bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting the cosmic web: Lyα emission from simulated filaments at z = 3
Authors: Elias Lydia M , Genel Shy , Sternberg Amiel , Devriendt Julien , Slyz Adrianne , Visbal Eli , Bouché Nicolas
Published: April 2020

The standard cosmological model (Λ cold dark matter, ΛCDM) predicts the existence of the cosmic web: a distribution of matter into sheets and filaments connecting massive haloes. However, observational evidence has been elusive due to the low surface brightness levels of the filaments. Recent deep Multi Unit Spectroscopic Explorer (MUSE)/Very Large Telescope (VLT) data and upcoming observations offer a promising avenue for Lyα detection, motivating the development of modern theoretical predictions. We use hydrodynamical cosmological simulations run with the arepo code to investigate the potential detectability of large-scale filaments, excluding contributions from the haloes embedded in them. We focus on filaments connecting massive ($M_{200c}\sim (1\!-\!3)\times 10^{12}\hbox{$\rm \, M_{\odot }$}$) haloes at z = 3, and compare different simulation resolutions, feedback levels, and mock image pixel sizes. We find increasing simulation resolution does not substantially improve detectability notwithstanding the intrinsic enhancement of internal filament structure. By contrast, for a MUSE integration of 31 h, including feedback increases the detectable area by a factor of ≃5.5 on average compared with simulations without feedback, implying that even the non-bound components of the filaments have substantial sensitivity to feedback. Degrading the image resolution from the native MUSE scale of 0.2 arcsec2 pixel−1 to 5.3 arcsec2 apertures has the strongest effect, increasing the detectable area by a median factor of ≃200 and is most effective when the size of the pixel roughly matches the width of the filament. Finally, we find the majority of Lyα emission is due to electron impact collisional excitations, as opposed to radiative recombination.
The exterior gravitational potential of toroids
Authors: Huré J-M , Basillais B , Karas V , Trova A , Semerák O
Published: April 2020

We perform a bivariate Taylor expansion of the axisymmetric Green function in order to determine the exterior potential of a static thin toroidal shell having a circular section, as given by the Laplace equation. This expansion, performed at the centre of the section, consists in an infinite series in the powers of the minor-to-major radius ratio e of the shell. It is appropriate for a solid, homogeneous torus, as well as for inhomogeneous bodies (the case of a core stratification is considered). We show that the leading term is identical to the potential of a loop having the same main radius and the same mass – this ‘similarity’ is shown to hold in the ${\cal O}(e^2)$ order. The series converges very well, especially close to the surface of the toroid where the average relative precision is ∼10−3 for e = 0.1 at order zero, and as low as a few 10−6 at second order. The Laplace equation is satisfied exactly in every order, so no extra density is induced by truncation. The gravitational acceleration, important in dynamical studies, is reproduced with the same accuracy. The technique also applies to the magnetic potential and field generated by azimuthal currents as met in terrestrial and astrophysical plasmas.
Interstellar comet 2I/Borisov exhibits a structure similar to native Solar system comets
Authors: Manzini F , Oldani V , Ochner P , Bedin L R
Published: April 2020

We processed images taken with the Hubble Space Telescope(HST) to investigate any morphological features in the inner coma suggestive of a peculiar activity on the nucleus of the interstellar comet 2I/Borisov. The coma shows an evident elongation, in the position angle (PA) ∼0−180○ direction, which appears related to the presence of a jet originating from a single active source on the nucleus. A counterpart of this jet directed towards PA ∼10○  was detected through analysis of the changes of the inner coma morphology on HST images taken on different dates and processed with different filters. These findings indicate that the nucleus is probably rotating with a spin axis projected near the plane of the sky and oriented at PA ∼100−280○ , and that the active source is lying in a near-equatorial position. Subsequent observations of HST allowed us to determine the direction of the spin axis at right ascension (RA) = 17h20m ± 15○  and declination (Dec.) = $-35^\circ \, \pm 10^\circ$. Photometry of the nucleus on HST images of 2019 October 12 only spans ∼7 h, insufficient to reveal a rotational period. The morphology exhibited by the interstellar comet 2I/Borisov is very similar to that of comet C/2014 B1 suggesting that the activation processes are the same as those observed in the Solar system native comets.
VarFish: comprehensive DNA variant analysis for diagnostics and research
Authors: Holtgrewe Manuel , Stolpe Oliver , Nieminen Mikko , Mundlos Stefan , Knaus Alexej , Kornak Uwe , Seelow Dominik , Segebrecht Lara , Spielmann Malte , Fischer-Zirnsak Björn , Boschann Felix , Scholl Ute , Ehmke Nadja , Beule Dieter
Published: April 2020

VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.
Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on “Head Start” III: a multi-institutional, prospective clinical trial
Authors: Dhall Girish , O’Neil Sharon H , Ji Lingyun , Haley Kelley , Whitaker Ashley M , Nelson Marvin D , Gilles Floyd , Gardner Sharon L , Allen Jeffrey C , Cornelius Albert S , Pradhan Kamnesh , Garvin James H , Olshefski Randal S , Hukin Juliette , Comito Melanie , Goldman Stewart , Atlas Mark P , Walter Andrew W , Sands Stephen , Sposto Richard , Finlay Jonathan L
Published: April 2020

Background

“Head Start” III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma.

