners that serve SE Asian populations may also be important.Grant Funding Source: USDA
Targeting chemotherapy induced adaptive resistance using hybrid nanoparticles (LB577)
Authors: Kulkarni Ashish , Rao Poornima , Goldman Aaron , Sengupta Shiladitya 
Published: June 2021

Chemotherapy is still a standard of care in adjuvant treatment of breast cancer, but it often leads to incomplete tumor response resulting in acquisition of chemoresistance and relapse, primarily due to upregulation of survival signals in tumor cells. To overcome this, chemotherapeutic agent and signaling inhibitor need to be delivered to the same cell sequentially with a precise spatial and temporal control. We designed a hybrid nanoparticle platform that synergistically integrates a cytotoxic agent with an ‘Oncogenic Signaling Inhibitor’ into a single nanovector thereby overcomes adaptive resistance to cytotoxics, increase efficacy &amp; minimize significant off‐target toxicities. As traditional approaches for nanoformulation were incompatible with cytotoxic molecules such as Paclitaxel (PTX) and PI3K inhibitors (PI103), we rationally re‐engineered these molecules by conjugating it to cholesterol to enable supramolecular nanoassembly. Hybrid supramolecular nanoparticles were synthesized by lipid film hydration method. In vitro cytotoxicity studies in multiple cell lines including Breast Cancer (4T1, MDA‐MB‐231), Ovarian Cancer (4306) and Lung Cancer (A549, LLC) showed that hybrid nanoparticles were as effective as free drug combinations and more potent that individual drug nanoparticles. In both 4T1 breast cancer and in a K‐RasLSL/+/Ptenfl/fl ovarian cancer model in vivo, hybrid nanoparticles exerted superior antitumor efficacy as compared with free drugs &amp; individual drug combination (p<0.01, one way ANOVA). Immunohistochemistry staining of tumor tissues for p‐AKT showed that the hybrid nanoparticles had significantly higher inhibition of p‐AKT as compared to individual drug nanoparticles (p<0.01, Student t‐test). These results posit supramolecular nanochemistry as a powerful approach that can potentially impact clinical translation of cytotoxic agents and PI3K inhibitors, and could be extended to enhance the efficacy of molecularly targeted therapeutics. Additionally, rational optimization of the chemical structures to facilitate supramolecular assembly can overcome existing limitations associated with parent molecules, thereby opening up possibility of resuscitating promising drug candidates that had failed to translate to clinics, rejuvenating drug pipelines.Grant Funding Source: National Institute of Health, Department of Defense, BCRP Collaborative Innovator award
Sodium and Proton effects On Inward Proton Transport through Na/K Pumps (LB848)
Authors: Artigas Pablo , Mitchell Travis , Zugaramurdi Camila , Gatto Craig 
Published: June 2021

The Na/K pump (NKA) exports 3Na in exchange for 2K, across animal plasma membranes. Ion binding sites I&amp;II can bind Na or K but site‐III exclusively binds Na in a voltage (V)‐dependent fashion. Without external Na or K the NKA imports H generating a current (IH). To crack IH relationship to ion interaction at their sites we investigated the characteristics of IH in ventricular myocytes and in Xenopus oocytes expressing ouabain‐resistant pumps. Lowering pH enlarged IH in both systems. In oocytes at pH 蠄5.6 a rapid increase in IH was followed by a slower inhibition (80% at pH 5). H‐activation was V‐dependent whilst H‐inhibition was V‐independent. In myocytes at pH 6 Nao stimulated IH at [Na] 蠄5 mM and inhibited at higher [Na]. In oocytes, only V‐independent Nao‐dependent inhibition was observed at pH 6 or 7.6 (K0.5~7 mM), but at pH 5 Na induced a nearly identical biphasic response than in myocytes at pH 6. Affinity for Ko was reduced (~10 fold) by pH 5 compared to pH 7.6. Our results suggest that H+ leak through site‐III, that binding of 2Na or 2H to sites‐I&amp;II inhibit permeation and that NKA with mixed Na/H occupancy of sites‐I&amp;II are also permeable to H. Supported by NSF MCB‐1243842.Grant Funding Source: NSF MCB‐1243842
Therapeutic Role of Ambrisentan for the Treatment of Hypoxic Pulmonary Vasoconstriction: Impact of Intrapulmonary Delivery
Authors: Ferguson Scott , Loomis Zoe , Harral Jules , Redinius Katherine , Dixon Kandice , Anderson Malcolm , Irwin David 
Published: June 2021

