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Pubblicazioni recenti - cardiac stem
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Adipocytes control haematopoiesis and inflammation through CD40 signaling.
Haematologica2022 Dec;():. doi: 10.3324/haematol.2022.281482.
Reiche Myrthe E, Poels Kikkie, Bosmans Laura A, Vos Winnie G, Van Tiel Claudia M, Gijbels Marion J J, Aarts Suzanne A B M, Den Toom Myrthe, Beckers Linda, Weber Christian, Atzler Dorothee, Rensen Patrick C N, Kooijman Sander, Lutgens Esther,
Abstract
The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with ageing. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte-CD40 in the aging haematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow (BM) haematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased BM adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid- and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in BM, spleen, and adipose tissue (AT), while B-cell numbers were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T-cells and larger necrotic cores. Analysis of peripheral AT in a diet-induced obesity model revealed that obese AdiCD40KO mice showed increased T-cell activation in AT and lymphoid organs, but exhibited decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in BM during ageing and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40-deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.
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Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes.
J Transl Med2022 Dec;20(1):568. doi: 10.1186/s12967-022-03795-9.
Zhang Ge, Liu Zaoqu, Deng Jinhai, Liu Long, Li Yu, Weng Siyuan, Guo Chunguang, Zhou Zhaokai, Zhang Li, Wang Xiaofang, Liu Gangqiong, Guo Jiacheng, Bai Jing, Wang Yunzhe, Du Youyou, Li Tao-Sheng, Tang Junnan, Zhang Jinying,
Abstract
BACKGROUND:
Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis.
METHODS:
The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded.
RESULTS:
We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment.
CONCLUSIONS:
This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.
© 2022. The Author(s).
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CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response.
Leukemia2022 Dec;():. doi: 10.1038/s41375-022-01781-0.
Jutzi Jonas S, Marneth Anna E, Jiménez-Santos María José, Hem Jessica, Guerra-Moreno Angel, Rolles Benjamin, Bhatt Shruti, Myers Samuel A, Carr Steven A, Hong Yuning, Pozdnyakova Olga, van Galen Peter, Al-Shahrour Fátima, Nam Anna S, Mullally Ann,
Abstract
Cancer is driven by somatic mutations that provide a fitness advantage. While targeted therapies often focus on the mutated gene or its direct downstream effectors, imbalances brought on by cell-state alterations may also confer unique vulnerabilities. In myeloproliferative neoplasms (MPN), somatic mutations in the calreticulin (CALR) gene are disease-initiating through aberrant binding of mutant CALR to the thrombopoietin receptor MPL and ligand-independent activation of JAK-STAT signaling. Despite these mechanistic insights into the pathogenesis of CALR-mutant MPN, there are currently no mutant CALR-selective therapies available. Here, we identified differential upregulation of unfolded proteins, the proteasome and the ER stress response in CALR-mutant hematopoietic stem cells (HSCs) and megakaryocyte progenitors. We further found that combined pharmacological inhibition of the proteasome and IRE1-XBP1 axis of the ER stress response preferentially targets Calr-mutated HSCs and megakaryocytic-lineage cells over wild-type cells in vivo, resulting in an amelioration of the MPN phenotype. In serial transplantation assays following combined proteasome/IRE1 inhibition for six weeks, we did not find preferential depletion of Calr-mutant long-term HSCs. Together, these findings leverage altered proteostasis in Calr-mutant MPN to identify combinatorial dependencies that may be targeted for therapeutic benefit and suggest that eradicating disease-propagating Calr-mutant LT-HSCs may require more sustained treatment.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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Viral Cultures, Cycle Threshold Values and Viral Load Estimation for Assessing SARS-CoV-2 Infectiousness in Haematopoietic Stem Cell and Solid Organ Transplant Patients: A Systematic Review.
J Hosp Infect2022 Dec;():. doi: S0195-6701(22)00372-3.