Methods

Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction.

Results

Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ± 5% and 62 ± 5% for all patients, 61 ± 8% and 77 ± 7% for localized medulloblastoma, and 35 ± 7% and 52 ± 7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ± 6% and 89 ± 6% compared with 26 ± 6% and 53 ± 7% for classic and 38 ± 13% and 46 ± 14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ± 8% for ND and 21 ± 5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average.

Conclusion

We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.
Effect of glucose and sucrose on cognition in healthy humans: a systematic review and meta-analysis of interventional studies
Authors: García Cristina Reche , Piernas Carmen , Martínez-Rodríguez Alejandro , Hernández-Morante Juan José
Published: April 2020

Context

Evidence suggests that plasma glucose levels may influence cognitive performance, but this has not been systematically reviewed and quantified.

Objective

The aim of this review was to investigate the potential effects of glucose and sucrose, compared with placebo, on cognition in healthy humans.

Data Sources

The electronic databases PubMed and Web of Science were searched up to December 2019. Reference lists of selected articles were checked manually.

Study Selection

Randomized controlled trials or crossover trials that compared glucose or sucrose with placebo for effects on cognition were eligible.

Data Extraction

Potentially eligible articles were selected independently by 2 authors. Risk of bias was assessed through the Cochrane Collaboration tool. Standardized mean differences (SMDs) were obtained from random-effects meta-analyses for a subsample of studies that reported the same outcomes.

Results

Thirty-seven trials were identified, of which 35 investigated the effect of glucose consumption compared with placebo on cognition. Two studies found no effect of glucose on cognition, while the others found mixed results. Only 3 of the 37 studies investigated the effects of sucrose intake, reporting mixed results. Meta-analyses revealed a significantly positive effect of glucose compared with control, but only when a verbal performance test (immediate word recall) was used in parallel-design studies (SMD = 0.61; 95%CI, 0.20–1.02; I2 = 0%). Twenty-four studies were classified as having high risk of bias for the selection procedure.

Conclusions

A limited body of evidence shows a beneficial effect of glucose in individuals performing immediate verbal tasks. High-quality trials with standardized cognitive measurements are needed to better establish the effect of glucose or sucrose on cognition.

Systematic Review Registration

PROSPERO registration number CRD42019122939.
PsbQ-Like Protein 3 Functions as an Assembly Factor for the Chloroplast NADH Dehydrogenase-Like Complex in Arabidopsis
Authors: Ishikawa Noriko , Yokoe Yuki , Nishimura Taishi , Nakano Takeshi , Ifuku Kentaro
Published: April 2020

Angiosperms have three PsbQ-like (PQL) proteins in addition to the PsbQ subunit of the oxygen-evolving complex of photosystem II. Previous studies have shown that two PQL proteins, PnsL2 and PnsL3, are subunits of the chloroplast NADH dehydrogenase-like (NDH) complex involved in the photosystem I (PSI) cyclic electron flow. In addition, another PsbQ homolog, PQL3, is required for the NDH activity; however, the molecular function of PQL3 has not been elucidated. Here, we show that PQL3 is an assembly factor, particularly for the accumulation of subcomplex B (SubB) of the chloroplast NDH. In the pql3 mutant of Arabidopsis thaliana, the amounts of NDH subunits in SubB, PnsB1 and PsnB4, were decreased, causing a severe reduction in the NDH–PSI supercomplex. Analysis using blue native polyacrylamide gel electrophoresis suggested that the incorporation of PnsL3 into SubB was affected in the pql3 mutant. Unlike other PsbQ homologs, PQL3 was weakly associated with thylakoid membranes and was only partially protected from thermolysin digestion. Consistent with the function as an assembly factor, PQL3 accumulated independently in other NDH mutants, such as pnsl1-3. Furthermore, PQL3 accumulated in young leaves in a manner similar to the accumulation of CRR3, an assembly factor for SubB. These results suggest that PQL3 has developed a distinct function as an assembly factor for the NDH complex during evolution of the PsbQ protein family in angiosperms.
Music Intervention in Pain Relief of Cardiovascular Patients in Cardiac Procedures: A Systematic Review and Meta-analysis
Authors: Wang Yiru , Wei Jing , Guan Xinzhu , Zhang Yifan , Zhang Yiyi , Zhang Na , Mao Meijiao , Du Wenting , Ren Yajuan , Shen Hong , Liu Ping
Published: April 2020

Background

Numerous meta-analyses have been conducted on music and pain, but no studies have investigated music and cardiac procedural pain.

Objective

To assess the effects of music intervention on pain in cardiac procedures in the published randomized controlled trials.

Methods

This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All the included randomized controlled studies were published between 1999 and 2016. Studies were obtained from electronic databases or by hand-searching of related journals and reference lists. The main outcome was pain intensity, and the secondary outcomes were vital signs such as heart rate, respiration rate, systolic blood pressure, and diastolic blood pressure. Risk of bias of the included studies was evaluated according to the Cochrane Collaboration guidelines.

Results

Analysis of 14 studies indicated that music interventions had statistically significant effects on decreasing pain scales (mean deviation [MD] = –1.84), heart rate (MD = –2.62), respiration rate (MD = –2.57), systolic blood pressure (MD = –5.11), and diastolic blood pressure (MD = 0.44). The subgroup analysis method was used in all five outcomes.

