bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionary Potential and Morphological Integration of the Shoulder Girdle Among Primates
Authors: Agosto Elizabeth R. , Auerbach Benjamin M. 
Published: April 2020

The morphology of the shoulder girdle is highly varied among primates, possibly reflecting an array of functional demands placed through the range of locomotor and behavioral movements exercised in the upper limb. Variation in the shoulder girdle, and especially the scapula, is hypothesized to be the result of directional selection for different functional demands. Evolutionary analyses of the shoulder girdle often assess this anatomical region and its traits individually, which implicitly models the evolution of the girdle as independent of other traits. However, the primate shoulder girdle has developmental and functional covariances with the basicranium, pelvis, humerus, and vertebral column that we have recently demonstrated have potential to influence its evolution through correlated responses to directional selection. Whether these relationships are similar across primate taxa and how these relationships may affect morphological variation among primates is unknown.Here we evaluate the strength of the covariance and evolutionary potential among four anatomical regions: shoulder girdle, basicranium, pelvis, and humerus. We obtained cranial and postcranial linear dimensions from Alouatta, Colobus, Homo, Hylobates, and Papio. Measurements were mean standardized prior to analysis. We estimated morphological integration using Wagner's variance of the eigenvalues (VE), and estimated evolutionary potential using Hansen and Houle's evolutionary flexibility (EF) with 1000 simulated random selection gradients. EF captures how closely the evolutionary response in a group of traits follows the direction of the selection. We evaluated differences in VE and EF among taxa by performing a pairwise comparison of the bootstrapped values for each. Analyses were performed using the R statistical environment.Our results show that patterns of morphological integration and evolutionary flexibility among anatomical regions differ across primate taxa, with humans having the greatest evolutionary potential and Papio the lowest. Broadly, the patterns revealed among taxa do not strictly correspond to the functional demands of the upper limb experienced by each; taxa with different locomotor demands on the upper limb have the same kinds of covariance or evolutionary flexibility. Thus, evolutionary hypotheses of primate shoulder girdle morphological variation that evaluate functional demands alone may not account for the effect of these relationships. We conclude that different trait covariances among anatomical regions may manifest as morphological differences in the primate shoulder girdle, which has important implications for models of shoulder evolution.Support or Funding InformationThis research is supported by a National Science Foundation Doctoral Dissertation Improvement Grant (NSF BCS‐1825995).
Assessing Undergraduate Competencies in Biochemistry and Molecular Biology via an Annual Exam
Authors: Tyler Ludmila , Carastro L. Michael , Zeidan Quira , Wolfson Adele J. , Tansey John T. , Offerdahl Erika G. , Del Gazio Moore Victoria , Martin Debra , Loertscher Jennifer , Kennelly Peter J. , Kanipes Margaret I. , Dries Daniel R. , Dean Diane M. , Bailey Cheryl 
Published: April 2020

Assessment of student learning can both provide a measure of individual achievement and support data‐driven decisions about educational programs. The annual American Society for Biochemistry and Molecular Biology (ASBMB) Certification Exam is an important component of the undergraduate accreditation program offered by the Society. Exam development and scoring have resulted in a community of scientist‐educators dedicated to the improvement of biochemistry and molecular biology (BMB) education. The exam assesses student competence in four BMB concept areas: energy and metabolism; structure and function; information storage and transfer; and quantitative reasoning. Undergraduate students nearing completion of their ASBMB‐accredited program are eligible to take the exam. A community of volunteers, aided by the organizational efforts of ASBMB staff, has come together to implement all aspects of the exam process. Over 50 volunteers from diverse institutions across the country helped score the exam in 2019, and additional volunteers are being recruited for 2020. This scoring community primarily consists of BMB faculty members, but also welcomes postdoctoral scientists and advanced graduate students. In preparation for the exam, scoring teams review and suggest revisions for proposed exam questions and answer keys. Several scoring teams of 3–5 members are assigned to each concept area, and each exam question is scored independently by one or more teams. Student responses are marked as “highly proficient”, “proficient”, or “not yet proficient”. Scoring is statistically analyzed for inter‐rater reliability. Any discrepancies are resolved cooperatively. Students’ overall exam scores are categorized as “Pass with Distinction”, “Pass”, or “Not Passing”. Since the exam was first administered in 2014, nearly 4,000 students have participated. Historically, the “Pass with Distinction” rate has ranged between 10% and 18% and the “Pass” rate 35% to 55%. Scorers value the opportunity to contribute to this national effort to support quality BMB education. Many have served in this role for multiple years, and 98% of the 2019 scorers report they plan to score again in 2020.Support or Funding InformationThis project is supported by the American Society for Biochemistry and Molecular Biology, through the Education and Professional Development Committee.