Jefferson Tom, Spencer Elizabeth A, Conly John M, Rosca Elena C, Maltoni Susanna, Brassey Jon, Onakpoya Igho J, Evans David H, Heneghan Carl J, Plüddemann Annette,
Abstract
BACKGROUND:
Solid organ and haematopoietic stem cell transplant recipients are at increased vulnerability to SARS-CoV-2 due to immunosuppression and may pose a continued transmission risk especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation.
OBJECTIVES:
We performed a systematic review to investigate the relationship in transplant recipients between serial SARS-CoV-2 RT-PCR cycle threshold (Ct) value or cycle of quantification value (Cq), or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship.
METHODS:
We searched LitCovid, medRxiv, Google Scholar and WHO Covid-19 databases, from 1 November 2019 until 26 October 2022. We included studies reporting relevant data for transplantees with SARS-CoV-2 infection: results from serial RT-PCR testing and viral culture data from the same respiratory samples. We assessed methodological quality using five criteria, and synthesised the data narratively and graphically.
RESULTS:
We included 13 case reports and case series reporting on 41 transplantees including 22 renal, 5 cardiac, 1 bone marrow, 2 liver, 1 bilateral lung, and 10 blood stem cell transplants. We observed a relationship between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2. Three individuals shed replication-competent viruses for over 100 days after infection onset. Lack of standardisation of testing and reporting platforms precludes establishing a definitive viral burden cut-off. However, the majority of transplantees stopped shedding replication-competent viruses when the RT-PCR cycle threshold was above 30 despite differences across platforms.
CONCLUSIONS:
Viral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardised study design and reporting are essential to standardise guidance based on an increasing evidence base.
Copyright © 2022. Published by Elsevier Ltd.
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[Medication rule of traditional Chinese medicine for heart failure after myocardial infarction: based on data mining].
Zhongguo Zhong Yao Za Zhi2022 Oct;47(20):5654-5661. doi: 10.19540/j.cnki.cjcmm.20220609.501.
Wei Jing-Jing, Zhu Zheng-Wang, Peng Guang-Cao, Yu Rui, Zhang Qing, Hao Peng-le, Zhou Cheng, Zhu Ming-Jun,
Abstract
This study aims to explore the medication rule of traditional Chinese medicine(TCM) for heart failure after myocardial infarction via data mining. To be specific, articles on the treatment of the disease with Chinese medicine were retrieved from CNKI, Wanfang, VIP, and SinoMed and related information was collected. A database was created with Microsoft Excel 2019, and SPSS Clementine 12.0 and IBM SPSS Statistics 23.0 were applied for association rules analysis, cluster analysis, and factor analysis. Finally, a total of 81 TCM prescriptions were screened out, involving 91 medicinals with cumulative use frequency of 740. The main syndromes were Qi deficiency and blood stasis, Yang Qi deficiency and blood stasis together with retained morbid fluid, deficiency of both Qi and Yin and blood stasis. The medicinals with high-frequency were Astragali Radix, Salviae Miltiorrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, Poria, and Aconiti Lateralis Radix Praeparata. The effects of the medicinals were tonifying deficiency, activating blood and resolving stasis, and promoting urination and draining dampness. The association rules analysis yielded "Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma" "Astragali Radix-Aconiti Lateralis Radix Praeparata-Salviae Miltiorrhizae Radix et Rhizoma" "Aconiti Lateralis Radix Praeparata-Ginseng Radix et Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma-Astragali Radix" combinations. Cluster analysis yielded 6 basic formulas for heart failure after myocardial infarction. Factor analysis extracted a total of 8 common factors. Heart failure after myocardial infarction is characterized by the syndrome of deficiency in nature and excess in superficiality. The core pathogenesis is "deficiency" "stasis" "retained morbid fluid", particularly "deficiency". This disease is closely related to the heart, lung, and spleen. The basic treatment principle is replenishing Qi and activating blood, and warming Yang, excreting water, and nourishing yin should also be emphasized. The common basic prescriptions, such as Siwu Decoction, Shengmai Powder, Xuefu Zhuyu Decoction, Linggui Zhugan Decoction, and Shenfu Decoction, have been discovered. This study provided data for clinical medication and drug development for heart failure after myocardial infarction.
