bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract MP110: Inhibition of the Unfolded Protein Response Reduces Arrhythmic Risk After Myocardial Infarction
Authors: Liu Man , Liu Hong , Parthiban Preethy , shi guangbin , Kang Gyeoung-Jin , Feng Feng , Zhou Anyu , Gu Lianzhi , Talkachova Alena , Dudley Samuel C
Published: October 2020

Background:
Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels and transporters. When activated, the protein kinase-like ER kinase (PERK) arm of the unfolded protein response (UPR) reduces protein translation and abundance. We hypothesize that inhibition of PERK could prevent cardiac ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI).

Methods:
The MI mouse model was induced by a left anterior descending coronary artery ligation. Pharmacological inhibition of PERK was achieved with a specific inhibitor, GSK2606414. Genetic inhibition of PERK was achieved by cardiac-specific PERK knockout in C57BL/6J mice (PERKKO). Echocardiography, telemetry, and electrophysiological measurements were performed to monitor cardiac function and arrhythmias.

Results:
Three weeks after surgery, the wild type MI mice exhibited decreased ejection fraction (EF%), ventricular tachycardia (VT) and prolonged QTc intervals. The UPR effectors (phospho-PERK, phospho-IRE1, and ATF6N) were elevated significantly (1.7- to 5.9-fold) at protein levels, and all major cardiac ion channels showed decreased protein expression in MI hearts. MI cardiomyocytes showed decreased currents for all major channels (I
Na
, I
CaL
, I
to
, I
K1
, and I
Kur
: 60±6%, 53±9%, 27±6%, 55±7%, and 40±7% of sham, respectively, P<0.05 vs. sham) with significantly prolonged action potential duration (APD
90
: 291±43 ms of MI vs. 100±12 ms of sham, P<0.05) and decreased maximum upstroke velocity (dV/dt
max
: 95±4 V/s of MI vs. 132±6 ms of sham, P<0.05) of the action potential phase 0. GSK treatment restored I
Na
and I
to
, shortened APD, and increased dV/dt
max
. PERKKO mice exhibited reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates.

Conclusion:
PERK is activated during MI and contributes to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.
Abstract MP114: Cardiotropic Adenovirus Increases Arrhythmia Susceptibility During Acute Infection
Authors: Padget Rachel L , King D. Ryan , North Michael D , Tanenbaum Mira N , Calhoun Patrick J , HOEKER Gregory S , Poelzing Steven , Smyth James W
Published: October 2020

Myocarditis is responsible for up to 42% of sudden cardiac death in young adults yet mechanisms underlying virally-induced arrhythmia remain elusive. Adenovirus is a leading etiological agent of myocarditis but due to species-specificity,
in vivo
models are limited. Altered cardiac gap junction function underlies sudden cardiac death and given that gap junctions also propagate antiviral immune responses, we hypothesized adenovirus would target intercellular coupling, leading to arrhythmogenesis. Employing a recently described strain of mouse adenovirus, MAdV-3, we investigated cardiotropism, arrhythmia susceptibility, and molecular mechanisms of a virally-induced arrhythmogenic substrate. Adult C57BL/6 mice were inoculated with MAdV-3 and infection allowed to progress for one week. Viral genomes were detected by qPCR to measure tissue tropism together with whole animal histopathology. Echo- and electrocardiography were used to measure cardiac function and electrical activity. Viral effects on transcription and junctional protein/ion channel expression and localization were quantified using RT-qPCR, confocal microscopy, and western blotting. Finally,
ex vivo
optical mapping was employed to test conduction defects and susceptibility to arrhythmia. We find MAdV-3 viral genomes specifically enriched in heart tissue, confirming cardiotropism. Immune cell infiltration was not detected in the heart and no cardiomyopathy was apparent by echocardiography. RR interval widening, however, does occur in MAdV-3 infected mice with reductions in cardiac ion channel and gap junction mRNA transcripts. Optical mapping experiments show that conduction velocity is altered in acutely infected hearts and norepinephrine challenge uncovered electrical impairment presenting as atrioventricular dissociation with increased premature ventricular contraction burden. Our data demonstrate that MAdV-3 is cardiotropic and acute infection result in changes in cardiac electrical activity prior to development of cardiomyopathy or a detectable immune response. MAdV-3 infection is a novel model for adenoviral myocarditis, providing insights into viral subversion of cardiac intercellular coupling and mechanisms of arrhythmogenesis.
Abstract MP135: Cardiac Sarcoplasmic Reticulum Calcium Cycling is Regulated by Kinase Independent Function of Pi3kgamma
Authors: Mohan Maradumane L , Witherow Conner P , Papay Robert S , Naga Prasad Sathyamangla V
Published: October 2020

