bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy
Authors: Luo Yuxuan , Jiang Nan , May Herman I. , Luo Xiang , Ferdous Anwarul , Schiattarella Gabriele G. , Chen Guihao , Li Qinfeng , Li Chao , Rothermel Beverly A. , Jiang Dingsheng , Lavandero Sergio , Gillette Thomas G. , Hill Joseph A. 
Published: April 2021

Background:
Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described.

Methods:
By engineering cardiomyocyte-specific ETS2 (a member of the E26 transformation-specific sequence [ETS] domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were used to evaluate ETS2 function in cell growth.

Results:

ETS2 is phosphorylated and activated by Erk1/2 on hypertrophic stimulation in both mouse (n=3) and human heart samples (n=8 to 19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload–induced cardiac hypertrophy (n=6 to 11). Silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n=8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as
ANP
,
BNP
, and
Rcan1.4
(n=4). We report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least 2 hypertrophy-stimulated genes:
Rcan1.4
and microRNA-223 (=n4 to 6). Suppression of microRNA-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n=6), revealing microRNA-223 as a novel prohypertrophic target of the calcineurin/NFAT and Erk1/2-ETS2 pathways.

Conclusions:
Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.
Zur Etymologie von ahd. sumbar ‚(geflochtener) Korb, Gefäß‘
Authors: Schuhmann Roland 
Published: April 2021

Abstract
The Old High German word sumbar m./n. ‘basket, vessel’ is up to now without a convincing etymology. It is shown that the word sumbar continues PIE *sm̥-bhoro‑ ‘one-carrier’, i.e. an object with one handle and that this is a parallel formation to Old High German zwibar, zubar n. ‘tub, jug’ < PIE *du̯i-bhoro‑ ‘two-carrier’, i.e. an object with two handles.
Lutherische Ethik der ‘Geselligkeit’
Authors: Voigt-Goy Christopher 
Published: April 2021

Abstract
Though sociability was not a guiding principle of early modern Lutheran ethics, it was not simply rejected by theologians in an indiscriminate manner. The following article outlines basic tenets of the 17th century Lutheran discussion of sociability in the framework of the adiaphora doctrine. The evaluation of phenomena like dance and theatre were strongly influenced by ‘confessional competition’. In demarcation to both ‘Calvinism’ and ‘Pietism’, Lutheran theologians stressed the positive function of dance and theatre, but also of gambling, for conviviality. Thus, in addition to the demand for the regulation of sociability by the government and the Church, the insight of an inherent rationale of early modern sociability gradually emerged.
Gegengeselligkeit
Authors: von Ammon Frieder 
Published: April 2021

Abstract
The present article focuses on the opening song Frischauf, ihr Klosterbrüder mein of the collection Studentenschmaus (‘Student Feast’) by Johann Hermann Schein (1626). The song is analyzed in form and content, and then interpreted as an example of ‘meta-sociability’, i.e. sociability is its message as well as its medium. By following the intertextual allusions to the humanistic satire Epistolae virorum obscurorum, and other references, it is shown that the ‘meta-sociability’ in Schein’s song is directed against other forms of sociability and can therefore be understood as ‘counter-sociability’.
Plain Language Summary: Opioid Prescribing for Analgesia After Common Otolaryngology Operations
Authors: Anne Samantha , Finestone Sandra A. , Paisley Allison , Monjur Taskin M. 
Published: April 2021

This plain language summary explains pain management and careful use of opioids after common otolaryngology operations. The summary applies to patients of any age who need treatment for pain within 30 days after having a common otolaryngologic operation (having to do with the ear, nose, or throat). It is based on the 2021 “Clinical Practice Guideline: Opioid Prescribing for Analgesia After Common Otolaryngology Operations.” This guideline uses available research to best advise health care providers, and it includes recommendations that are explained in this summary. Recommendations may not apply to every patient but can be used to facilitate shared decision making between patients and their health care providers.
A randomized study of natalizumab dosing regimens for relapsing–remitting multiple sclerosis
Authors: Trojano Maria , Ramió-Torrentà Lluís , Grimaldi Luigi ME , Lubetzki Catherine , Schippling Sven , Evans Karleyton C , Ren Zheng , Muralidharan Kumar Kandadi , Licata Stephanie , Gafson Arie R 
Published: April 2021