Hypoxic pulmonary vasoconstriction (HPV) results in robust increases in pulmonary artery pressures (PAP), which underlie the development of pulmonary hypertension (PH), and potentially edema, in those that travel to or work at altitude. Endothelin‐1 receptor (ET‐1) antagonists are currently given orally to treat PH, however intrapulmonary delivery of this therapeutic may provide acute relief of the HPV response at a lower dose and thus could ameliorate the functional impairments caused by PH whilst minimizing the amount of drug required. Despite this potential, the efficacy of intrapulmonary ET‐1 antagonist therapy to treat hypoxia induced PH has yet to be determined. We tested the hypothesis that intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan would attenuate an HPV mediated increase in PAP when compared to a saline control. Adult male Sprague‐Dawley rats were randomized into three groups to receive aerosolized saline (Saline, n=8), a low dose (ALD, 1 mg/kg, n=8) or high dose (AHD, 5 mg/kg, n=8) of Ambrisentan (administered via a microinhaler) following the induction of HPV (via 13% inspired O2, simulating ~4000m). PAP were monitored continuously throughout the procedure via indwelling catheters. Pre‐hypoxia PAP values were not different between groups (Saline: 18 ± 1, ALD 19 ± 1, AHD: 17 ± 1 mmHg, P>0.05). Following an initial hypoxia induced increase in PAP (Saline: 37 ± 1, ALD: 30 ± 2, AHD: 33 ± 2 mmHg, P<0.05 vs. pre‐hypoxia for all) intrapulmonary Ambrisentan reduced significantly PAP when compared to Saline (Saline: 34 ± 1, ALD: 23 ± 1, AHD, 23 ±1 mmHg, P<0.05) with no significant differences between ALD and AHD (P>0.05). Intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan reduced significantly the increase in PAP following exposure to hypoxia with no significant differences between low and high doses. These results suggest that intrapulmonary delivery of Ambrisentan, at a dose approximating 1/5th of that given orally, may be an effective therapeutic for the treatment of hypoxia induced PH. Given the life threatening complications and impaired work capacity associated with PH and high altitude pulmonary edema (HAPE), individuals traveling to or working at altitude (i.e. military and mining personnel, mountain athletes) as well as those suffering from pathologically induced PH may benefit from acute intrapulmonary delivery of Ambrisentan.Support or Funding InformationONR# N00014‐14‐1‐0699DARPA # N66001‐10‐C‐2134
Interactions Among rsm ncRNAs and Rsm RNA‐binding Proteins in the Plant Pathogen Pseudomonas syringae DC3000
Authors: Rous Clarissa J. , Fishman Max , Filiatrault Melanie J. 
Published: June 2021

In response to changing environmental stimuli, many bacterial species utilize the Csr/Rsm system of posttranscriptional gene expression regulation to control metabolism, motility, biofilm formation, and quorum sensing. Most Csr/Rsm RNA binding proteins are thought to bind near the 5′ end of mRNA transcripts to prevent translation. Small noncoding RNA molecules (ncRNAs), containing conserved binding sites, can sequester the Csr/Rsm proteins to allow translation of mRNA targets. This system consists of one to two proteins and two to three ncRNAs in most bacteria. However, the genome of Pseudomonas syringae pv. tomato strain DC3000 is predicted to encode five Rsm proteins and seven ncRNAs and it is currently unknown which ncRNAs and mRNAs targets bind to each protein. This project sought to determine the conditions of protein expression and to identify which ncRNAs and mRNAs targets bind to each protein. DC3000 strains were designed to express each of the RNA‐binding proteins with a peptide tag, to facilitate immunoprecipitation and isolation of bound mRNAs and ncRNAs. We found that RsmA1, 4, and 5 were not expressed under the conditions tested. RsmA2 and RsmA3 were both expressed in stationary phase in Mannitol‐glutamate media. RNA immunoprecipitation (RIP) followed by qRT‐PCR showed that RsmA2 binds to (in order of decreasing abundance) ncRNAs rsmX‐1, rsmX‐2, rsmX‐3, and rsmY; RsmA3 binds to rsmX‐1, rsmX‐2, and rsmY. Transcripts for rsmZ and rsmX‐4 were not detected. The ncRNA rsmX‐5 was expressed but not significantly enriched in RIP, indicating that it does not bind to RsmA2 or 3 under these conditions. Additionally, mRNA targets were identified based on homology to computationally predicted targets in Pseudomonas aeruginosa. None of the predicted mRNA targets (PSPTO 1951, 0823, 3382, 5128, 0816, 1994, 4224) showed enrichment. It may be that these are not targets, or that the proteins were sequestered by the ncRNAs and not binding to mRNA under the experimental conditions. These results have shed light on the highly complex Rsm system in P. syringae and provide a foundation for future experimentation on Rsm protein associations with mRNAs and ncRNAs under various conditions in order to delineate the mechanisms of this global system of gene regulation.Support or Funding InformationThis project was funded by National Science Foundation grant DBI‐1263103.
Conformational Flexibility Enables Function of a BECN1 Region Essential for Starvation‐Mediated Autophagy
Authors: Sinha Sangita , Mei Yang , Ramanathan Arvind , Glover Karen , Yang Zhongyu , Colbert Christopher 
Published: June 2021