Genetic deletion of Phosphoinositide 3-kinase (PI3Kγ) in mice (PI3Kγ
-/-
) results in increased cAMP levels and enhanced ventricular contractility. We investigated whether the lack of PI3Kγ plays a role in cardiac contractility by altering intracellular calcium recycling. Isolated cardiomyocytes from PI3Kγ
-/-
mice showed significantly reduced calcium reuptake by sarcoendoplasmic reticulum (SR) following caffeine induced calcium release indicating that PI3Kγ locally regulates the function of SR. The intracellular calcium remained at elevated levels in the cardiomyocytes of PI3Kγ
-/-
for a prolonged period after caffeine treatment. This could be due to changes in phosphorylation of SERCA2, Ryanodine receptor (RyR
2
) or phospholamban (PLN). In fact, when we looked at phosphorylation of PLN in cardiac lysates, a major regulator of cardiac contractility and relaxation, PI3Kγ
-/-
mice showed significantly reduced PLN phosphorylation compared to littermate controls. Previous studies from our laboratory suggested that absence of PI3Kγ leads to increase in protein phosphatase (PP) activity which could be possible reason for rapid dephosphorylation of PLN, resulting in inhibition of SERCA2 pump. We observed increased SR associated PP activity and PLN associated PP activity in PI3Kγ
-/-
mice. We also observed increased association of PP-1 and PP2A with PLN in the absence of PI3Kγ. The altered calcium handling in the cardiomyocytes of PI3Kγ
-/-
mice could be restored to the level of WT controls by okadaic acid mediated inhibition of PP, suggesting that PI3Kγ plays a role in regulating PP activity associated with SR. To test whether PI3Kγ activity is required for PLN dephosphorylation and SR calcium cycling, we used mice with cardiac specific overexpression of kinase dead PI3Kγ (PI3Kγ
inact
) in global PI3Kγ
-/-
mice (PI3Kγ
inact
/PI3Kγ
-/-
). PI3Kγ
inact
/PI3Kγ
-/-
mice showed restored PLN phosphorylation, improved caffeine induced calcium reuptake, decreased SR and PLN associated PP activity. These studies show a novel regulation of PP and SR calcium regulation by kinase independent function of PI3Kγ. The underlying mechanism of PP regulation by PI3Kγ will be presented.
Abstract MP141: Role of Cryptochrome in Angiogenesis
Authors: Tsuzuki Kazuhito , Shimizu Yuuki , Pu Zhongyue , Suzuki Jyunya , Murohara Toyoaki
Published: October 2020

Background:
Although clock genes generate oscillations in about 10 % of all gene expressions as a 24-hour cycle in the cellular level cooperating with the central clock, little is known about the role of clock genes in angiogenesis.

Objective:
The aim of this study was to determine if a peripheral clock would modulate angiogenesis in a hind limb ischemia (HLI) model.

Methods and Results:
First, we surgically induced the HLI model in C57BL/6J (wild type; WT) mice (N=6 for each time point) and checked mRNA expressions of clock genes in a local ischemic tissue by PCR array in the setting of blood perfusion recovery. In vitro study, we next investigated those gene expressions in human umbilical vein endothelial cells (HUVECs) with or without stimulation by growth factors. Those data demonstrated that the peripheral clock genes were modulated in ECs and tissues in the presence of growth factors and tissue ischemia. Then, we examined whether inhibition of clock gene expressions had any effects on angiogenesis. For this study, we focused on Cryptochrome (Cry), which is well known as one of the core-loop forming clock genes producing circadian rhythm in mammals. Our loss-of-function study revealed that the abilities of proliferation, migration and tube formation were significantly inhibited by Cry1 and Cry2 double knockdown in HUVECs. Interestingly, although the knockdown of Cry1 and Cry2 changed the mRNA expression of Period2, it did not affect those of BMAL1 and Clock in HUVECs. Finally, we tested if Cry1 and Cry2 double hetero knockout mice of HLI models displayed worse blood perfusion recoveries with deterioration of angiogenesis. As results, compared with control WT mice, Cry1 and Cry2 double knockout mice showed the low capillary density detected by CD31-immunohistochemistry and low tissue blood perfusion demonstrated by laser Doppler perfusion imaging (LDPI) in a HLI.

Conclusion:
Our data indicated that Cryptochrome as a peripheral clock plays an important role in angiogenesis of the reparative tissue ischemia model.
Abstract MP142: Genome-wide Studies Reveal the Essential and Opposite Roles of Arid1a in Controlling Human Cardiogenesis and Neurogenesis From Pluripotent Stem Cells
Authors: Liu Juli , Liu Sheng , Gao Hongyu , Han Lei , Chu Xiaona , Sheng Yi , Wang Yue , Liu Yunlong , Wan Jun , YANG Lei
Published: October 2020

Background:
Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene/complex underlying both cardiogenesis and neurogenesis. However, due to lack of
in vivo
studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. The evolutionarily conserved ATP-dependent SWI/SNF complex is one of the largest chromatin remodeling complexes, consisting of ~15 subunits, including SMARCA2 (also known as BRM) or SMARCA4 (also known as BRG1) as the ATPase catalytic subunit. Several BRG1-associated factors (BAFs), such as ARID1A (Baf250a), have DNA binding capacity and assemble with either BRM or BRG1 to form a functional chromatin-remodeling complex. A single amino acid mutation (Arid1aV
1068G/V1068G
), impaired Arid1a-DNA interactions and resulted in both cardiac neural defects. Mutations in 4 different SWI/SNF subunits including ARID1A/B were identified in human congenital syndromes that include both neural and cardiac defects.