Background: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing–remitting multiple sclerosis (RRMS) patients. Objective: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients. Methods: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60. Results: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable. Conclusion: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
Intensive care unit visiting and family communication during the COVID-19 pandemic: A UK survey
Authors: Boulton Adam J , Jordan Helen , Adams Claire E , Polgarova Petra ,   TRIC Network (Corporate Author), WMTRAIN (Corporate Author), Morris Andrew Conway , Arora Nitin 
Published: April 2021

Background Frequent visiting and communication with patients’ families are embedded within normal ICU practice, however the COVID-19 pandemic has challenged this, and it is unclear how ICUs are managing. We aimed to investigate how NHS ICUs are approaching family communications and visiting during the COVID-19 pandemic. Methods An electronic snapshot survey was delivered between 16th April and 4th May 2020 and was open to NHS ICUs. Replies from 134 individual ICUs with COVID patients were included. Results All reported that visiting was more restricted than normal with 29 (22%) not allowing any visitors, 71 (53%) allowing visitors at the end of a patient’s life (EOL) only, and 30 (22%) allowing visitors for vulnerable patients or EOL. Nearly all (n = 130, 97%) were updating families daily, with most initiating the update (n = 120, 92%). Daily telephone calls were routinely made by the medical (n = 75, 55%) or nursing team (n = 50, 37%). Video calling was used by 63 (47%), and 39 (29%) ICUs had developed a dedicated family communication team. Resuscitation and EOL discussions were most frequently via telephone (n = 129, 96%), with 24 (18%) having used video calling, and 15 (11%) reporting discussions had occurred in person. Clinicians expressed their dissatisfaction with the situation and raised concerns about the detrimental effect on patients, families, and staff. Conclusions COVID-19 has resulted in significant changes across NHS ICUs in how they interact with families. Many units are adapting and moving toward distant and technology-assisted communication. Despite innovative solutions, challenges remain and there may be a role for local and national guidance.
The Damage Sensory Molecule TRPA1 Positively Regulates Endogenous Thymic Regeneration after Damage
Authors: Argyropoulos Kimon , Velardi Enrico , Tsai Jennifer , Lazrak Amina , Jahn Lorenz , Dudakov Jarrod A , van den Brink Marcel R.M. 
Published: April 2021

Abstract
The thymus is extremely sensitive to exogenous insults but has a remarkable capacity to regenerate which is lost with age. Reactive oxygen species (ROS) accumulate early after tissue damage and despite their toxic potential, ROS and their byproducts (such as lipid peroxidation products-LPPs) can act as regeneration signals by activating membrane or intracellular sensors and subsequent stress-response signalling pathways. Using Sublethal Total Body Irradiation (SL-TBI) as a model of acute thymic injury, we found a rapid accumulation of thymic ROS as well as lipid peroxidation products on cell membranes after SLTBI (Figure 1A&B).
The damage-sensing ion channel Transient Receptor Potential cation channel family A member 1 (TRPA1) represents one of the major damage sensing receptors that can mediate cellular responses to oxidative stress mediators, such as LPPs. Using immunofluorescence (IF) microscopy we found that TRPA1 is enriched in the thymic medulla. Interestingly, although TRPA1 has been classically identified in nociceptive fibers, the major TRPA1 expressing structures in the thymus were not nerve fiber terminals, but primarily thymic endothelial cells (Figure1C), fibroblasts and subsets of epithelial cells. We have recently demonstrated that thymic endothelial cells can regulate regeneration through secretion of BMP-4, which can enhance Foxn1 expression and proliferation of thymic epithelial cells. In order to assess the functional role of TRPA1 in thymic regeneration after injury, we utilized TRPA1 knockout (TRPA1-/-) mice and quantified thymic reconstitution after SL-TBI. TRPA1-/- mice had significantly lower thymic cellularity compared to their age- and sex-matched WT controls, suggesting an association between TRPA1 deficiency and delayed endogenous thymic recovery (Figure 1D). The major deficit in thymocyte counts primarily affected double negative-4 (DN4), double positive (DP) and CD4+ single positive (SP-CD4+) thymocyte numbers. The thymic stroma of TRPA1-/- mice had lower endothelial cell and fibroblast counts (Figure 1D). In accordance with these findings drinking water administration of the TRPA1 agonist Allyl-Isothiocyanate (AITC), resulted in enhanced thymic regeneration after radiation exposure. Besides its positive effects on thymocyte counts, AITC significantly augmented endothelial cell counts after irradiation (Figure 1E).
In conclusion these results suggest that TRPA1 plays a non-redundant role in thymic regeneration and that exogenous TRPA1 stimulation can enhance immune recovery after damage.