Conclusions

Considering all the possible benefits, music intervention may provide an effective complement for the relief of cardiac procedural pain.
Development of the PROMIS Pediatric Physical Activity Item Banks
Authors: Tucker Carole A , Bevans Katherine B , Becker Brandon D , Teneralli Rachel , Forrest Christopher B
Published: April 2020

Objective

The purpose of this study was to develop self-report and parent-proxy measures of children’s physical activity for clinical research and practice and to demonstrate a valid and reliable instrument of children’s lived experience of physical activity as reported by the children themselves or their parent proxies.

Methods

This study involved qualitative development of item pools followed by 2 cross-sectional validity and reliability studies. The National Institutes of Health Patient Reported Outcome Measurement Information System (PROMIS) instrument development standards were applied to create child self-report and parent-proxy physical activity instruments from previously developed, content-valid pools of physical activity items. Each item used a 7-day recall period and had 5 response options. Item bank calibration was based on national samples totaling 3033 children aged 8 to 17 years and 2336 parents of children aged 5 to 17 years. Quantitative analyses included reliability assessments, factor analyses, item response theory calibration, differential item functioning, and construct validation.

Results

The final item banks comprised 10 items each. The items were selected based on content and psychometric properties. The item banks appeared to be unidimensional and free from differential item functioning. They showed excellent reliability and a high degree of precision across the range of the latent variable. Child-report and parent-proxy 4- and 8-item fixed-length instruments were specified. The instruments showed moderate correlation with existing self-report measures of physical activity.

Conclusion

The PROMIS Pediatric Physical Activity instruments provide precise and valid measurement of children’s lived experiences of physical activity.

Impact

The availability of the PROMIS Pediatric Physical Activity instruments will support advances in clinical practice and research that require measurement of pediatric physical activity by self- and parent-proxy report.
Optimal Timing of Policy Announcements in Dynamic Election Campaigns*
Authors: Kamada Yuichiro , Sugaya Takuo
Published: April 2020

We construct a dynamic model of election campaigns. In the model, opportunities for candidates to refine/clarify their policy positions are limited and arrive stochastically along the course of the campaign until the predetermined election date. We show that this simple friction leads to rich and subtle campaign dynamics. We first demonstrate these effects in a series of canonical static models of elections that we extend to dynamic settings, including models with valence and a multidimensional policy space. We then present general principles that underlie the results from those models. In particular, we establish that candidates spend a long time using ambiguous language during the election campaign in equilibrium.
Corporate Governance in China: A Survey*
Authors: Jiang Fuxiu , Kim Kenneth A
Published: April 2020

This article surveys corporate governance in China, as described in a growing literature published in top journals. Unlike the classical vertical agency problems in Western countries, the dominant agency problem in China is the horizontal agency conflict between controlling and minority shareholders arising from concentrated ownership structure; thus one cannot automatically apply what is known about the USA to China. As these features are also prevalent in many other countries, insights from this survey can also be applied to countries far beyond China. We start by describing controlling shareholder and agency problems in China, and then discuss how law and institutions are particularly important for China, where controlling shareholders have great power. As state-owned enterprises have their own features, we separately discuss their corporate governance. We also briefly discuss corporate social responsibility in China. Finally, we provide an agenda for future research.
Recalibration of insecticide-measuring containers could prevent underdosing of insecticide during indoor residual spraying for visceral leishmaniasis (kala-azar) elimination in India
Authors: Saurabh Suman , Yadav Ravindra Kumar
Published: April 2020

Background

The visceral leishmaniasis (kala-azar) elimination programme in India relies on indoor residual spraying (IRS) for sand-fly vector control. Insecticide supplied by a new manufacturer was introduced for IRS in 2019. We aimed to explore whether this led to a change in insecticide quantity being used in the field.

Methods

We compared measurements of weights of 250 mL of insecticide powder of two different manufacturers using a certified and calibrated weighing instrument.

Results

The density of insecticide supplied in 2019 was 43.4% lower than that in 2018, thereby leading to underdosing during current IRS activity.

Conclusions

Insecticide-measuring containers should be recalibrated prior to every IRS round and also when an insecticide manufacturer changes, so that the insecticide dose is maintained within the recommended range.
Natural Infection of Southern Highbush Blueberry (Vaccinium corymbosum Interspecific Hybrids) by Xylella fastidiosa subsp. fastidiosa
Authors: Di Genova Dario , Lewis Kippy J. , Oliver Jonathan E.
Published: April 2020