Results:
Here, we report ARID1A, which is a DNA-binding-subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) via employing distinct mechanisms. CRISPR/Cas-9 knockout of ARID1A (ARID1A
-/-
) led to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A
-/-
hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Whole genome-wide ChIP-seq and ATAC-seq analyses revealed that ARID1A was required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during neural development, transcription of most essential neurogenic genes was dependent on ARID1A and ARID1A could interact with REST, which is a known transcriptional repressor.

Conclusions:
We uncovered the key and opposite roles by ARID1A to govern both early human cardiac and neural development and characterized the mechanisms. We found global chromatin accessibility on cardiogenic genes was dependent on ARID1A, whereas transcriptional activity of neurogenic genes was regulated by ARID1A, possibly through ARID1A-REST interaction.
Abstract MP143: Harnessing Glycomics to Understand Cardiac Biology and Disease
Authors: Ashwood Christopher , Berg Luecke Linda , Gundry Rebekah L
Published: October 2020

Cell surface glycoproteins play critical roles in maintaining cardiac structure and function, and the glycan-moiety attached to a protein is critical for proper protein folding, stability, and signaling. Despite mounting evidence that glycan structures are key modulators of heart function and must be considered when developing cardiac biomarkers, we currently do not have a comprehensive view of the glycans present in the normal human heart. Here, we used an innovative mass spectrometry approach to generate the first glycan structure libraries for primary human heart tissue, cardiomyocytes (CM) enriched from human heart tissue, and human induced pluripotent stem cell derived CM (hiPSC-CM), containing >260
N-
and
O-
glycans. Comparing the glycome of CM enriched from primary heart tissue to that of heart tissue homogenate, 21 structures significantly differed, and the high mannose class is increased in enriched CM. Moreover, >30% of the glycome significantly changed across 20-100 days of
in vitro
differentiation, and only 23% of the
N
-glycan structures were shared between hiPSC-CM and primary CM. Overall, these observations are an important complement to genomic, transcriptomic, and proteomic profiling and reveal new considerations for the use and interpretation of hiPSC-CM models for studies of human development, disease, and drug testing. These data are also expected to aid in the evaluation of the immunogenic potential of hiPSC-CM for transplantation. Finally, harnessing differences observed between immature, proliferative hiPSC-CM and adult primary CM may be exploited to drive
in vitro
differentiation towards a more mature phenotype. Building on these data, current efforts are underway to develop chamber- and cell-type specific views (
e.g.
cardiomyocytes, fibroblasts) of the glycome in the healthy and failing human heart. Such analyses provide a key link to understand the role glycosylation plays in cell-type specific functions and cardiac disease. The structural differences observed here, either among cell types or stages of differentiation, require complex regulation of multiple enzymes in the biosynthetic pathway, and therefore would be challenging to measure with antibody arrays, RNAseq, or proteomics. Therefore, continued application of structure-based glycomics approaches, such as the method used here, will be essential for elucidating the roles that glycans and glycoproteins play during developmental and disease processes in the human heart.
Abstract MP144: Identification of Epigenetic Regulators of Cardiac Hypertrophy by an Epigenome-wide Association Study in Mice
Authors: Rau Christoph D , Romay Milagros , Wong Eleanor , Tan Wilson , Lusis Aldons J , Foo Roger , Wang Yibin
Published: October 2020

We previously reported a study of heart failure in a large cohort of inbred mouse strains, the Hybrid Mouse Diversity Panel (HMDP), treated with the beta-adrenergic agonist isoproterenol, which identified over 30 genome-wide significant loci for heart failure-related traits. Our approach combined systems-level tools with the benefits of a curated model organism population to identify genetic variations that drive heart failure.

We now expand this study into the epigenome. Recent research has demonstrated that DNA methylation affects the progression of cardiovascular phenotypes. This research suggests that DNA methylation may serve as an additional marker of genes involved in heart failure-associated phenotypes. Using Reduced Representational Bisulfite Sequencing, we profiled left ventricular tissue samples from 88 strains of the HMDP both before and after isoproterenol challenge (30 mg/kg/day for 21 days). We identified approximately 168,000 CpGs that vary across the panel and associated them with a set of phenotypes in both control and treated animals using the epigenome-wide association study (EWAS) algorithm MACAU. 179 significant associations were recovered at an FDR of 5%, including loci that associated pre-treatment CpG methylation with 19 different post-treatment phenotypes.