Disclosures
van den Brink: Seres: Research Funding; Jazz Pharmaceuticals: Consultancy; PureTech Health: Consultancy; Therakos Institute: Other: Speaking engagement.
Fine Temporal Mapping of Plasmodium Falciparum growth Inhibition in Hypoxic Sickle Cell Trait Erythrocytes
Authors: Archer Natasha , Petersen Nicole , Clark Martha , Duraisingh Manoj 
Published: April 2021

Abstract
Background: Despite the global acceptance of Haldane's hypothesis that individuals with sickle cell trait (AS) are protected against malaria, an exact mechanism of resistance remains unknown. Several theories to explain the resistance such as increased splenic destruction, impaired hemoglobin digestion, reduced cytoadherence and specific translocation of host specific microRNAs have been proposed. Here we carefully examine the influence of hypoxia and its relation to parasite cytoadherence and growth in AS and normal (AA) human red blood cells (RBCs).
Materials and Methods: To assess the influence of oxygen tension on parasite proliferation in AS RBCs, we followed the proliferation of tightly synchronized P. falciparum within AS and AA RBCs at 1, 5, 10, and 17% oxygen by flow cytometry and microscopy. Carbon monoxide (CO) studies were performed by introducing 100% CO gas into our enclosed chamber system every 21 hours to prevent sickling at low oxygen.
Results: Flow cytometry assessment of DNA content confirms the absence of DNA replication within parasites in AS erythrocytes at low oxygen, however normal DNA replication is observed in the presence of high oxygen tension and when CO is introduced at low oxygen. Moving parasites from high to low oxygen tension greatly influences the extent of parasite maturity; parasites moved at 16 and 20 hours post invasion (hpi) do not mature beyond that of the late ring/early trophozoite stage while parasites moved at 24, 28, and 32 hpi develop increasingly more merozoites.
Conclusion: Here, we show that in hypoxic conditions parasites in AS erythrocytes stall at the late ring/early trophozoite stage and do not replicate their DNA. We also show that treatment of AS erythrocytes with high oxygen tension or carbon monoxide, a potent inhibitor of sickle hemoglobin polymerization, reverses this phenotype. We propose that the mechanism of AS protection is largely due to P.falciparum's inability to digest polymerized sickle hemoglobin once the parasite sequesters in the hypoxic microvasculature. This is likely a key driver of the reduced parasite densities observed in actual infections in AS individuals.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Pegylated Carboxyhemoglobin Bovine (SANGUINATE®) Restores RBCs Roundness and Reduces Pain during a Sickle Cell Vaso-Occlusive Crisis
Authors: Buontempo Peter , Jubin Ronald G. , Buontempo Cathy , Real Rosa , Kazo Friedericke , O'Brien Siobhan , Adeel Faiza , Abuchowski Abraham 
Published: April 2021

