bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multisystem Inflammatory Syndrome in Children During Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta and Omicron Variant Circulation—United States, July 2021–January 2022
Authors: Miller Allison D , Yousaf Anna R , Bornstein Ethan , Wu Michael J , Lindsey Katherine , Melgar Michael , Oster Matthew E , Zambrano Laura D , Campbell Angela P 
Published: June 2022

Abstract
We describe 2116 multisystem inflammatory syndrome in children (MIS-C) cases reported to the Centers for Disease Control and Prevention during Delta and Omicron circulation from July 2021 through January 2022. Half of MIS-C patients were aged 5–11 years, 52% received intensive care unit–level care, and 1.1% died. Only 3.0% of eligible patients were fully vaccinated prior to MIS-C onset.
Maturation of hiPSC-derived cardiomyocytes in cardiac microtissues promotes adult alternative splicing of sodium channel revealing mutation effects associated with cardiac arrhythmia
Authors: Campostrini G , Ward-Van Oostwaard D , Kosmidis G , Verkerk AO , Bezzina CR , Mummery CL , Bellin M 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Marie Skłodowska-Curie Actions - Individual Fellowship

Background
The cardiac sodium channel encoded by SCN5A gene undergoes fetal-to-adult isoform switch postnatally, regulated by alternative splicing. Various mutations in SCN5A associated with severe cardiac arrhythmia have been previously studied using cardiomyocytes derived from human induced pluripotent stem-cells (hiPSC-CMs), demonstrating the importance of a human cardiac cellular context for such analysis. Mutations in the adult isoform of SCN5A are however of difficult evaluation in hiPSC-CMs, because of their typical immature/fetal-like characteristics. Combining hiPSC-CMs in 3-dimensional microtissues together with hiPSC-derived cardiac fibroblasts and endothelial cells induced maturation in gene expression and functional properties, including electrophysiology.

Purpose
We investigated whether the maturation promoted by the microtissue system could reveal the functional phenotype of a mutation in the adult isoform of SCN5A.

Methods
We derived hiPSC-CMs from a cardiac arrhythmia patient carrying two compound mutations in SCN5A: p.W156X in exon 4 and p.R225W in the adult splicing variant of exon 6 (exon 6B). Using CRISPR/Cas9, we corrected exon 4 mutation to investigate specific effects of exon 6B mutation on sodium current by single-cell patch clamp. HiPSC-CMs were matured in tricell-type cardiac microtissues and analysed after dissociation. The mechanism underlying exon 6B expression was investigated by overexpressing or knocking-out the alternative splicing regulator MBNL1 in hiPSC-CMs.

Results
ddPCR analysis showed low expression of exon 6B-containing transcripts in hiPSC-CMs, accompanied by no effect of exon 6B mutation on the sodium current. Instead, maturing hiPSC-CMs in cardiac microtissues promoted SCN5A exon 6B expression and revealed the contribution of both SCN5A mutations to the diseased cellular electrophysiology. MBNL1 was upregulated in microtissues and indeed its overexpression was sufficient to increase exon 6B levels in hiPSC-CMs, while lack of MBNL1 prevented the switch of SCN5A splicing isoforms.

Conclusions
Our data demonstrate that a maturation of hiPSC-CMs is required to express the adult SCN5A isoform. This was achieved in the microtissue system via upregulation of MBNL1, and allowed to reveal SCN5A mutation contributions, by dissecting changes in ionic current that cause adult arrhythmic disease phenotypes in humans.
Comparative characterization of single cells and engineered heart tissues from hiPSC-derived cardiomyocyte subtypes
Authors: Li J , Wiesinger A , Fokkert L , Boukens B , Verkerk A , Christoffels V , Boink G , Devalla H 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research council starting grant 714866 and associated proof-of-concept grant 899422
ZonMW and the Dutch Heart foundation MKMD grant 114021512 and Dutch Heart Foundation Dekker fellowship 2020T023
Rationale: Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes represent an excellent in vitro platform to study cardiac development and model patient-specific diseases. However, their widespread application in drug discovery and regenerative approaches has not yet been realized at least in part due to limited comparative characterization of the available cardiomyocyte subtypes and lack of multicellular models that allow assessment of physiologically relevant parameters.