Structural and Functional Insights into Aldosterone Synthase Interaction with Ligands and Redox Partner Proteins for Enhanced Treatment of Hypertension
Authors: Brixius-Anderko Simone , Scott Emily 
Published: April 2020

Primary aldosteronism is the most common form of secondary hypertension and is often associated with cardiac disease. Primary aldosteronism develops due to excessive amounts of the steroid hormone aldosterone, the most potent human mineralocorticoid. Aldosterone synthesized by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) regulates blood pressure and mineral homeostasis. CYP11B2 is 93% identical to the cortisol‐producing CYP11B1. As a result, treatment of aldosterone‐derived hypertension is impeded due to the lack of drugs specifically targeting CYP11B2.Herein a structure/function approach was used to examine CYP11B2 interaction with both 1) drugs and 2) its redox partner protein adrenodoxin. First, the X‐ray structure of CYP11B2 was determined with the drug LCI699. LCI699 was initially developed as CYP11B2 inhibitor but is now the first drug in clinical trials for the treatment of Cushing’s disease as an inhibitor of CYP11B1. LCI699 positioning in the CYP11B2 active site and comparison with similar compounds in CYP11B1 provides valuable clues for enhanced design of drugs for both enzymes. The second half of this study is focused on CYP11B2 interaction with its redox partner protein adrenodoxin. Studies revealed that adrenodoxin promotes CYP11B2 binding of its physiological substrate 11‐deoxycorticosterone and an adrenodoxin/CYP11B2 fusion protein was generated to examine the protein/protein interaction. An X‐ray structure of this complex identified the adrenodoxin binding site on the proximal face of CYP11B2 and specific interactions. Overall these studies improve our understanding of the aldosterone biosynthetic system and support the design of selective drugs for primary aldosteronism.Support or Funding InformationThe research was funded by a postdoctoral fellowship from the American Heart Association (19POST34430199, SBA) and startup funds from the University of Michigan (EES).
Exercise Preconditioning Prevents Chemotherapy‐Induced Alterations to Transport Proteins Required for Mitochondrial Iron Uptake and Metabolism in the Diaphragm
Authors: Smuder Ashley J. , Huertas Andres Mor , Morton Aaron B. 