By combining these EWAS loci with information from the Wellcome Trust Mouse Genomes Resource and prior work done in the heart failure HMDP, we identify several high-confidence candidate genes, including
Coro1a
, a gene whose pre-treatment promoter methylation status predicts post-treatment wall thickening and
Eprs
, which predicts right ventricular weight post-treatment.
Mospd3
, a gene that was associated with right ventricular weight post-treatment in both EWAS and GWAS analyses was studied further using neonatal rat ventricular myocytes. This
in vitro
work demonstrates that
Mospd3
knockdown results in reduced cellular hypertrophy and changes to hypertrophy-related gene expression. Further analysis of the EWAS loci using
in vitro
and
in
vivo techniques will likely validate additional genes and elucidate how DNA methylation acts to regulate pathways underlying heart failure.
Abstract MP153: TET2 Regulates Type I Interferon Signaling in the Hematopoietic Response to Myocardial Infarction
Authors: Zhang Claire , Calcagno David M , Toomu Avinash , Huang Kenneth M , Fu Zhenxing , King Kevin R
Published: October 2020

Myocardial infarction (MI) elicits a rapid and vigorous reaction from the bone marrow hematopoietic compartment, inducing a massive efflux of myeloid first responders into the bloodstream. These cells traffic to the infarct, where they mediate cardiac remodeling and repair through inflammatory signaling and recruitment of additional immune cells to the injured myocardium. A hyperinflammatory myeloid compartment, as is produced by mutations in epigenetic regulator TET2 associated with clonal hematopoiesis, can thus drive adverse cardiac remodeling after MI and accelerate progression to heart failure. Whether loss of TET2 alters the transcriptional landscape of MI-induced myelopoiesis remains to be investigated in an unbiased fashion.

Here, we performed single-cell RNA sequencing of >16,000 bone marrow myeloid cells isolated from wild-type and
Tet2
-/-
mice after MI to characterize the emergency hematopoietic response in the presence and absence of TET2. Our data capture distinct transitional states of myeloid lineage commitment and maturation, originating from myeloid progenitors and progressing along divergent granulocytic and monocytic differentiation trajectories. Additionally, we delineate a subpopulation of interferon (IFN)-activated myeloid progenitors, monocytes, and neutrophils characterized by the concerted upregulation of various Type I IFN-stimulated genes, and find the fraction of IFN-activated cells, as well as the degree of activation, to be markedly higher in
Tet2
-/-
mice. We have previously described activation of this pathway after MI in mice, and demonstrated cardioprotective effects of its genetic or pharmacological inhibition.

Our findings reveal heightened activation of the antiviral Type I interferon response among bone marrow myeloid cells of
Tet2
-/-
mice during MI-induced emergency hematopoiesis. This highlights IFN signaling as a potential candidate driver of cardiovascular pathologies (including atherosclerosis, myocardial infarction, and heart failure) associated with TET2-mediated clonal hematopoiesis. Further studies are necessary to investigate whether
Tet2
-/-
mice exhibit enhanced response to blockade of Type I IFN signaling after MI, and to determine whether myeloid cells of
TET2
-mutant humans are similarly activated.
Abstract MP163: Renal Sympathetic Denervation (RDN) Improves Exercise Performance and Vascular Function in the Setting of Cardiometabolic HFpEF
Authors: Hidalgo Hunter , Gao Juan , Li Zhen , Sharp Thomas E , Xia Huijing , Kapusta Daniel R , Goodchild Traci T , Lefer David J
Published: October 2020

Background:
Heart failure with preserved ejection fraction (HFpEF) has emerged as a subclass of heart failure for which there are no effective treatments. HFpEF is induced in a large number of patients by central obesity, metabolic syndrome, and sustained activation of the sympathetic nervous system (SNS).

Methods:
We examined the effects of RDN in a clinically relevant model of HFpEF. The ZSF1-Obese rat exhibits the key components of cardiometabolic HFpEF including hypertension and diabetes. At 20 wks of age, ZSF1-Obese rats underwent bilateral radiofrequency RDN (RF-RDN) or sham RF-RDN and were followed for 6 weeks. LV function, blood pressure, LVEDP, vascular function, myocardial fibrosis, metabolic profiling, and exercise capacity were evaluated. We also assessed mitochondrial function of cardiac and skeletal muscle.

Results:
RF-RDN resulted in significant improvements in LV diastolic function, vascular relaxation, and exercise capacity. Significant reductions in blood pressure and LVEDP were observed following RF-RDN treatment. RF-RDN ameliorated cardiac fibrosis while improving cardiac and skeletal muscle mitochondrial function. We did not observe any effects of RF-RDN on the metabolic status of the ZSF-1 rat.

Conclusion:
Our data suggest that RF-RDN is a viable treatment option for cardiometabolic HFpEF through halting renal SNS hyperactivation and enhancing mitochondrial function to exert beneficial effects on the heart and circulation.
Abstract MP164: Electrophysiologic Conservation of Epicardial Conduction Dynamics After Myocardial Infarction in Newborn Piglets
Authors: Wang Hanjay , Pong Terrence , Lucian Haley , Aparicio-Valenzuela Joy , Tada Yuko , Sakhamuri Sasank , Baker Sam W , Tran Nicholas A , Paulsen Michael J , Zhu Yuanjia , LEE Anson M , Woo Y. Joseph
Published: October 2020

Introduction:
Newborn piglets reportedly exhibit natural heart regeneration after myocardial infarction (MI). However, the electrophysiologic properties of this regenerated muscle have not been examined. We hypothesized that epicardial electrical conduction is preserved after MI in newborn piglets.