Objective
Perform comprehensive characterization of hiPSC-derived sinoatrial nodal cardiomyocytes (SANCM), atrial cardiomyocytes (ACM) and ventricular cardiomyocytes (VCM) from 2D and 3D cultures.

Methods
SANCM, ACM and VCM were generated using directed differentiation protocols. Electrophysiological analysis was performed by single cell patch-clamp. Subtype-specific differences were further characterized by response to neurohumoral agents noradrenaline, and carbachol and If blocker ivabradine. Next, we generated EHTs to evaluate the effect of 3D culturing on cardiomyocyte subtypes and performed optical mapping. To establish a model to study impulse initiation and propagation in vitro, we generated binary EHTs (BIN-EHTs) composed of heteropolar ends of SANCM and ACM.

Results
Gene expression analysis and single cell electrophysiology confirmed identities of respective cardiomyocyte subtypes. While response to noradrenaline and carbachol were as expected, ivabradine testing showed the functional presence of pacemaker current If in ACM, besides SANCM. After three weeks in culture as EHTs, cardiac structural genes were markedly upregulated in all groups. Optical mapping demonstrated a three-fold increase in conduction velocities in ACM and VCM while SANCM EHTs retained slower conduction velocities recapitulating in vivo differences. In BIN-EHTs, SANCM end of the EHT consistently paced the tissues under baseline conditions. Upon treatment with ivabradine, cycle length of BIN-EHTs increased and impulse initiation switched to ACM end in the majority of tissues.

Conclusions
We performed comprehensive characterization of hiPSC-cardiomyocyte subtypes, which recapitulated salient features of their in vivo counterparts. BIN-EHT constructs composed of SANCM and ACM are a valuable rudimentary model for investigating impulse formation and propagation in vitro.
Helium conditioning increases cardiac fibroblast migration which effect is not propagated via soluble factors or extracellular vesicles
Authors: Kovacshazi C , Jelemensky M , Ferenczyova K , Hofbauerova M , Kiss B , Pallinger E , Kittel A , Sayour V N , Gorbe A , Hambalko SZ , Kindernay L , Barancik M , Ferdinandy P , Bartekova M , Giricz Z 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Project was supported by the National Research, Development and Innovation Office of Hungary

Background
Helium inhalation induces cardioprotection against ischemia/reperfusion injury, of which cellular mechanism is not fully elucidated. Extracellular vesicles (EVs) are cell-derived, nano-sized membrane vesicles which play role in cardioprotective mechanisms, but their function in helium-conditioning (HeC) is not elucidated.

Purpose
To investigate, how HeC affects cardiac fibroblasts and if their HeC-induced EVs or other secreted factors mediates remodeling of the cardiac tissue.

Methods
Neonatal rat cardiac fibroblasts (NRCF) were exposed to glucose deprivation and HeC rendered by four cycles of 95% helium + 5% CO2 for one hour, followed by one hour of normal culturing conditions. 40 hours later, NRCF migration was analyzed and Western Blot and quantitative PCR were used to analyze the expression of fibroblast to myofibroblast transformation markers. From the cell supernatant, medium-sized extracellular vesicles (mEVs) were isolated with differential centrifugation and analyzed with WB, transmission electron microscopy and nanoparticle tracking analysis. Supernatant of HeC-treated NRCF was transferred to naïve NRCF or immortalized human umbilical vein endothelia cells (HUVEC/TERT2) and migration and in vitro angiogenesis assay was performed.

Results
HeC accelerated the migration of NRCF. Meanwhile, HeC did not increase the expression of myofibroblast markers. HeC tended to decrease mEV secretion of NRCFs, but supernatant of HeC-NRCF neither accelerate the migration of naïve NRCF, nor affect the angiogenic potential of HUVEC/TERT2.