Xylella fastidiosa (Xf) is an emerging insect-vectored, xylem-limited bacterium that can cause disease on several economically important fruit and tree crops including almond, blueberry, citrus, grapevine, peach, and pecan. On blueberry, Xf causes bacterial leaf scorch (BLS), which is prevalent in the southeastern United States. This disease, previously reported to be caused by Xf subsp. multiplex (Xfm), can result in rapid plant decline and death of southern highbush (SHB) blueberry cultivars. In 2017, a survey of blueberry plantings in southern Georgia (U.S.A.) confirmed the presence of Xf-infected plants in eight of nine sites examined, and seven isolates were cultured from infected plants. Genetic characterization of these isolates through single-locus and multilocus sequence analysis revealed that three isolates from two sites belonged to Xf subsp. fastidiosa (Xff), with significant similarity to isolates from grapevine. After these three isolates were artificially inoculated onto greenhouse-grown SHB blueberries (cv. ‘Rebel’), symptoms typical of BLS developed, and Xff infection was confirmed through genetic characterization and reisolation of the bacterium to fulfill Koch’s postulates. Because all previously reported Xf isolates from blueberry have been characterized as Xfm, this is the first time that isolation of Xff has been reported from naturally infected blueberry plantings. The potential impact of Xff isolates on disease management in blueberry requires further exploration. Furthermore, given that isolates from both Xfm and Xff were obtained within a single naturally infected blueberry planting, blueberry in southern Georgia may provide opportunities for intersubspecific recombination between Xff and Xfm isolates.
Effects of maltreatment on cortisol and inflammatory analytes
Authors: Wong Kingston E. , Molnar Danielle S. , Maguire Aindriu R. R. , Moore Jessy , O’Leary Deborah D. , MacNeil Adam J. , Wade Terrance J.
Published: April 2020

Adverse childhood experiences (ACEs) such as maltreatment have been associated with a disease risk phenotype that is characterized by altered regulation of the hypothalamic‐pituitary‐axis (HPA) and elevated pro‐inflammatory cytokines. However, there is evidence that different subtypes of ACEs elicit different physiological profiles. More specifically children with a history of physical abuse have lower cortisol levels whereas children with a history of sexual abuse have elevated cortisol levels compared to those in other maltreatment and non‐abused subgroups. The objective of the present study was to investigate if different maltreatment exposures, specifically physical and sexual abuse, are associated with HPA axis and inflammation by measuring levels of cortisol and inflammatory analytes. This study examines 156 young adults using the pilot data from the Niagara Longitudinal Heart Study (NLHS). Inflammatory analytes were assessed with blood serum. Retrospective chronic cortisol was measured through hair taken from the back of the scalp. Maltreatment was self‐reported using the Childhood Trust Event survey questionnaire. The NLHS study was approved by the Brock University’s Research Ethic Board. All analysis of variance models were not statistically significant. Those who reported sexual abuse had the highest cortisol levels. Those who reported physical abuse had the lowest cortisol levels compared to other subtypes. Interleukin 6 (IL6), C‐reactive protein (CRP), tumor necrosis factor α (TNFα), soluble tumor necrosis factor receptor 1 and 2 (sTNFR1 and sTNFR2) levels were higher among those with physical and sexual exposure compared to other subtypes. Levels of interleukin 6 receptor α (IL6Rα), glycoprotein (gp130), and interferon γ (IFNγ) were similar across all subtypes. The direction of cortisol levels pertaining to the subtypes of ACEs in the present study was consistent with the literature where physical abuse was linked to lower cortisol levels and sexual abuse was related to higher cortisol levels. Both physical and sexual abuse were trending towards statistical significance to some inflammatory analytes but not others. As the current pilot sample is underpowered for the effect sizes of cortisol and inflammatory analytes, the models used in analysis are likely to achieve statistical significance in a larger sample.

Support or Funding Information

The NLHS is funded by the Canadian Institutes of Health Research (CIHR #s 363774, 399332). ARRM is supported by the Ontario Graduate Scholarship (OGS) program.
Translational and Systems‐based Pharmacokinetic/pharmacodynamic Model for Predicting Abemaciclib and Doxorubicin Clinical Interaction in Rb‐positive Triple Negative Breast Cancer
Authors: Fleisher Brett , Lezeau Jovin , Werkman Carolin , Jacobs Brehanna , Ait-Oudhia Sihem
Published: April 2020

Background

Triple‐negative breast cancer (TNBC) is a breast cancer (BC) subtype that lacks the three hallmark BC receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC therapy. Its over‐expression in TNBC cells is associated with increased resistance to doxorubicin (DOX) treatment in this BC patient population.

Methods

The drug‐drug interaction (DDI) between DOX (0.01–20 μM) and the CDK4/6 inhibitor, abemaciclib (ABE, 1–6 μM), was examined on TNBC cells that are Rb‐positive (MDA‐MB‐231) and Rb‐negative (MDA‐MB‐468) over a time span exposure of 72 hours. The DDI was quantified for all examined drugs’ concentrations by calculating combination indices (CI) using Compusyn software. Temporal changes in %cell viability were measured using CCK‐8 assay. The fold‐change from control (untreated) and from baseline (time=0) of phosphorylated‐Rb proteins (pRb) were measured using a commercially available ELISA kit. An in vitro pharmacodynamic (PD) model was developed by linking pRb dynamics to temporal changes in %cell viability. Clinical pharmacokinetic (PK) models capturing clinical data extracted from the literature were linked to the developed PD model. A clinically scaled‐up PK/PD model was used to simulate the time‐to‐tumor progression (TTP) as defined by the RECIST and WHO criteria for optimized human dosing regimens of both drugs in combination.