Published: April 2020

Doxorubicin (DOX) is an anthracycline antibiotic used in cancer treatment. Unfortunately, the clinical use of this highly efficacious anticancer drug is limited due to the development of respiratory and diaphragm muscle dysfunction in patients. DOX‐induced ventilatory impairment is a debilitating condition that promotes the onset of dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOX‐induced respiratory insufficiency are unclear, it has been proposed that DOX myotoxicity develops as a result of increased cellular reactive oxygen species production and mitochondrial iron accumulation. Conversely, endurance exercise training performed prior to DOX administration has been shown to prevent the chemotherapy‐induced diaphragm weakness and mitochondrial dysfunction. While the mechanisms for this protection remain elusive, evidence suggests that exercise may provide protection by attenuating DOX‐induced alterations to proteins required to maintain mitochondrial iron homeostasis. Cause and effect were determined by exposing Sprague‐Dawley rats to a two‐week treadmill preconditioning protocol (5 days/week; 60 min/day; 30 m/min). Twenty‐four hours following the last exercise training period, animals received either saline or DOX (20mg/kg ip) treatment. Our results demonstrate that DOX administration in sedentary animals results in increased expression of the mitochondrial iron importer mitoferrin‐1 and a significant reduction in the cellular iron importer transferrin receptor 1 in the diaphragm. In addition, DOX also stimulated a significant decrease in the expression of sideroflexin 2 and SLC25A28, proteins required for mitochondrial heme biosynthesis. Importantly, exercise training prior to DOX administration prevented the DOX‐induced increase in mitoferrin‐1, and also reduced mitoferrin‐2 below that of sedentary animals treated with DOX. Moreover, diaphragm expression of SLC25A38 was maintained in exercise trained animals receiving DOX. These findings confirm a role for mitochondrial iron accumulation and dysregulation of heme synthesis in the development of DOX‐induced respiratory dysfunction, and demonstrate that exercise preconditioning may ameliorate DOX‐mediated diaphragm muscle pathology through the prevention of mitochondrial iron dysregulation.Support or Funding InformationThis work was supported by NIH R01 HL146443 awarded to AJS
Simvastatin in Endothelial Cell Barrier Regulation: A Novel Role for SAMD4A
Authors: Faraj Reem , Kelly Gabriel T. , Feng Anlin , Roberts Rebecca , Kheshtchin-Kamel Nabia , Wang Ting 
Published: April 2020

IntroductionAcute lung injury (ALI) is a critical illness which results in significant morbidity and mortality. Endothelial barrier disruption is a key pathologic feature of ALI and serves as the main cause of life‐threatening microvascular leakage and alveolar flooding. Efforts to develop novel therapeutics have been futile with only a handful of agents available, none of which prevent or reverse endothelial barrier disruption. We believe that the answer may lie in the most unlikely of places: a cholesterol‐lowering drug. Simvastatin confers vascular protection through modulation of the endothelial barrier, attenuation of vascular leak, and promotion of endothelial repair following lung inflammation. Integrin β4 (ITGβ4, gene code: ITGB4), a transmembrane receptor protein, plays a key role in endothelial barrier regulation during ALI, and its upregulation is necessary for the enhanced barrier function seen following administration of simvastatin.RationaleThe mechanism by which simvastatin up‐regulates ITGβ4 expression has not been elucidated. We sought to define the mechanistic pharmacology that controls the regulation of ITGβ4 mRNA and protein expression by simvastatin.MethodsIn this study, we identified potential RNA binding proteins regulated by simvastatin and inflammatory mediators that target ITGB4 using genomic analysis and molecular biology methods (western blotting and silencing), and further validated with endothelial cell biology approaches. Endothelial barrier function modulation is also investigated by electric cell‐substrate impedance sensing (ECIS).ResultsWe have identified that Sterile Alpha Motif Domain‐Containing Protein 4A (SAMD4A), an ITGB4 RNA binding protein, is up‐regulated by LPS or TNFa, and downregulated by simvastatin. Additionally, intracellular SAMD4A levels are negatively correlated with ITGB4 mRNA levels. Silencing of SAMD4A in endothelial cells (ECs) results in increased mRNA expression of ITGB4 and enhances ITGB4‐mediated barrier function in ECs.ConclusionOur results suggest that simvastatin upregulates ITGB4 via the suppression of SAMD4A, an ITGB4 RNA binding protein, leading to enhanced endothelial cell barrier function. These findings have re‐defined the pharmacology of simvastatin on ITGB4 regulation. Furthermore, SAMD4A may serve as a novel therapeutic target for ALI via the modulation of EC barrier.Support or Funding InformationThis study is supported by NIH grants HL134610 and T32HL007249.