Conclusion
Since HeC increased the migration of NRCF but HeC-NRCF mEVs did not affect the function of remote cells, HeC may exert its cardioprotective effect via NRCFs, but not affect cardiac remodeling remotely, via NRCF mEVs.
Diabetes impairs osteogenic differentiation of bone marrow mesenchymal stem cells
Authors: Chiva-Blanch G , Arderiu G , Vilahur G , Badimon L 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation (MICINN)
Diabetes impairs osteogenic differentiation of bone marrow mesenchymal stem cells

Background
Diabetes is a severe metabolic condition that induces micro- and macrovascular disease, including atherosclerotic vascular disease, cutaneous lesions and bone necrosis. Whether it affects stem cell function is a matter of investigation. When the self-renewing capacity of mesenchymal stem cells (MSC) is compromised, their regenerative potential for cell therapy is impaired.

Purpose
We aimed to investigate the effects of diabetes on bone marrow- mesenchymal stem cells (BM-MSC) transcriptomics to evidence their potential for differentiation.

Methods
Bone marrow was extracted from femurs of Zucker rats, and BM-MSC were isolated by culturing adherent cells of extracted bone marrow in DMEM low glucose/ 20% FBS/ 1% P/S under hypoxic conditions (1% oxygen). After one week, MSC were characterized by flow cytometry. Gene expression arrays were used to analyse the expression of BM-MSC of Zucker rats with diabetes (ZD) compared to those of lean-normoglycemic controls (ZC) with the same genetic background (n=6). Results were analysed in silico to identify significantly modified signalling pathways. In addition, BM-MSC differentiation into endothelial, adipogenic and osteogenic cells was investigated in vitro.

Results
95-99% of cells isolated from BM expressed CD90, a marker of MSC. Expression data analyses revealed a down-regulation of transcription factors related to the osteogenic pathway (Abcb1a, Adipoq, Fut1, Il1b, Kdr, Nes, Rhoa, Runx2, Tbx5, Tert and Tgfb3), and up-regulation of adipogenic- and angiogenic-related genes such as Bmp7, Casp3, Cd44, Csf2, Erbb2, Gdf7, Il10, Mcam, Nt5e, Pparg, Sox2, Vegfa and Vwf, in BM-MSC from animals with diabetes compared to lean controls. Concomitantly, BM-MSC from rats with diabetes showed impaired osteogenic differentiation in vitro compared to lean controls. No significant differences in adipogenesis or endothelial differentiation were observed between BM-MSC of rats with diabetes and lean controls.

Conclusions
Diabetes down-regulates several factors involved in the osteogenic differentiation pathway resulting in impaired osteogenesis. The imbalance in gene expression and MSC differentiation may partially explain the impaired regenerative capacity in diabetes.
Liraglutide treatment attenuates dysfunction-related changes in the cardiac and cerebral microvasculature in streptozotocin-induced diabetic rats
Authors: Korn A , Baylan U , Emmens RW , Schalkwijk CG , Niessen HWM , Krijnen PAJ , Simsek S 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Novo Nordisk

Background
Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 receptor analogue, inhibited the reactive oxygen species producing enzyme NOX2 and adhesion molecules in isolated endothelial cells. Here we have studied how Liraglutide affects advanced glycation, NOX expression and inflammatory status of the cardiac and cerebral microvasculature in vivo in diabetic rats.

Methods
DM was induced in Sprague Dawley rats (n=15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg body weight). 10 control rats remained non-diabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n=7) or vehicle (n=8) was injected subcutaneously daily until termination on day 29. The advanced glycation end-product N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently analysed using immunohistochemistry and quantified to compare Liraglutide treatment to placebo.

Results
DM increased CML, NOX2, ICAM-1 and VCAM-1 in the intramyocardial vasculature, although not significant for NOX2. NOX4 was not significantly increased in the ventricles and absent in the atria. In the cerebral vasculature, CML, NOX2 and NOX4 were significantly increased, but not ICAM-1 and VCAM-1. Liraglutide significantly reduced the DM-associated CML accumulation and expression of NOX2, ICAM-1 and VCAM-1 in the intramyocardial, and CML, NOX2 and NOX4 in the cerebral vasculature. Liraglutide had these effects without changing blood glucose levels or body weight.