Results

The combination DOX+ABE is synergistic in MDA‐MB‐231 (CI<1) and antagonistic in MDA‐MB‐468 (CI>1). The potencies (maximum inhibitory effects, Imax) for both drugs were fixed to 1. The estimated sensitivities (IC50, concentrations producing 50% of Imax) were 0.565 (DOX) and 3.23 μM (ABE) for MDA‐MB‐231 and 0.121 (DOX) and 2.03 μM (ABE) for MDA‐MB‐468. Model‐based simulations over 60 days treatment period with DOX (75 mg/m2, intravenous, every 21 days) and ABE (200 mg, oral, twice a day) predicted TTP of 0.5 (DOX) and 6.2 days (ABE) shorter compared to control. Paradoxically, TTP for DOX+ABE was 1.1 days shorter than control suggesting DOX antagonizing ABE effects.

Conclusion

The developed translational and systems‐based PK/PD model for DOX and ABE combinatorial effects in Rb‐positive TNBC captured well all observed data (in vitro and clinical). While in vitro experiments in MDA‐MB‐231 cells suggest synergistic DDI for DOX and ABE, model‐based predictions of clinical TTP in Rb‐positive TNBC patients suggest a reduced TTP. Further clinical investigations to support model predictions are warranted.

Support or Funding Information

This work was supported by the American Foundation for Pharmaceutical Education (AFPE).
Assessing the epigenetics effects on the expression of the Fabp3 promoter region of Zinc‐Transporter 7‐deficient mice
Authors: Scherpel Victoria Grace , Kirschke Catherine Patricia , Huang Liping
Published: April 2020

Zinc is an essential trace mineral for life. Zinc transporter 7 (ZNT7) transports zinc from the cytosol to the Golgi to maintain cellular zinc homeostasis. Mice with null‐Znt7 gene expression exhibit low zinc status, low body weight, as well as alterations in glucose and triglyceride homeostasis leading to a reduction in fat storage in adipocytes, and subsequently an increase in fat accumulation in muscle. The increase in muscle‐triglycerides in the Znt7KO mice is accompanied by a surge in the expression of Fabp3. Fatty‐Acid binding proteins (FABPs) belong to a family of proteins involved in intracellular lipid transport and status, yet some functions remain unknown. Fabp3 is found to be abundantly expressed in the heart, but it can also be moderately detected in skeletal muscle. Altered Fabp3 expression has been linked to a higher risk of developing metabolic syndrome in humans, hence this area of research is promising as rates of obesity and obesity‐related diseases continue to rise. DNA methylation has been shown to regulate human Fabp3 mRNA expression. Therefore, we aim to discover the methylation status of the mouse Fabp3 gene in a zinc deficient state using Znt7KO mice and determine a relationship between cellular zinc deficiency and the increased lipid accumulation in muscle, a cause of insulin resistance in Znt7KO male mice. Our preliminary results indicate that the cellular zinc level‐related DNA demethylation mainly occur in the area surround the transcriptional start site of Fabp3.

Support or Funding Information

USDA/ARS 2032‐51000‐005‐00D
Loss of Repressor Activator Protein 1 Precipitates Cardiac Aging in Mice via p53/PPARα Signaling
Authors: CAI YIN , XIA ZHENGYUAN
Published: April 2020

Background

Telomere dysfunction has been linked to many aspects of the aging process. Increasing evidence indicates that telomere dysfunction leads to cardiac mitochondrial defects. Mammalian repressor activator protein 1 (Rap1) is one of the components of shelterin complex and essential for the maintenance of telomere length and structural integrity. Our preliminary work showed that aged Rap1 knockout (Rap1−/−) mice exhibited more pronounced aging‐associated phenotypes (including earlier hair graying, hair loss, reduced body weight). However, the effects of Rap1 on mitochondrial function and its contribution to cardiac aging are largely unknown. Thus, the present study investigated whether or not loss of Rap1 in mice precipitates cardiac aging and explored the underlying mechanisms.

Methods and Results

Mice cardiac function was assessed with transthoracic echocardiography performed noninvasively using a Vevo 2100 high‐resolution imaging system. Deletion of Rap1 in mice aggravated aging‐related cardiac structural changes and dysfunction, as evidenced by increased left ventricular (LV) posterior wall end‐diastole and LV mass, reductions in ejection fraction and fractional shortening, as well as significantly reduced myocardial performance index (all p < 0.05, Rap1−/− vs. age‐matched counterparts). These changes were associated with greater cardiac senescence (enhanced SA‐β‐gal staining), cardiac hypertrophy (enhanced wheat germ agglutinin staining and increased the ratio of heart weight with body weight), abnormalities in the mitochondrial ultrastructure (cristae fragmentation, vacuolization). Mechanistically, Rap1 deficiency led to shorter telomere (T/S ratio), enhanced DNA damage (γH2AX) and increased nuclear p53 level in vivo in the myocardium and in primary cardiomyocytes when compared to age‐matched counterparts (one year old). Chromatin immunoprecipitation revealed that p53 directly binded to the promote site of PPARα [a central regulator of cardiac fatty acid metabolism (FAM)] and repressed its expression. Rap1 deficiency impaired FAM (reduced CD36, CPT1α, ACADL level and palmitate‐induced oxygen consumption), while PFTα (a p53 inhibitor, i.p. 1.1 mg/kg/day) treatment in Rap1−/− mice significantly alleviated cardiac aging and enhanced FAM by restoration of PPARα.