Detecting early onset of chemotherapy‐related cardiac dysfunction in breast cancer patients in the West Virginian population using a novel panel of biomarkers
Authors: Lakhani Hari Vishal , Zehra Mishghan , Pillai Sneha S. , Desauguste Rutmann , Thompson Ellen , Tirona Maria Tria , Sodhi Komal 
Published: April 2020

BackgroundCardiotoxicity has been intricately linked in breast cancer patients receiving anthracyclines therapy in the clinical setting. The cumulative line of evidence has demonstrated that cardiotoxic manifestation associated with breast cancer treatment increases patients’ susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post‐anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. An important role of altered levels of serum biomarkers and circulating miRNAs have been implicated in modulating cardiac vasculature and cardiac damage.HypothesisThis study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, to assess the correlation between anthracycline agents and development of cardiac dysfunction, which will allow to monitor and detect early‐onset of chemotherapy related cardiac dysfunction.Materials and MethodsA total of 17 female patients with a clinical diagnosis of invasive ductal carcinoma were enrolled for the study. Blood was withdrawn and echocardiography assessment was performed at baseline (prior to initiation of anthracyclines), 3months and 6months post‐initiation of anthracycline agents. Subsequently, a total of 17 healthy controls were also recruited for the study without any form of cancer or cardiovascular complications. Enzyme Linked Immunosorbent Assays (ELISA) were performed for biomarker analysis and RT‐PCR was performed for expression of circulating miRNA levels.ResultsOur results showed that interleukin‐6 (IL‐6), matrix metalloproteinase ‐2 (MMP2) and ‐9 (MMP9), myeloperoxidase (MPO) and topoisomerase II beta (TOP2B) were significantly upregulated in serum obtained at 3months and 6months study interval post anthracycline initiation, as compared to baseline and healthy controls (p<0.01). The circulating levels of miR‐34a, miR‐208b, miR‐126, miR‐150, miR‐423 and miR‐499a were positively correlated and showed elevated levels at 3months and even higher in 6months study interval, while levels of miR‐29a were reduced at 3months, and much lower at 6months, as compared to control group (p<0.01). Assessment of echocardiographic measurements exhibited greater extent of cardiac dysfunction at 3months and 6month study interval.ConclusionOur results support the clinical application of these serum biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.Support or Funding InformationThis work was supported by the Brickstreet Foundation (J.I.S.).
Optimization of Propargylcholine to Label Newly Synthesized Myelin in the Rhesus Monkey Brain
Authors: Bottenfield Karen R. , Moore Tara L. , Mortazavi Farzad , Rosene Doug L. 
Published: April 2020

Neuropathology in monkey and human brains often involves loss or damage to myelin and is a major factor impacting normal function as myelin constitutes 35%–40% of the forebrain. Methods to assess alterations in myelin include electron microscopy, histological stains (e.g. Luxol Fast Blue), immunohistochemistry (e.g. for myelin basic protein) and a label free confocal method (SCoRe), as well as diffusion MRI. Each method has advantages but none offer a reliable, validated method to assess microscopic changes in myelin (synthesis or repair) across the entire forebrain from gray matter fascicles to subcortical white matter. Here we present preliminary data that newly synthesized myelin can be detected with in vivo administration of a choline analog, propargylcholine (P‐Cho), that is readily incorporated into all classes of choline phospholipids including major components of the myelin sheath, phosphatidylcholine and sphingomyelin. Importantly, since P‐Cho contains an alkyne moiety, it can be visualized post mortem by conjugation with a fluoro‐labeled azide using click chemistry and detection with confocal microscopy. P‐Cho can be administered by intraperitoneal injection where it enters the circulation and is incorporated into myelin, allowing detection and quantification of newly synthesized myelin. While previous research has demonstrated the use of P‐Cho for assessing remyelination in mice, its efficacy and safety in monkeys has yet to be explored. This is important for our monkey model of normal aging where age‐related myelin pathology accounts for cognitive