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Linking single nucleotide polymorphisms to signaling blueprints in abdominal aortic aneurysms.
Sci Rep2022 Dec;12(1):20990. doi: 10.1038/s41598-022-25144-y.
Lim Chrysania, Pratama Muhammad Yogi, Rivera Cristobal, Silvestro Michele, Tsao Philip S, Maegdefessel Lars, Gallagher Katherine A, Maldonado Thomas, Ramkhelawon Bhama,
Abstract
Abdominal aortic aneurysms (AAA) is a multifactorial complex disease with life-threatening consequences. While Genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) located in the genome of individuals with AAA, the link between SNPs with the associated pathological signals, the influence of risk factors on their distribution and their combined analysis is not fully understood. We integrated 86 AAA SNPs from GWAS and clinical cohorts from the literature to determine their phenotypical vulnerabilities and association with AAA risk factors. The SNPs were annotated using snpXplorer AnnotateMe tool to identify their chromosomal position, minor allele frequency, CADD (Combined Annotation Dependent Depletion), annotation-based pathogenicity score, variant consequence, and their associated gene. Gene enrichment analysis was performed using Gene Ontology and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to identify network integration with associated genes and functions. 15 SNPs affecting 20 genes with a CADD score above ten were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 SNP obtained high frequency in AAA and associated with proinflammatory and vascular remodeling phenotypes. SNPs presence positively correlated with hypertension, dyslipidemia and smoking history. GO showed that AAA SNPs and their associated genes could regulate lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that part of these AAA traits could stem from genetic abnormalities. We show a library of inborn SNPs and associated genes that manifest in AAA. We uncover their pathological signaling trajectories that likely fuel AAA development.
© 2022. The Author(s).
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dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
J Mol Cell Cardiol2022 Dec;():. doi: S0022-2828(22)00570-3.
Mhatre Ketaki N, Murray Jason D, Flint Galina, McMillen Timothy S, Weber Gerhard, Shakeri Majid, Tu An-Yue, Steczina Sonette, Weiss Robert, Marcinek David J, Murry Charles E, Raftery Daniel, Tian Rong, Moussavi-Harami Farid, Regnier Michael,
Abstract
Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.
Copyright © 2022. Published by Elsevier Ltd.
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Cardiovascular screening prior to stem cell transplantation in the United Kingdom.
EJHaem2022 Nov;3(4):1455-1458. doi: 10.1002/jha2.599.
Gent David G, Saif Muhammad, Lee Julia, Tóth Arpad G, Tholouli Eleni, Dobson Rebecca, Wright David J,
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Xeno-Free Integrated Platform for Robust Production of Cardiomyocyte Sheets from hiPSCs.
Stem Cells Int2022 ;2022():4542719. doi: 4542719.
Dias Tiago P, Baltazar Tânia, Pinto Sandra N, Fernandes Tiago G, Fernandes Fábio, Diogo Maria Margarida, Prieto Manuel, Cabral Joaquim M S,
Abstract
Human induced pluripotent stem cells (hiPSCs) can be efficiently differentiated into cardiomyocytes (CMs), which can be used for cardiac disease modeling, for drug screening, and to regenerate damaged myocardium. Implementation of xeno-free culture systems is essential to fully explore the potential of these cells. However, differentiation using xeno-free adhesion matrices often results in low CM yields and lack of functional CM sheets, capable of enduring additional maturation stages. Here, we established a xeno-free CM differentiation platform using TeSR/Synthemax, including a replating step and integrated with two versatile purification/enrichment metabolic approaches. Results showed that the replating step was essential to reestablish a fully integrated, closely-knit CM sheet. In addition, replating contributed to increase the cTnT expression from 65% to 75% and the output from 2.2 to 3.1 CM per hiPSC, comparable with the efficiency observed when using TeSR/Matrigel. In addition, supplementation with PluriSin1 and GluLac medium allowed increasing the CM content over 80% without compromising CM sheet integrity or functionality. Thus, this xeno-free differentiation platform is a reliable and robust method to produce hiPSC-derived CMs, increasing the possibility of using these cells safely for a wide range of applications.