Conclusions

With aging, Rap1 deficiency may lead to shorter telomere length, increase DNA damage and thereby activate p53, which in turn suppresses PPARα, leading to impaired FAM and mitochondrial defects with abnormal cardiac structure and dysfunction. These findings may identify a new cardiac dimension in the physiological role played by telomere‐Rap1.

Support or Funding Information

The authors’ work was supported by the General Research Fund (17123718M, Research Grants Council of Hong Kong).
IEX‐1 is Required for Vitamin D‐induced Inhibition of Proinflammatory State of Macrophages
Authors: Khan Faaeiza , Owens Elan , Singh Sandeep , Ahern Alex , Shahid Mohd
Published: April 2020

Vitamin D (Vit‐D) deficiency is linked to several metabolic diseases. However, the underlying mechanism remains elusive. Immediate early response gene x‐1 (IEX‐1)—which is negatively regulated by Vit‐D—plays a pathogenic role in obesity and atherosclerosis. IEX‐1 paucity inhibits macrophage‐mediated inflammation and protects against these diseases. We hypothesize that Vit‐D promotes anti‐inflammatory state of macrophages via inhibiting IEX‐1 expression.

We harvested bone marrow cells from wild‐type (WT) and IEX‐1 knockout (KO) mice and cultured them with macrophage‐colony stimulating factor (M‐CSF) to mature into macrophages. The cells were differentiated into pro‐ or anti‐inflammatory macrophages by treatment with LPS (10 ng/ml) or IL‐4 (10 nM), for 24 hours in the absence/presence of Vit‐D (10 nM). Total RNA was extracted and cDNA was synthesized. The mRNA levels of IEX‐1, pro‐, and anti‐inflammatory marker genes were quantified by qRT‐PCR. The TNF‐α protein level was measured in supernatant using ELISA. Further, impact of IEX‐1 deficiency on LPS‐induced pro‐inflammatory macrophage formation and apoptosis was determined using flow cytometry. Vit‐D inhibited LPS‐induced increases in mRNA levels of TNF‐α (42±5 vs. 58±5‐fold, p<0.05) and iNOS (327±29 vs. 523±102‐fold, p<0.05) in WT cells. Vit‐D also suppressed LPS‐induced TNF‐α protein production by macrophages (18±1 vs. 27±1 ng/ml, p<0.05). Conversely, Vit‐D potentiated IL‐4‐induced increases in expression of anti‐inflammatory genes Arg‐1 (15204±2780 vs. 4362±1624‐fold, p<0.01), MRC‐1 (13±3 vs. 6±1‐fold, p<0.05), and Clec10a (8±1 vs. 4±1‐fold, p<0.05). However, these effects of Vit‐D were markedly attenuated in IEX‐1 KO cells. In WT cells, Vit‐D treatment dose‐dependently decreased IEX‐1 expression, showing negative regulation of IEX‐1 by Vit‐D. Flow cytometry analysis demonstrated that IEX‐1 deficiency alone was sufficient to inhibit LPS‐induced pro‐inflammatory macrophage formation (11±1 vs. 26±3%, p<0.05). This effect was concomitant with an increase in apoptosis (10±1 vs. 18±2‐fold, p<0.05) during LPS treatment.

These results suggest that Vit‐D favors the anti‐inflammatory state of macrophages in part via repressing IEX‐1 expression.

Support or Funding Information

CTRE Faculty Development Seed Grant, Chicago State University
Ameliorative effects of Moringa oleifera (MO) seeds on L‐NAME‐induced hypertension in rats
Authors: Omóbòwálé Temidayo Olutayo , Oyagbemi Ademola , Aderoju Abiodun , Adejumobi Olumuyiwa A. , Adedapo Adeolu , Gbadamosi Idayat , Yakubu Momoh
Published: April 2020

Cardiovascular diseases including hypertension, have been recognized as leading causes of death worldwide. In this study we investigated the effect of Moringa oleifera on L‐NAME induced hypertension in rats. Fifty (50) Wistar albino rats were grouped into five groups. Group A, the control, was administered water only. Groups B‐E received orally, 40 mg/kg of L‐NAME only, 40 mg/kg of L‐NAME and 10% MO feed inclusion, 40 mg/kg of L‐NAME and 20% MO feed inclusion, and 40 mg/kg of L‐NAME and 10 mg/kg of lisinopril, respectively for 35 days. Treatment with L‐NAME caused a significant (p< 0.05) reduction in Nitric oxide concentration as well as an increase in blood pressure measurements when compared with the control. These were however ameliorated by the administration of MO seeds and lisinopril. Markers of oxidative stress (malondialdehyde and Hydrogen peroxide) increased significantly (p<0.05) in the group treated with L‐NAME alone while the administration of MO seeds and lisinopril caused a significant decrease in their values when compared with the controls. Also, the administration of L‐NAME caused a significant (p<0.05) decrease in the activities of enzymic antioxidants (Glutathione peroxidase and Glutathione‐S‐transferase) while there was reduction in the levels of reduced glutathione level as well as activities of superoxide dismutase, glutathione peroxidase and glutathione‐S‐transferase when compared with the control. These were however significantly (p<0.05) ameliorated by the administration of MO seeds and lisinopril. Taken together, Moringa oleifera seed inclusion in the feed of rats ameliorated L‐NAME induced hypertension by improving Nitric oxide bioavailability as well as its antioxidant activities