Methods:
Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation on postnatal day 1 (P1, n=4) or postnatal day 7 (P7, n=7), infarcting the anteroseptal left ventricle through which the Purkinje conduction system passes. After 7 weeks, cardiac magnetic resonance imaging (MRI) was performed with late gadolinium enhancement for fibrosis analysis. Epicardial conduction mapping was performed using custom 3D-printed, 256-channel high-resolution mapping arrays (Fig 1A). Age- and weight-matched healthy pigs served as controls (n=7). Data are expressed as mean±SD.

Results:
MRI analysis revealed significant differences between the control, P1, and P7 groups in ejection fraction (47.6±3.1% vs 37.6±3.3% vs 30.2±6.6%, p<0.001, Fig 1B) and the degree of transmural anteroseptal LV scar (0.0±0.0% vs 9.1±5.4% vs 15.4±4.2%, p<0.001), respectively. Evidence of infarcted myocardium was identified with high-resolution mapping in the P1 and P7 piglets (black arrows, Fig 1C-F). Epicardial electrical conduction was preserved in control and all P1 pigs (Figs 1C-D), whereas variable conduction block or aberrant propagation were observed in all P7 pigs (Fig 1E-F, p=0.001).

Conclusion:
P1 piglets exhibited incomplete natural cardiac regeneration after MI but nevertheless demonstrated electrophysiologic conservation of epicardial conduction dynamics.
Abstract MP165: Exosome-mediated Encapsulation Alters AAV Antigenicity and Infectivity: Implications for Gene Delivery in the Heart
Authors: Adamiak Marta , Liang Yaxuan , Sherman Cherrie , Lodha Shweta , Kohlbrenner Erik , Jeong Dongtak , Ceholski Delaine K , Dogra Navneet , Dubois Nicole , Hajjar Roger J , SAHOO Susmita
Published: October 2020

Gene therapy is a promising approach for the treatment of cardiovascular disease. Current strategies for myocardial gene transfer include the use of adeno-associated virus (AAV) vectors. However, AAVs may not be ideal for gene therapy vectors owing to pre-existing AAV capsid immunity in the human population that may reduce transduction efficacy and hinder preclinical-to-clinical translation. Interestingly, recent studies suggest that exosome-mediated encapsulation may protect viruses from neutralizing antibodies (NAbs) against the capsid and promote viral infectivity. Here, we describe the ability of exosome-enveloped AAVs, i.e. exosomal AAVs (eAAVs), to evade NAbs and serve as a highly efficient gene delivery tool for cardiovascular therapeutics. We have developed a method to purifiy eAAVs from AAV-producing HEK-293T cells, and used electron/confocal microscopy, qPCR, immunoblotting, dynamic light scattering and interferometric imaging measurements to characterize eAAV morphology, contents and mechanism of action. We confirmed eAAVs represent vesicular fractions that exhibit common exosome phenotype, along with the presence of virus particles, and demonstrated that eAAV infectious entry potentially involves trafficking via endocytic compartments. Using flow cytometry, Langendorff perfusion system and bioluminescence imaging, we then evaluated efficiency of heart targeting for eAAV9/eAAV6 and standard AAV9/AAV6 encoding for mCherry or firefly luciferase in human cardiomyocytes
in vitro
and in mouse model
in vivo
. Regardless of the presence or absence of NAbs, we showed that eAAVs are more efficient in transduction in the same titer ranges as compared to standard AAVs. To test therapeutic efficacy, we intramyocardially injected eAAV9 or AAV9 vectors encoding for SERCA2a in NAb+ post-myocardial infarction mice and further evaluated cardiac function using echocardiography. Remarkably, eAAV9-SERCA2a outperformed standard AAVs significantly improving cardiac function in the presence of NAbs (%EF 55.14 ± 3.50 compared to 27.31 ± 1.63 at 6 weeks, respectively). In summary, delivery of AAVs protected by carrier exosomes (i.e. eAAVs) may retain the clinical benefits of AAVs while addressing one of its major challenges.
Abstract MP170: Increased Ga
o
Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca
2+
Homeostasis
Authors: Inazumi Hideaki , Nakagawa Yasuaki , Moriuchi Kenji , Kuwahara Koichiro
Published: October 2020

Background:
In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however.

Purpose:
To elucidate molecular mechanisms by which NRSF maintains normal cardiac function.

Methods and Results:
Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα
o
, a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα
o
in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα
o
increases current density in surface sarcolemmal L-type Ca
2
+ channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca
2+
handling and systolic dysfunction. Furthermore, expression of Gα
o
is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα
o
prevented the progression of cardiac dysfunction.

Conclusions:
Increased expression of Gα
o
, induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca
2+
homeostasis. Gα
o
is a potential therapeutic target for heart failure.
Ischemic Stroke Occurs Less Frequently in Patients With COVID-19
Authors: Bekelis Kimon , Missios Symeon , Ahmad Javaad , Labropoulos Nicos , Schirmer Clemens M. , Calnan Daniel R. , Skinner Jonathan , MacKenzie Todd A.
Published: October 2020

Background and Purpose:

The impact of coronavirus disease 2019 (COVID-19) on the occurrence of ischemic stroke has been the subject of increased speculation but has not been confirmed in large observational studies. We investigated the association between COVID-19 and stroke.