Copyright © 2022 Tiago P. Dias et al.
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Wnt signaling directs human pluripotent stem cells into vascularized cardiac organoids with chamber-like structures.
Front Bioeng Biotechnol2022 ;10():1059243. doi: 1059243.
Liang Po-Yu, Chang Yun, Jin Gyuhyung, Lian Xiaojun, Bao Xiaoping,
Abstract
Heart diseases are leading cause of death around the world. Given their unique capacity to self-renew and differentiate into all types of somatic cells, human pluripotent stem cells (hPSCs) hold great promise for heart disease modeling and cardiotoxic drug screening. hPSC-derived cardiac organoids are emerging biomimetic models for studying heart development and cardiovascular diseases, but it remains challenging to make mature organoids with a native-like structure . In this study, temporal modulation of Wnt signaling pathway co-differentiated hPSCs into beating cardiomyocytes and cardiac endothelial-like cells in 3D organoids, resulting in cardiac endothelial-bounded chamber formation. These chambered cardiac organoids exhibited more mature membrane potential compared to cardiac organoids composed of only cardiomyocytes. Furthermore, a better response to toxic drugs was observed in chamber-contained cardiac organoids. In summary, spatiotemporal signaling pathway modulation may lead to more mature cardiac organoids for studying cardiovascular development and diseases.
Copyright © 2022 Liang, Chang, Jin, Lian and Bao.
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Chick early amniotic fluid component improves heart function and protects against inflammation after myocardial infarction in mice.
Front Cardiovasc Med2022 ;9():1042852. doi: 1042852.
Wang Juan, Chen Xiejiu, Zhang Lihong, Zheng Yufan, Qian Jin, Sun Ning, Ding Xiaolei, Cui Baiping,
Abstract
Myocardial infarction (MI) is the major cause of mortality around the world. We recently demonstrated that chick early amniotic fluid (ceAF) can effectively rescue ischemic heart injury, indicating that it has a therapeutic function in MI. However, its functional components and the underlying mechanisms remain to be clarified. Here, we demonstrated that a fraction of ceAF, peak 8 (P8), had a protective effect on acute MI. P8 significantly decreased cardiomyocyte cross-sectional areas and cardiomyocyte apoptosis in MI mice. Using a human embryonic stem cell-derived cardiomyocyte model, which was subjected to hypoxia and reoxygenation, mimicking MI state, we found that P8 treatment reduced apoptosis and reversed myocardial contractility. Mechanistically, P8 improved cardiac function by inhibiting NF-?B signaling and downregulating inflammatory cytokine expression. Using mass spectrometry, we identified that guanosine and deoxynucleoside were the main functional components of P8 that suppressed the inflammatory response in human embryonic stem cell-derived cardiomyocytes. Collectively, our data suggest that specific components from ceAF are promising therapeutic agents for ischemic heart injury and could be a potential supplement to current medications for MI.
Copyright © 2022 Wang, Chen, Zhang, Zheng, Qian, Sun, Ding and Cui.
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Single Center Experience of Autologous Stem Cell Transplantation in Patients with Systemic Light Chain Amyloidosis in Korea.
Clin Lymphoma Myeloma Leuk2022 Oct;():. doi: S2152-2650(22)01713-X.