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None
Modulation of Cytokine Secretion from Thp‐1 Macrophages by Adenosine Receptors
Authors: Eudy Brandon James , da Silva Robin P.
Published: April 2020

Macrophages serve a major role in the innate immune system by directing the inflammatory response in tissues. By secreting cytokines and chemokines, macrophages direct other immune cells to sites of inflammation. Once inflammatory stimuli are removed, macrophages play a major role in initiating resolution of inflammation by secreting anti‐inflammatory cytokines, greatly influencing immune function and chemotaxis. However, the signals which tune cytokine production towards resolution of inflammation are not yet fully understood. Small metabolites such as adenosine can initiate cell signaling pathways which direct cytokine secretion. Adenosine acts on four cell surface g‐protein coupled receptors (A1, A2A, A2B, and A3 adenosine receptors) and is understood to be a potent immunosuppressive molecule by stimulating IL‐10 secretion. However, the full influence of adenosine receptor agonism on cytokine secretion is not known. Therefore, our primary aim was to determine how adenosine alters the pattern of cytokines secreted during an inflammatory response. We used a multiplex immunoassay to measure secretion of several cytokines in conditioned medium from LPS‐stimulated THP‐1 monocyte derived macrophages treated with adenosine or a vehicle control. We also used siRNAs directed against each adenosine receptor to determine which receptor mediated the effect of adenosine on each of these cytokines. LPS‐stimulated THP‐1 macrophages treated for four hours with adenosine showed increased IL‐10 and IL‐1β secretion and reduced IL‐6 and MCP‐1 secretion. We found the A1 receptor is required for the stimulatory effect of adenosine on IL‐10 and IL‐1β secretion while the A2B receptor is required for the inhibitory effect of adenosine on IL‐6 and MCP‐1 secretion. We also show that under basal adenosine concentrations the adenosine receptors serve to suppress and modulate various cytokines. These data show adenosine receptors are important regulators of cytokine secretion in macrophages. Adenosine, by signaling through the A1 and A2B adenosine receptors, stimulates IL‐10 and IL‐1β secretion while reducing IL‐6 and MCP‐1 secretion which signals priming of immune cells and tips the balance towards a pro‐resolution state which is of value in the context of several pathologies involving chronic inflammation such as metabolic syndrome, arthritis, and cancer. Future studies should determine how adenosine, by altering cytokine patterns, may affect other aspects of macrophage phenotype including ROS production and phagocytic function.

Support or Funding Information

Funded by the UF/IFAS Agricultural Experiment Station.
Regulator of G protein signaling complex, Gβ5‐R7, promotes glucose‐ and extracellular signal‐stimulated insulin secretion
Authors: Slepak Vladlen , Wang Qiang , Henry Taylor , Pronin Alexey , Lubaczeuski Camila , Jang Geeng-Fu , Crabb John , Bernal-Misrachi Ernesto
Published: April 2020

Glucose‐stimulated insulin secretion (GSIS) is essential for maintaining energy homeostasis. G protein‐coupled receptors (GPCRs) are important modulators of this process by extracellular signals such as hormones, neurotransmitters and non‐glucose metabolites. We investigated the role of Gβ5‐R7, the protein complex consisting of the atypical G protein β subunit Gβ5 and a regulator of G protein signaling (RGS) of the R7 family. To analyze the effects of Gnb5 knockout on insulin secretion we used mouse insulinoma MIN6 cell line and pancreatic islets isolated from the Gnb5−/− mice. Consistent with previous work, Gnb5knockout diminished insulin secretion evoked by cholinergic agonist Oxo‐M. Here, we found that Gnb5 knockout also attenuated activity of other GPCR agonists ADP, AVP, GLP‐1, forskolin and, surprisingly, the response to high glucose. Our experiments also provided evidence that Gnb5 knockout eliminated the positive effect of cell adhesion on Oxo‐M‐stimulated GSIS, likely through adhesion GPCR GPR56. Total insulin content and the amount of insulin released in response to K+‐evoked membrane depolarization in Gnb5 −/− islets or MIN6 cells was normal. The pleiotropic effect on several GPCRs led us to the hypothesis that Gβ5‐R7 may play a non‐canonical role in insulin secretory pathway downstream of G protein signaling and glucose‐activated membrane depolarization. We found that Gnb5 knockout does not influence cortical actin depolymerization, but influences activity of protein kinase C, and thus far identified 14‐3‐3ɛ as one of the affected substrates. Together, these results allow us to propose that the Gβ5‐R7 complex regulates a phosphorylation event participating in the vesicular trafficking pathway, downstream of G protein signaling and actin depolymerization, but upstream of insulin granule release.