Abstract

Background: Pain during Vaso-Occlusive Crisis (VOC) is a hallmark of sickle cell disease (SCD) as deoxygenated (sickled) red blood cells (RBC) aggregate in the microvasculature due to Hemoglobin S (HbS) polymerization. PEGylated carboxyhemoglobin bovine (PEG-COHb; SANGUINATE®) was designed as a gas transfer agent to depolymerize HbS resulting from hypoxia. Prior in vitro studies have shown PEG-COHb capability to transfer carbon monoxide (CO) and oxygen (O2) to SCD hypoxic RBCs, reversing sickling. A prospective, randomized, single-dose Phase II clinical study is in progress (NCT02411708) evaluating the safety and efficacy of PEG-COHb in the treatment of severe VOC including pain reduction in the ambulatory setting. This study is also evaluating the levels of RBC sickling following treatment and association with pain scoring.
Methods: Participants were randomized to a PEG-COHb (320 mg/kg) or saline (placebo) arm, in addition to standard treatment and IV opioid per institutional practice. Pain was assessed using a 10-point pain scale at screening, pre-infusion, hourly until discharge, 24-hours, 72-hours, and Day 7 post-infusion. Blood was collected at pre-infusion, time for readiness to discharge and 72 hours post-infusion to assess RBC shape morphology changes using image-based flow cytometry.
Results: Interim results showed PEG-COHb treated subjects experienced significant reduction at discharge in pain score of 4.3 (±0.3) compared to 2.4 (±0.6) reduction in the placebo arm (p&lt;0.01) (Fig 1). All PEG-COHb participants exhibited RBC morphology changes consistent with unsickling shortly after administration (Fig 2). There were no drug-related severe adverse events.
Conclusions: PEG-COHb appeared to be safe, well tolerated, and associated with significantly reduced pain scores. The flow cytometry analysis of blood samples revealed PEG-COHb treatment reverted RBC to a more normal round morphology when compared to the placebo group. Individual patient data showed a trend between RBC unsickling (roundness) and pain score reductions. These results are consistent with depolymerization of HbS resulting from transfer of CO and/or O2 to sickled RBCs and O2 delivery to hypoxic tissue. This study supports advanced clinical trials of PEG-COHb as a potential therapy to reduce the pain associated with VOC.

Disclosures
Buontempo: Prolong Pharmaceuticals: Employment. Jubin: Prolong Pharmaceuticals: Employment. Buontempo: Prolong Pharmaceuticals: Employment. Real: Prolong Pharmaceuticals: Employment. Kazo: Prolong Pharmaceuticals: Employment. O'Brien: Prolong Pharmaceuticals: Employment. Adeel: Prolong Pharmaceuticals: Employment. Abuchowski: Prolong Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.
Apolipoprotein L1 Genetic Variants Are Associated with Evidence of Early Kidney Injury in Sickle Cell Disease
Authors: Moodalbail Divya G , Falkner Bonita 
Published: April 2021