BECN1 is essential for autophagy, a critical eukaryotic cellular homeostasis pathway. Here we delineate a highly conserved BECN1 domain (residues 141–171), located between the previously characterized BH3 and coiled‐coil domains, and elucidate its structure and role in autophagy. The 2.0 Å Sulfur‐Single Wavelength Anomalous Diffraction crystal structure of this domain demonstrates that its N‐terminal half is unstructured, while its C‐terminal half is helical, hence we name it the Flexible Helical Domain (FHD). Circular dichroism, Double‐Electron‐Electron Resonance‐Electron Paramagnetic Resonance and Small Angle X‐ray Scattering (SAXS) analyses confirm that this domain is partially disordered even in the context of adjacent BECN1 domains. Molecular dynamic simulations fitted to SAXS data indicate that the FHD transiently samples more helical conformations in solution. Strikingly, the FHD is predicted to fold upon binding, and we find it becomes more helical in the presence 2,2,2‐trifluoroethanol, indicating it may undergo a disorder‐to‐helix conformational change upon binding to a partner. A completely helical conformation would place highly conserved FHD residues on the same face of the helix, suggesting that these residues may be involved in binding. Lastly, cellular studies show that highly conserved FHD residues are essential for the starvation‐induced up‐regulation of autophagy, the first BECN1 region shown to be critical for starvation‐induced autophagy rather than basal autophagy. Thus, our combined data suggest that the FHD likely undergoes a disorder‐to‐helix transition upon binding to appropriate partners, and conserved residues critical for this interaction are essential for starvation‐induced up‐regulation of autophagy.Support or Funding InformationThis work was supported by National Institutes of Health grants RO3 NS090939 (S.S.) and R15 GM113227 (C.C.); a National Science Foundation grant MCB‐1413525 (S.S.); North Dakota EPSCoR doctoral dissertation award for Y.M. (S.S.). AR was supported by a ORNL Laboratory Director's Research and Development SEED proposal 7278.
Comparative Genomics and Functional Analysis of Carbohydrate Utilization Networks in Unicyanobacterial Consortia Derived from Hypersaline Lake Microbial Mats
Authors: Leyn Semen A , Maezato Yukari , Romine Margie , Rodionov Dmitry A 
Published: June 2021