Support or Funding Information

This work was supported by National Institutes of Health Grants R01DK1054127(to V.S.), RO1‐DK073716, DK084236 (to E.B.M), EY11373 (to J.C.).
Elucidating the Protein‐Protein Interactions between Nontypeable Haemophilus Influenzae Outer Membrane Proteins Omp26 and Protein D
Authors: Farquharson Kara Louise , Jackson Niaya , Cheng Susan Shi , Kaur Ravinder , Michel Lea Vacca
Published: April 2020

Two leading protein vaccine candidates from Nontypeable Haemophilus Influenzae (NTHi) are outer membrane proteins Omp26 and Protein D. When administered individually, Omp26 and Protein D elicit an antibody response in mice; when combined, the Protein D antibody response is significantly suppressed. Here, we describe a biochemical approach toward elucidating the interactions between Omp26 and Protein D, which we propose contribute to the suppression of Protein D‐specific antibody production. Preliminary data from enzyme‐linked immunosorbent assays and other standard protein detection methods suggest that Protein D binds strongly to Omp26 in vitro and perhaps in vivo in mice.
Leptin activates PKA via a novel mechanism to regulate KATP channel trafficking in pancreatic β‐cells
Authors: Cochrane Veronica , Shyng Show-Ling
Published: April 2020

The adipocyte hormone leptin has a well‐established role in energy homeostasis via its actions in the central nervous system. In addition, leptin has been shown to have direct actions on peripheral tissues. In pancreatic β‐cells leptin inhibits insulin secretion by increasing conductance of ATP‐sensitive potassium (KATP) channels, which causes membrane hyperpolarization and reduces β‐cell electrical activity. There is evidence that disrupting leptin signaling at the β‐cell level may lead to excessive insulin secretion and contribute to insulin resistance and eventually type 2 diabetes. Recent studies have shown that leptin promotes KATP channel trafficking to increase KATP channel surface density and thereby KATP conductance in β‐cells. We found that leptin triggers a signaling pathway that involves potentiation of NMDA receptors, leading to an influx of calcium and activation of CaMKKβ, which then phosphorylates and activates AMPK; downstream of AMPK actin remodeling occurs in a PKA‐dependent manner that allows vesicles containing KATP channels to traffic to the β‐cell membrane. A knowledge gap in this pathway is whether PKA plays a permissive role or whether leptin signaling that results in AMPK activation leads to increased PKA activity for actin remodeling. Here we implement a FRET‐based PKA activity reporter to show that leptin signaling does indeed increase PKA activity and that this occurs via the NMDAR‐CaMKKβ‐AMPK signaling axis. Moreover, we provide evidence that the ability of leptin to regulate KATP channel trafficking requires that PKA is anchored to PKA anchoring proteins (AKAPs). AKAPs are scaffolding proteins known to organize signaling complexes for localized PKA signaling. Our results suggest that leptin signaling in β‐cells may be localized via a signaling complex involving AKAP to achieve spatiotemporal specificity. Additional studies into AKAP‐mediated organization of leptin signaling molecules in β‐cells will likely provide insight as to how leptin signaling may be disrupted in pathophysiological states such as type 2 diabetes.

Support or Funding Information

NIH grant R01 DK57699 to SLS
PALMATINE ACTIVATES INSULIN RELEASE VIA PI3K – GLUT4 INSULIN DEPENDENT PATHWAY EX‐VIVO
Authors: Okechukwu Patrick Nwabueze , Ekeuku Sophia Ogechi , Sharma Mridula , Froemming Gabriele Ruth Anisah
Published: April 2020

Background

Palmatine is a protoberberine alkaloid which identified to be the bioactive compound present in stem extract of Cosininum Fenestratum plant. Our previous research have reported the plasma glucose lowering activity of Palmatine and its effect on liver, kidney and antioxidant enzymes parameters in STZ induced diabetic rat model. We also reported that the molecular mechanism of action of palmatine insulin release is through activation insulin‐dependent pathway in vivo and in vitro.

Objective

The focus of this study was to determine the effect of Palmatine on insulin dependent signaling pathway in insulin resistance rat skeletal muscle ex‐vivo.

Method

Normal Male SD rats (180–200g) were sacrificed and skeletal muscles were harvested. The smaller size skeletal muscles from rats were mounted in the Krebs‐Henseleit buffer (KHB) buffer to maintain the resting position. The tissues were then incubated at 37°C under 95% O2‐ 5%CO2 in Glucose free KHB containing 01% BSA and 1mM pyruvate for 1hr, and KHB in 500nmol/L insulin and 125nmol/L glucose for 24hrs. After incubation with insulin/glucose KHB, tissues were transferred to KHB buffer with 250mmol/L glucose for 5hrs, and then KHB with insulin for 30 mints. After induction tissue were replaced with fresh KHB drug was administered by pipetting drug into the organ bath and was allowed to incubate for 24hrs. RNA was extracted and converted to cDNA according manufacturer protocol and the expression of IRS‐1, PI3K, PKC, AKT2 and GLUT4 genes involved in insulin dependent signaling pathway were evaluated using qPCR.

Result

Palmatine showed an increase in fold expression of PI3K, PKC, AKT2 and GLUT 4 compared to negative control. The result was similar to standard drug metformin. The increase in fold expression of the insulin dependent pathway genes shows they were revived as a result of Palmatine treatment.

Conclusion

Palmatine were able to rejuvenate PI3K, PKC, AKT2 and GLUT 4 in Palmatine treated group, which is usual impaired in insulin resistance skeletal muscle. The result is in consonance with the previous finding of in vitro and in vivo. Currently work is on‐going to investigate the effect of palmatine on the insulin‐independent pathway.

Support or Funding Information

UCSI University