Methods:

We performed a cross-sectional study involving patients discharged from a healthcare system in New York State, from January to April 2020. A mixed-effects logistic regression analysis and a propensity score–weighted analysis were used to control for confounders and investigate the association of COVID-19 with ischemic stroke. Similar techniques were used to detect the impact of concurrent COVID-19 infection on unfavorable outcomes for patients with stroke.

Results:

Among 24 808 discharges, 2513 (10.1%) were diagnosed with COVID-19, and 566 (0.2%) presented with acute ischemic stroke. Patients diagnosed with COVID-19 were at one-quarter the odds of stroke compared with other patients (odds ratio, 0.25 [95% CI, 0.16–0.40]). This association was consistent in all age groups. Our results were robust in sensitivity analyses, including propensity score–weighted regression models. In patients presenting with stroke, concurrent infection with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was associated with higher case-fatality (odds ratio, 10.50 [95% CI, 3.54–31.18]) and a trend towards increased occurrence of discharge to rehabilitation (odds ratio, 2.45 [95% CI, 0.81–1.25]).

Conclusions:

Using a comprehensive cross-section of patients from a large NY-based healthcare system, we did not identify a positive association between ischemic stroke and COVID-19. However, patients with stroke with COVID-19 had worse outcomes compared with those without, with over a 9-fold increase in mortality. Although no definitive conclusions can be reached from our observational study, our data do not support the concerns for an epidemic of stroke in young adults with COVID-19.
The Jewish Complex, Whose Complex Is It?
Authors: Cerminara Barbara
Published: October 2020

In 1934, attempting to extricate himself from the accusation of connivance with the Nazis, Jung conjectured about the existence of a Jewish complex. Recently, Jungian analyst Tirzah Firestone has argued that Jews suffer from a Jewish cultural complex which revolves around clusters of tribal traumatic experience. This discussion takes up from both Jung and Firestone addressing the question: The Jewish complex, whose complex is it? Stressing the relational element of Jung’s complex theory, developed into a theory of cultural complexes by Singer and Kimbles, the author of this paper, whose grandfather died in Auschwitz, places the Jewish complex among us Westerners, Jews and non-Jews. The Jewish complex is considered an affectively charged shared mental representation of a traumatic history, whose denouement is the Shoah, that affects us all. Cultural complexes such as the Jewish complex need to be understood relationally if there is to be any form of ‘resolution’.
The covid-19 Crisis and Religious Freedom
Authors: Berkmann Burkhard J.
Published: October 2020

The article provides an overview of anti-covid-19 measures in Germany, especially in Bavaria. Public worship services were banned for seven weeks, but have been permitted again since the 4th of May, 2020, under safeguards. By comparing state law and Catholic canon law, the article investigates whether church norms merely “react” to state norms or are independent of them. Do they correspond to them or even go beyond them in their content? The article also examines whether state orders violate religious freedom. To this end, the relevant case law in Germany is analyzed. Since church and state have coordinated their actions, believers find it more difficult to exercise religious freedom.
Vulgar Pleasures
Authors: Stanton Anna Ziajka
Published: October 2020

This essay examines Richard Francis Burton’s The Book of the Thousand Nights and a Night (1885–1888), an English translation of the Arabic Alf Laylah wa-Laylah stories that was enormously popular in its own time and continues to be widely admired today – despite the fact that Burton plagiarized extensively from the work of another translator. I argue that Burton’s Nights is neither a faithful nor an original translation of the Arabic stories, but rather an English text whose aesthetic enjoyment is proffered as an affective engagement with the literary aesthetics of the source text, translated through Burton’s own pleasurable experiences of Arabic literary language. Framing the reception of Burton’s Nights, through the Arabic concept of ṭarab, as a process of iterative cycles of pleasure that move between the translator and his readers, I contend that what makes Burton’s Nights enjoyable to read also makes it scandalous to the world literary system within which it has circulated.
Constructing Two-Dimensional Carbonitride Carbon/Cuprous Oxide Nanoheterostructures Toward Enhanced Visible Light Photodegradation of Organic Pollutants
Authors: Zhang Jie , Tian Jingzhi , Jing Tao , Li Shuo , Ma Yong , Das Rajib , Dong Binbin , Hou Hua , Fan Jincheng , Zheng Yongjie , Guo Zhanhu
Published: October 2020

Small specific surface area as well as fast recombination rate of photoelectron–hole pairs deteriorated the photocatalytic performances of carbonitride carbon (g-C3N4) in solving environmental pollution and energy crises. In this study, cuprous oxide (Cu2O)
nanocubes grew on the g-C3N4 porous nanosheet to form a n–p nanoheterostructure. This unique structure of the prepared g-C3N4/Cu2O photocatalyst resulted in the photogenerated electron–hole pairs having enhanced separation
rates. Under visible light irradiation, heterojunction degradation ability of methyl orange was significantly increased and its enhanced mechanism was systematically studied.
Adoption of Photoelectric Sensor in Automobile Electronic Detection
Authors: Zhou Xiaohua , Zhang Ximing , Wang Zhaofeng , Guan Zhe , Meng Jin , Liu Weiping
Published: October 2020