Kim Hye Ryeon, Yoon Sang Eun, Kim Darae, Choi Jin-Oh, Min Ju-Hong, Kim Byung Jun, Kim Jung Sun, Lee Jung Eun, Choi Joon Young, Jeon Eun-Seok, Kim Seok Jin, Kim Kihyun,
Abstract
BACKGROUND:
Systemic light chains is the most common systemic amyloidosis. In patients with AL amyloidosis, the prognosis is influenced by the extent of organ damage, especially cardiac involvement. Autologous stem cell transplantation (ASCT) is a highly effective treatment for AL amyloidosis for selective patient METHODS: One hundred patients treated with ASCT for AL amyloidosis were reviewed in the Samsung Medical Center amyloidosis cohort. The cardiac, renal, and hematologic response was analyzed, and survival results compared based on organ involvement and hematologic response.
RESULTS:
The most common involved organ was kidney (n = 62) followed by heart (n = 50). The organ response rate was 44.0% and 37.1% in the patients with cardiac and renal involvement, respectively. In hematologic response, overall response rate (ORR) was 79.0%, including 48.0% complete response (CR). Median overall survival (OS) in patients with and without hematologic CR were not reached and 64.2 months (95% CI, 19.5 to 109.0), respectively (P
CONCLUSIONS:
ASCT is an effective treatment option for eligible patients with AL amyloidosis. Achieving hematologic CR is essential for long-term survival.
Copyright © 2022. Published by Elsevier Inc.
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Development of a Thalassemia International Prognostic Scoring System (TIPSS).
Blood Cells Mol Dis2022 Nov;99():102710. doi: 10.1016/j.bcmd.2022.102710.
Vitrano Angela, Musallam Khaled M, Meloni Antonella, Karimi Mehran, Daar Shahina, Ricchi Paolo, Costantini Silvia, Vlachaki Efthymia, Di Marco Vito, El-Beshlawy Amal, Hajipour Mahmoud, Ansari Saqib Hussain, Filosa Aldo, Ceci Adriana, Singer Sylvia Titi, Naserullah Zaki A, Pepe Alessia, Cademartiri Filippo, Pollina Sebastiano Addario, Scondotto Salvatore, Dardanoni Gabriella, Bonifazi Fedele, Sankaran Vijay G, Vichinsky Elliott, Taher Ali T, Maggio Aurelio, ,
Abstract
A prognostic scoring system that can differentiate ?-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ?-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ? Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ?42 IU/L + 0.6 × hemoglobin ?9 g/dL + 0.4 × serum ferritin ?1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as
Copyright © 2022. Published by Elsevier Inc.
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Generation of human induced pluripotent stem cell line encoding for a genetically encoded voltage indicator Arclight A242.
Stem Cell Res2022 Nov;66():102981. doi: 10.1016/j.scr.2022.102981.
Vivekanandan Rajesh, Szepes Monika, Ricci Signorini Maria Elena, Kravchenko Denys, Kiefer Johanna, Berger Steffen, Fricke Veronika, Göhring Gudrun, Gruh Ina,
Abstract
Genetically encoded voltage indicators (GEVIs) allow for monitoring membrane potential changes in neurons and cardiomyocytes (CMs) as an alternative to patch-clamp techniques. GEVIs facilitate non-invasive, high throughput screening of electrophysiological properties of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A dual transgenic hiPSC line with Arclight A242 (GEVI) and an antibiotic resistance cardiac selection cassette was successfully generated from an earlier established hiPSC line MHHi001-A. After cardiac differentiation and selection, purified populations of CMs with constitutive GEVI expression can be utilized for studying cardiac development, disease modeling, and drug testing.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
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Structural Landscape of nsp Coding Genomic Regions of SARS-CoV-2-ssRNA Genome: A Structural Genomics Approach Toward Identification of Druggable Genome, Ligand-Binding Pockets, and Structure-Based Druggability.
Mol Biotechnol2022 Dec;():. doi: 10.1007/s12033-022-00605-x.