Conclusions
Our study implies that Liraglutide protects the cardiac and cerebral microvasculature against diabetes-induced dysfunction, independent of a blood glucose lowering effect in a type 1 diabetes rat model.
Hypoxia-inducible factors: roles in cardiovascular disease progression, prevention, and treatment
Authors: Semenza Gregg L 
Published: June 2022

AbstractHypoxia-inducible factors (HIF)-1 and HIF-2 are master regulators of oxygen homeostasis that regulate the expression of thousands of genes in order to match O2 supply and demand. A large body of experimental data links HIF activity to protection against multiple disorders affecting the cardiovascular system: ischemic cardiovascular disease (including coronary artery disease and peripheral artery disease), through collateral blood vessel formation and preconditioning phenomena; emphysema; lymphedema; and lung transplant rejection. In these disorders, strategies to increase the expression of one or both HIFs may be of therapeutic utility. Conversely, extensive data link HIFs to the pathogenesis of pulmonary arterial hypertension and drugs that inhibit one or both HIFs may be useful in treating this disease.
Heart in a shell—a cascade of classical findings: a case report
Authors: Khan Hafiz Muhammad Waqas , Munir Ahmad , Sud Anup , Moza Ankush 
Published: June 2022

Abstract

Background
Idiopathic chronic constrictive pericarditis (CP) is an uncommon yet very important clinical entity as prompt diagnosis and early treatment are affiliated with improved outcomes. We describe an uncommon case of CP with a series of textbook findings and received successful treatment with surgical pericardiectomy (SP).

Case summary
A 58-year-old male presented to the emergency department with exertional dyspnoea and anasarca. The past medical history was negative for infections like tuberculosis, viral, etc., connective tissue disease, prior cardiac surgery, human immunodeficiency virus, or any radiation therapy. The vital signs were within normal limits except mild hypoxia while the physical examination was consistent with congestive heart failure. Further investigations with laboratory testing, imaging with chest X-ray, computed tomography, echocardiogram, and invasive study with right heart catheterization were all consistent with idiopathic chronic CP. The patient underwent successful SP with significant improvement in clinical condition.

Discussion
This case highlights the classical signs and symptoms along with important diagnostic features of CP. It is uncommon to see all the classical features of CP in one patient as described in the above case. Familiarity with these findings is crucial to make the diagnosis as early treatment is affiliated with improved outcomes.
Development of a Controlled Laboratory-scale Inoculation System to Study Vibrio parahaemolyticus-oyster Interactions
Authors: Hines Ian S , Smith Stephen A , Kuhn David D , Stevens Ann M 
Published: June 2022

Abstract
Prevalence of seafood-borne gastroenteritis caused by the human pathogen Vibrio parahaemolyticus is increasing globally despite current preventative measures. The United States Centers for Disease Control have designated V. parahaemolyticus as a reportable emerging human pathogen. The Eastern oyster (Crassostrea virginica) is a natural reservoir of the bacterium in marine environments, but little is actually known regarding interactions between oysters and V. parahaemolyticus. Therefore, a laboratory-scale Biosafety Level-2 (BSL2) inoculation system was developed wherein Chesapeake Bay region oysters harvested during summer or winter months, were exposed to the clinical RIMD2210633 strain carrying a chloramphenicol-selective marker (VP RIMDmC). Homogenized whole oyster tissues were spread on selective and differential agar medium to measure viable VP RIMDmC levels. Endogenous Vibrio spp. cell numbers were significantly reduced followed chloramphenicol treatment and this likely contributed to higher VP RIMDmC oyster-associated levels, especially using winter-harvested animals. Summer-harvested oysters had significantly higher existing Vibrio levels and a lower level of artificial oyster-associated VP RIMDmC. Thus, the pre-existing microbiome appears to afford some protection from an external V. parahaemolyticus challenge. Overall, this system successfully enabled controlled manipulation of parameters influencing V. parahaemolyticus–oyster interactions and will be useful in safely testing additional pertinent environmental variables and potential mitigation strategies.
Mantle dynamics of the North China Craton: new insights from mantle transition zone imaging constrained by P-to-S receiver functions
Authors: Liu Lin , Gao Stephen S , Liu Kelly H , Griffin William L , Li Sanzhong , Tong Siyou , Ning Jieyuan 
Published: June 2022