The continuous improvement of auto-related electronic detection technology has become a new direction of the development of the automobile industry. First, the ZigBee technology is compared with other wireless communication technologies, and the advantages of ZigBee technology are analyzed.
Then it is used in automobile electronic detection jointly with photoelectric sensor. The wireless sensor network (WSN) composed of photoelectric sensor is introduced into automobile electronic detection platform, and a set of information acquisition system for automobile electronic detection
based on ZigBee technology is designed. In the hardware field, CC2520 chip is selected as the main data transmission chip according to the actual needs of the system. The ZigBee node with CC2520 and photoelectric sensor as the core architecture is mainly discussed. At the same time, the anti-interference
design of the node is added, so that the node has the ability to collect information such as tire pressure, speed, acceleration, temperature, and humidity. In the software field, IAR Embedded Workbench is used to debug the program of ZigBee node based on CC2520+ photoelectric sensor, so as
to establish coordination points and optimize network performance. During the experiment, it is necessary to build a WSN based on photoelectric sensor and ZigBee technology. ZigBee nodes have fast response speed, accurate data return, and improved transmission speed. The WSN based on photoelectric
sensor +ZigBee technology can maintain good communication quality and low packet loss rate. After applying it to speed information collection, the results further verify the accuracy of data collection of WSN established in this study.
Decadal Variability in the Impact of Atmospheric Circulation Patterns on the Winter Climate of Northern Russia
Authors: Marshall Gareth J.
Published: October 2020

The Arctic continues to warm at a much faster rate than the global average. One process contributing to “Arctic amplification” involves changes in low-frequency macroscale atmospheric circulation patterns and their consequent influence on regional climate. Here, using ERA5 data, we examine decadal changes in the impact of seven such patterns on winter near-surface temperature (SAT) and precipitation (PPN) in northern Russia and calculate the temporal consistency of any statistically significant relationships. We demonstrate that the 40-yr climatology hides considerable decadal variability in the spatial extent of such circulation pattern–climate relationships across the region, with few areas where their temporal consistency exceeds 60%. This is primarily a response to the pronounced decadal expansion/contraction and/or mobility of the circulation patterns’ centers of action. The North Atlantic Oscillation (NAO) is the dominant pattern (having the highest temporal consistency) affecting SAT west of the Urals. Farther east, the Scandinavian (SCA), Polar/Eurasian (POL), and West Pacific patterns are successively the dominant pattern influencing SAT across the West Siberian Plains, Central Siberian Plateau, and mountains of Far East Siberia, respectively. From west to east, the SCA, POL, and Pacific–North American patterns exert the most consistent decadal influence on PPN. The only temporally invariant significant decadal relationships occur between the NAO and SAT and the SCA and PPN in small areas of the North European Plain.
Rethinking schools, rethinking learning
Authors: de Royston Maxine McKinney , Lee Carol , Nasir Na’ilah Suad , Pea Roy
Published: October 2020

The COVID-19 pandemic and social unrest offer an opportunity to clarify what learning is and rethink how to design and assess a “good” school. Schools — online, hybrid, or in-person — should foster learning for all students. Yet, too often, schools paradoxically act as both drivers of equity and reproducers of inequities, both inviting and foreclosing certain types of learning. Maxine McKinney de Royston, Carol Lee, Na’ilah Suad Nasir, and Roy Pea argue that a good school takes an expansive understanding of learning and recognizes learning as fundamentally cultural and rooted in human systems of power and ideology.
A good school is good for students of all abilities
Authors: Rhim Lauren Morando
Published: October 2020

A school cannot be “good” unless it is good for all students — including those with disabilities. In the 2018-19 school year, 14% of students in U.S. public schools received special education services under the Individuals with Disabilities Education Act, yet effective inclusion of students with disabilities is too often an afterthought. Lauren Morando Rhim describes how good schools recognize and embrace the unique learning needs of students with disabilities, creating an environment in which all students can thrive.
Good schools for a troubled democracy
Authors: Valant Jon
Published: October 2020

Current ideas of what makes a school “good” are rooted in past anxieties about America’s place in the global economy, argue Jon Valant. These anxieties have led to the prioritization of knowledge and skills needed for workforce success, with little attention to what is needed to build a cohesive society and stable democracy. Valant argues that schools should begin to prioritize digital and media literacy, social skills, and compassion.
Structural racism and the urban geography of education
Authors: Noguera Pedro A. , Alicea Julio Angel
Published: October 2020

Although we often look to schools to solve complex social problems, many educators are not ready to address the structural racism behind many contemporary conflicts. Pedro Noguera and Julio Angel Alicia present a brief history of the socioeconomic forces that drove school closures and gentrification in Chicago, the remaking of New Orleans after Hurricane Katrina, and generations of disadvantage in Los Angeles. By becoming aware of the structural barriers to change, educators will be better equipped to lead discussions with students about the need for justice in our society.
Washington View: How the federal government can support schools: Words of wisdom from Richard Riley
Authors: Ferguson Maria
Published: October 2020