Hot Lake is a meromictic, hypersaline lake located in Washington state, USA. It harbors a phototrophic microbial mat community stable in dramatic seasonal environmental changes. The complexity of natural community hinders to analyze metabolic interactions between its members. To manage this obstacle, unicyanobacterial consortia (UCC) were sampled from the community and sequenced. UCC is a microbial community in which one cyanobacterium serves as the sole primary producer of carbon sources to several heterotrophic bacteria.Recently available metagenomes for two UCC revealed a shared set of 19 microbial operational taxonomic units (OTU), whose individual genomes were reconstructed by co‐assembly and abundance profile binning. We used this genomic data and a comparative genomics approach to infer carbohydrate utilization pathways and their transcription regulation.We scanned all UCC proteomes against the KEGG Orthology, Pfam, GO and SEED databases to reveal genes potentially involved in sugar utilization. Then we analyzed the genomic and functional contexts of gene loci encoding the obtained proteins and reconstructed the respective metabolic pathways and transcriptional regulons.As result, we observed catabolic pathways for 32 various carbohydrates and their derivatives. Distribution of the inferred catabolic pathways has highly mosaic structure across the UCC genomes. The largest number of pathways was observed in two representatives of the Halomonas genus (14–15 pathways) and one Rhodobacteriaceae sp. (15 pathways). In other UCC genomes, we found up to 10 carbohydrate utilization pathways per genome. However in 7 genomes we didn't observe any pathway. The most widely distributed pathways in UCC were the alpha‐glucosides and the DeLey‐Doudoroff galactose utilization pathways. Both were found in 7 genomes. Majority of pathways are distributed among 1–3 genomes. The reconstructed catabolic pathways were partially validated by phenotypic analyses of UCC community members that were isolated in a pure culture.In the Rhodobacteriaceae sp., we found a novel catabolic pathway that was proposed to be involved in mannoheptulose utilization. To our knowledge, the proposed mannoheptulose catabolic pathway is the first case of a pathway for heptose utilization and will require further experimental validation.The identified pathways are potentially regulated by local transcription factors (TFs) that are often co‐localized with the respective sugar catabolic gene loci. For 63 out of the 80 identified TFs we identified their cognate DNA binding motifs and reconstructed regulons using the bioinformatics approach.Support or Funding InformationThis research was supported by the Genomic Science Program (GSP), Office of Biological and Environmental Research (OBER), and U.S. Department of Energy (DOE) and is a contribution of the Pacific Northwest National Laboratory (PNNL) Foundational Scientific Focus Area.
Deciphering the Metal Dependency of Novel Nicotinate Hydroxylase from Bacillus niacini
Authors: Meek Jessica A , Sherer Laura A , Snider Mark J 
Published: June 2021

N‐Heterocyclic compounds are becoming increasingly common in the environment due to their miscibility in water and pose potential threats to wildlife due to their carcinogenic properties. Nicotinic acid (NA), a nontoxic ‐N‐heterocyclic aromatic compound, serves as a useful model for this class of compounds and is known to be degraded by a number of soil bacteria. Knowledge of the chemistries involved in NA degradation by these bacteria can be applied to bioremediation techniques to remove similar contaminates from the environment. Bacillus niacini is a common soil bacterium that is able to completely degrade and utilize nicotinic acid by a pathway that is largely uncharacterized. A gene cluster hypothesized to code the enzymes responsible for nicotinate degradation in B. niacini suggests that four proteins are involved in the first two steps of the nicotinate degradation pathway. The sequences predict that two Mo‐dependent hydroxylases (NicB1 and NicB2), a flavin‐dependent protein (NicA2) and a protein containing an [2Fe‐2S] cluster (NicA1) are potentially important for the first two oxidation steps of nicotinate degradation. To determine the metal dependency and further understand the mechanism of the NicAB enzymes, heterologous expression and purification of each of these enzymes was achieved from E. coli and Pseudomonas chlororaphis, analyzed for metal content and ability to catalyze the double hydroxylation of nicotinate to 2,6‐dihydroxynicotinate.Support or Funding InformationThis work was supported by funding from the College of Wooster Department of Chemistry and the National Science Foundation.
A Biophysical Analysis of Aspartic Acid Cyclization Coupled to Peptide Bond Cleavage
Authors: Koulopoulos Michael , Giaccone Zach , Reitter Julie , Mills Kenneth 
Published: June 2021

Protein splicing is the process by which a polypeptide chain, called an intein, catalyzes its excision from two flanking polypeptides, called exteins, concomitant with the exteins ligating together. We are interested in how inteins catalyze the splicing reaction and therefore are studying the third step of the mechanism via a fluorescence‐based assay using a model peptide. Currently, we are analyzing peptide bond cleavage due to cyclization of aspartic acid rather than asparagine, which is promoted at low pH and high temperature. We are currently studying the potential catalytic role of an adjacent histidine residue and carefully determining the influence of pH and temperature on the reaction.Support or Funding InformationThis material is based upon work supported by the National Science Foundation under grants MCB‐1244089 and MCB‐1517138 and by a Henry Dreyfus Teacher‐Scholar Award (KVM).