Abstract

Background and Objectives: Apolipoprotein L1 (APOL1) renal risk variants prevalent in African-ancestry populations are associated with chronic kidney disease (CKD). CKD is a major cause of morbidity and mortality in sickle cell disease (SCD) in adults; yet the prevalence and significance of APOL1 renal-risk variants in this population remains unknown. Our objective was to determine expression of biomarkers of early kidney disease in African American youth with SCD, based on their APOL1 genotype.
Methods:We enrolled65 African American subjects between 5 to 21 years of age with SCD (Hb SS or Hb S β0 thalassemia). Blood and concurrent urine samples were collected. Allenrolled subjects underwent APOL1 genotyping by PCR analysis of DNA extracted from whole blood. Presence of two renal-risk variants qualified for APOL1 High Risk (HR) genotype, while presence of zero or one copy of renal-risk variants qualified for APOL1 Low Risk (LR) genotype.
Results: APOL1 HR genotype was expressed by 22% of our subjects; this is comparable to 23% prevalence of APOL1 HR genotype in African American adults with CKD (AASK study). Both groups were similar with respect to distribution of age, BMI z-scores, renal function and urine osmolality. Hyperfiltration was noted in both groups based on low serum creatinine for age, and elevated eGFR based on creatinine clearance. However, median urine albumin excretion rate was significantly higher in HR group vs. LR group.
Conclusions: Preliminary data in this cohort of 65 children and adolescents with SCD detected greater urine albumin excretion rate in the presence of APOL1 HR genotype. Screening SCD youth for heightened CKD risk may be an avenue to initiate targeted preventive interventions to preserve renal function and reduce progression of kidney disease.
Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod).

Disclosures
No relevant conflicts of interest to declare.
Poly-P as Modulator of Hemostasis, Thrombosis, and Inflammation
Authors: Morrissey James H. 
Published: April 2021

Polyphosphate (polyP), consisting of linear polymers of inorganic phosphates, is ubiquitous in biology. PolyP metabolism has been most extensively explored in microbes, but until very recently, roles for polyP in mammalian cells have been poorly understood. In 2004, polyP was shown to be a major component of dense granules in human platelets, and to be secreted upon platelet activation.1 In 2006, we demonstrated that polyP is a potent modulator of the blood clotting system.2 Subsequent work from our lab and others has shown that polyP accelerates blood clotting and slows fibrinolysis, in a manner that is highly dependent on polymer length.3 Long-chain polyP (present in infectious microorganisms) potently triggers the contact pathway and may participate in innate immunity/host responses to pathogens. PolyP of the size secreted by platelets (60 to 100 phosphates long) accelerates factor V activation, abrogates the anticoagulant activity of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. PolyP also enhances the proinflammatory activity of histones and inhibits complement. PolyP is a potential antithrombotic drug target, with a novel mechanism of action and possibly fewer bleeding side-effects compared to conventional anticoagulant drugs.4
1. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem . 2004;279(43):44250-44257.
2. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A . 2006;103(4):903-908.
3. Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost . 2015;13 Suppl 1:S92-97.
4. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood . 2014;124(22):3183-3190.

Disclosures
Morrissey: Novo Nordisk: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Paul, Weiss, Rifkind, Wharton & Garrison LLP: Consultancy; Cayuga Pharmaceuticals: Consultancy; PrevThro Pharmaceuticals: Equity Ownership; Kerafast, Inc.: Research Funding.
Reciprocal Interactions Between Platelets and Metastatic Tumors
Authors: Byzova Tatiana V. 
Published: April 2021

The presentation will address the possible mechanisms underlying the crosstalk between circulating platelets and the growing tumor. The emphasis will be on the reciprocal nature of this crosstalk. It is well accepted that the presence of platelets and their activation generally promotes tumor growth and its metastasis; the effect of tumor on platelet activation and subsequent thrombosis have been also known for many years. The highly metastatic tumors are able to affect the gene expression and functional characteristics of other cells in their micro and macro environment. The easiest targets for tumor interference are blood cells. Due to their ability to capture and accumulate proteins, small particles and even cell fragments, platelets represent a unique "delivery" system. Many proteins stored in alpha-granules of platelets circulating in blood of tumor-bearing host carry proteins of the tumor rather than the host origin. Tumor hijacks the platelet system for the delivery of its growth factors and cytokines and it also induces platelet activation. The possible mechanisms of tumor-induced platelet activation will be discussed. Results demonstrating the mode of tumor-platelet interactions in animal models will be combined with clinical evidence. Understanding of these mechanisms will facilitate the development of therapeutic strategies aimed to prevent cancer-induced thrombosis without disturbing the hemostatic balance.

Disclosures
No relevant conflicts of interest to declare.