Maria Ferguson interviews Richard Riley, former U.S. secretary of education. Riley shares his thoughts on what the federal government should be doing to support schools during the COVID-19 pandemic, the importance of highlighting schools that are doing well, and how education has changed since his time as secretary.
Career Confidential: Distance learning frustrations
Authors: Fagell Phyllis L.
Published: October 2020

In this monthly advice column, Phyllis Fagell answers questions from educators who are frustrated with distance learning during the COVID-19 pandemic — and with managing other people’s frustrations about it. A principal wants to know how to be supportive of teachers and staff who are unhappy with district-level decisions while also pushing them to do the work that must be done. A teacher is having trouble listening to parents’ complaints about distance learning, especially when she knows they’re right.
Bookshelf: Kappan authors on their favorite reads
Authors: Sternberg Robert J.
Published: October 2020

In this monthly column, Kappan authors discuss books and articles that have informed their views on education. Robert Sternberg recommends Cognition and Reality by Ulric Neisser, Julio Angel Alicea recommends The Future Is Black by Carl A. Grant, Ashley N. Woodson, and Michael J. Dumas, and Jeremy Glazer recommends Ms. Hempel Chronicles by Sarah Shun-Lien Bynum.
Isolated pancreatic and peripancreatic nodal tuberculosis: A single-centre experience
Authors: Ray Sukanta , Das Kshaunish , Ghosh Ranajoy
Published: October 2020

Isolated pancreatic and peripancreatic nodal tuberculosis may mimic pancreatic malignancy and may result in unnecessary surgery. Being a treatable disease, it is desirable to diagnose this condition without a laparotomy. Pancreatic tuberculosis should be considered in the differential diagnosis of a peripancreatic mass if the patient is young, residing in endemic tuberculosis regions, or has had a history of tuberculosis. We report our experience with pancreatic tuberculosis. Over a period of 12 years, we have managed 16 such patients, of whom 10 were diagnosed preoperatively. In six, the diagnosis was only made after extensive surgery. All 16 patients received antitubercular drugs and were well at a median follow-up of 52 months. Although pancreatic tuberculosis can be diagnosed by modern image-guided biopsy in a fair number of patients, if a high index of suspicion is maintained, a laparotomy may still be unavoidable in a subset of patients.
The management of venous leg ulceration post the EVRA (early venous reflux ablation) ulcer trial: Management of venous ulceration post EVRA
Authors: Salim Safa , Heatley Francine , Bolton Layla , Khatri Amulya , Onida Sarah , Davies Alun H
Published: October 2020

Objectives

This survey study evaluates current management strategies for venous ulceration and the impacts of the EVRA trial results.

Methods

An online survey was disseminated to approximately 15000 clinicians, through 12 vascular societies in 2018. Survey themes included: referral times, treatment times and strategies, knowledge of the EVRA trial and service barriers to managing venous ulceration. Data analysis was performed using Microsoft Excel and SPSS.

Results

664 responses were received from 78 countries. Respondents were predominantly European (55%) and North American (23%) vascular surgeons (74%). Responses varied between different countries. The median vascular clinic referral time was 6 weeks and time to be seen in clinic was 2 weeks. This was significantly higher in the UK (p ≤ 0.02). 77% of respondents performed surgical/endovenous interventions prior to ulcer healing, the median time to intervention was 4 weeks. 31% of participants changed their practice following EVRA. Frequently encountered barriers to implementing change were a lack of operating space/time (18%).

Conclusion

Venous ulcers are not managed as quickly as they should be. An evaluation of local resource requirements should be performed to improve service provision for venous ulceration. When interpreting the results of this survey consideration should be given to the response rate.
Study on the performance of gas foil journal bearings with bump-type shim foil
Authors: Hu Hongyang , Feng Ming , Ren Tianming
Published: October 2020

The upscaling of turbomachinery using gas foil journal bearings (GFJBs) is limited because of their limited load capacity and dynamic stability. The improvement potential of shim foil inserted under the bump foil of such bearings is investigated in terms of better bearing performance. The arch height difference Δ hb between the shim foil and bump foil can be zero or not to attain the different effect. By considering the local hardening structural stiffness and an Initial installation clearance due to the shim foil, the static and dynamic characteristics of the novel bearing were calculated through the finite difference method (FDM) and perturbation method, respectively. In the analysis, a modified bump stiffness model considering the variable foil thickness was established, and a 2 D thick plate model was adopted for the top foil. The characteristics of novel GFJB with and without preload were compared with the traditional bearing. The results indicate that the load capacity and direct stiffness of the novel GFJB with shim foil can be increased largely, especially when there is a preload (Δ hb≠0). And the improvement is reinforced as the increment of Δ hb. Moreover, the stability threshold speed ( STS) of rotor supported by the novel GFJBs is enhanced by the preload, which means better stability. In addition, an air compressor test has also been conducted to verify the improved supporting performance of novel bearings. Based on this study it is convinced that the addition of shim foil under a GFJB's bump foil can be of practical interest in the quest of enhanced load capacity and dynamic stability. Moreover, the installation of shim foil is not affected by the working environment and could even be retrofited on the existing GFJBs.