deficits and for our studies of recovery after damage to the motor cortex. The ability to quantify myelin plasticity in both of these models could provide significant insight into myelin pathology, repair, and maintenance. To test this, we administered P‐Cho daily for 6 days via IP injections (3.5 – 4.0 mg/kg) to 6 young adult and 1 older adult monkey at different time points before euthanasia (1, 2 and 6 weeks). Frozen brain sections were cut, labeled with a fluorescent azide, and the sections evaluated for the presence and specificity of P‐Cho by co‐labeling the tissue with antibodies for axons (SMI‐312) and newly formed actively myelinating oligodendrocytes (BCAS1). Co‐localization of P‐Cho was also performed using confocal reflectance microscopy (SCoRe). Preliminary analyses suggest effective incorporation of P‐Cho into newly synthesized myelin within 1 week of dosing and sustained presence beyond 6 weeks. These results demonstrate a promising new method for investigating remyelination and white matter pathologies related to aging that could also be applied to studies of neurodegeneration, brain injury, and neurological diseases in an animal model highly translatable to humans.Support or Funding InformationNIH Grants R01‐AG062831, R01‐AG043640; R01‐AG042512; R21‐AG061678; R21‐NS111174, U01‐NS076474
Nuclear Receptor Small Heterodimer Partner Inhibits Proinflammatory Macrophage Polarization in Liver Disease
Authors: Ahamed Forkan , Magee Nancy , Zhang Yuxia 
Published: April 2020

ObjectiveMacrophages are the first responding cells to hepatocyte injuries and play a central role in innate immune response during the pathogenesis of liver diseases. Macrophage polarization to pro‐inflammatory M1 or anti‐inflammatory M2 sub‐populations is a critical event of inflammatory response which balances tissue injury and repair. Various types of signaling pathways have been identified that direct macrophage polarization; however, the regulatory mechanisms that coordinate the pathways are still not well understood. In this study we investigated the role of small heterodimer partner (Shp), an orphan nuclear receptor, in regulating the signaling pathways involved in macrophage polarization during the development of liver diseases.MethodsPrimary macrophages isolated from mouse liver were differentiated into pro‐inflammatory M1 or anti‐inflammatory M2 macrophages and Shp expression was determined during the differentiation. Mouse macrophage cell line RAW 264.7 overexpressed with Shp was treated with lipopolysaccharide (LPS) to evaluate inflammatory response. For the in vivo studies, we generated macrophage‐specific Shp deficient mice (Shp‐MKO represents Shp flox/flox; LysMCre+/−) and littermate controls (Shp‐WT represents Shp flox/flox; LysMCre−/−). Two different animal models were used to assess inflammatory responses in the liver, including high fat, cholesterol, and fructose (HFCF) diet‐induced nonalcoholic steatohepatitis (NASH) model and LPS‐induced acute inflammatory model.ResultsShp expression was down‐regulated during pro‐inflammatory M1 macrophage differentiation and up‐regulated in anti‐inflammatory M2 macrophage differentiation. Overexpression of Shp in Raw 264.7 cells resulted in inhibition of LPS‐induced activation of NF‐κB pathway compared to control cells. In addition, Shp overexpression downregulated MAP kinase pathway activation by inhibiting the phosphorylation of MKK4, JNK and c‐jun. Consistently, the in vivo study showed that both NF‐κB and MAP kinase signaling pathways were highly activated in the Shp‐MKO with the increased serum levels of TNF‐α and CCL2 after LPS treatment. Strikingly, macrophage polarization toward pro‐inflammatory M1 stage was enhanced in the Shp‐MKO liver in comparison to the Shp‐WT, which is evidenced by increased iNOS, IL‐6 and TNF‐α production upon LPS injection. On the molecular level we found that SHP interacted with proteins involved in NF‐κB and MAP kinase pathways and thereby coordinated macrophage polarization. Finally, without affecting hepatocyte steatosis Shp‐MKO mice were more susceptible to HFCF‐induced NASH progression with monocyte infiltration and liver fibrosis.ConclusionOur study uncovered a unique role of SHP in regulating macrophage polarization that couples both NF‐κB and MAP kinase pathways, which impacts the pathogenesis of acute and chronic inflammatory liver diseases.Support or Funding InformationThis project was supported by grants NCI K22CA184146, R01DK119131 and NIH P20 GM103549.