SUMMARY
Cratons are generally defined as stable continental blocks with a strong cratonic root that typically is at least ∼200 km thick. Many cratons have undergone little internal tectonism and destruction since their formation, but some of them, such as the eastern part of the North China Craton (NCC), the Dharwar Craton and the Wyoming Craton, have lost their thick cratonic root and become reactivated in recent geological history, leading to widespread Meso-Cenozoic volcanisms. The mechanisms responsible for such decratonization remain debated. To provide new constraints on models leading to decratonization, in this study we stack 612 854 source-normalized P-to-S conversions (receiver functions or RFs) from the 410 and 660 km discontinuities (d410 and d660, respectively) bordering the mantle transition zone (MTZ) recorded at 1986 stations in the NCC. Both the number of RFs and the number of stations are unprecedented in the study area. The average apparent depths of the d410 and d660 and the thickness of the MTZ are 413 ± 6, 669 ± 8 and 255 ± 6 km, respectively. A depression of up to 37 km and mean 11 km of the d660 are clearly observed beneath the eastern NCC, mainly caused by the possible existence of a relatively large amount of water in the MTZ. Our study provides strong observational evidence for geodynamic modelling that suggests water in the MTZ can be driven out into the upper mantle by poloidal mantle flow induced by the subduction and retreat of subducted oceanic slabs. The results are consistent with the weakening of the lithosphere beneath the eastern NCC by the release of water (in the form of structurally bound H/OH) brought down to the MTZ by subduction of the Pacific slab. Continuous slab dehydration and the ascent of fluids would have triggered intraplate volcanism and mantle upwelling in the eastern NCC, as evidenced by the spatial correspondence among the lower-than-normal upper-mantle seismic velocities, unusually large depressions of the d660, Cenozoic basaltic volcanism and thinning of the cratonic lithosphere.
Mobility of FLOWERING LOCUS T protein as a systemic signal in trifoliate orange and its low accumulation in grafted juvenile scions
Authors: Wu Yan-Mei , Ma Yu-Jiao , Wang Min , Zhou Huan , Gan Zhi-Meng , Zeng Ren-Fang , Ye Li-Xia , Zhou Jing-Jing , Zhang Jin-Zhi , Hu Chun-Gen 
Published: June 2022

AbstractThe long juvenile period of perennial woody plants is a major constraint in breeding programs. FLOWERING LOCUS T (FT) protein is an important mobile florigen signal that induces plant flowering. However, whether FT can be transported in woody plants to shorten the juvenile period is unknown, and its transport mechanism remains unclear. In this study, trifoliate orange FT (ToFT) and Arabidopsis FT (AtFT, which has been confirmed to be transportable in Arabidopsis) as a control were transformed into tomato and trifoliate orange, and early flowering was induced in the transgenic plants. Long-distance and two-way (upward and downward) transmission of ToFT and AtFT proteins was confirmed in both tomato and trifoliate orange using grafting and western blot analysis. However, rootstocks of transgenic trifoliate orange could not induce flowering in grafted wild-type juvenile scions because of the low accumulation of total FT protein in the grafted scions. It was further confirmed that endogenous ToFT protein was reduced in trifoliate orange, and the accumulation of the transported ToFT and AtFT proteins was lower than that in grafted juvenile tomato scions. Furthermore, the trifoliate orange FT-INTERACTING PROTEIN1 homolog (ToFTIP1) was isolated by yeast two-hybrid analysis. The FTIP1 homolog may regulate FT transport by interacting with FT in tomato and trifoliate orange. Our findings suggest that FT transport may be conserved between the tomato model and woody plants. However, in woody plants, the transported FT protein did not accumulate in significant amounts in the grafted wild-type juvenile scions and induce the scions to flower.