Chakraborty Chiranjib, Bhattacharya Manojit, Sharma Ashish Ranjan, Chatterjee Srijan, Agoramoorthy Govindasamy, Lee Sang-Soo,
Abstract
SARS-CoV-2 has a single-stranded RNA genome (+ssRNA), and synthesizes structural and non-structural proteins (nsps). All 16 nsp are synthesized from the ORF1a, and ORF1b regions associated with different life cycle preprocesses, including replication. The regions of ORF1a synthesizes nsp1 to 11, and ORF1b synthesizes nsp12 to 16. In this paper, we have predicted the secondary structure conformations, entropy & mountain plots, RNA secondary structure in a linear fashion, and 3D structure of nsp coding genes of the SARS-CoV-2 genome. We have also analyzed the A, T, G, C, A+T, and G+C contents, GC-profiling of these genes, showing the range of the GC content from 34.23 to 48.52%. We have observed that the GC-profile value of the nsp coding genomic regions was less (about 0.375) compared to the whole genome (about 0.38). Additionally, druggable pockets were identified from the secondary structure-guided 3D structural conformations. For secondary structure generation of all the nsp coding genes (nsp 1-16), we used a recent algorithm-based tool (deep learning-based) along with the conventional algorithms (centroid and MFE-based) to develop secondary structural conformations, and we found stem-loop, multi-branch loop, pseudoknot, and the bulge structural components, etc. The 3D model shows bound and unbound forms, branched structures, duplex structures, three-way junctions, four-way junctions, etc. Finally, we identified binding pockets of nsp coding genes which will help as a fundamental resource for future researchers to develop RNA-targeted therapeutics using the druggable genome.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Membrane curvature governs the distribution of Piezo1 in live cells.
Nat Commun2022 Dec;13(1):7467. doi: 7467.
Yang Shilong, Miao Xinwen, Arnold Steven, Li Boxuan, Ly Alan T, Wang Huan, Wang Matthew, Guo Xiangfu, Pathak Medha M, Zhao Wenting, Cox Charles D, Shi Zheng,
Abstract
Piezo1 is a bona fide mechanosensitive ion channel ubiquitously expressed in mammalian cells. The distribution of Piezo1 within a cell is essential for various biological processes including cytokinesis, cell migration, and wound healing. However, the underlying principles that guide the subcellular distribution of Piezo1 remain largely unexplored. Here, we demonstrate that membrane curvature serves as a key regulator of the spatial distribution of Piezo1 in the plasma membrane of living cells. Piezo1 depletes from highly curved membrane protrusions such as filopodia and enriches to nanoscale membrane invaginations. Quantification of the curvature-dependent sorting of Piezo1 directly reveals the in situ nano-geometry of the Piezo1-membrane complex. Piezo1 density on filopodia increases upon activation, independent of calcium, suggesting flattening of the channel upon opening. Consequently, the expression of Piezo1 inhibits filopodia formation, an effect that diminishes with channel activation.
© 2022. The Author(s).
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A Case of Neonatal Lupus Presenting with Myocardial Dysfunction in the Absence of Congenital Heart Block (CHB): Clinical Management and Brief Literature Review of Neonatal Cardiac Lupus.
Pediatr Cardiol2022 Dec;():. doi: 10.1007/s00246-022-03056-y.
Jain Samhita, Spadafora Ruggero, Maxwell Sarah, Botas Carlos, Nawaytou Hythem, von Scheven Emily, Crouch Elizabeth E,
Abstract
Neonatal lupus (NLE) is a rare acquired autoimmune disorder caused by transplacental passage of maternal autoantibodies to Sjogren's Syndrome A or B (SSA-SSB) autoantigens (Vanoni et al. in Clin Rev Allerg Immunol 53:469-476, 2017) which target fetal and neonatal tissues for immune destruction. The cardiac trademark of NLE is autoimmune heart block, which accounts for more than 80% of cases of complete atrioventricular heart block (AVB) in newborns with a structurally normal heart (Martin in Cardiol Young 24: 41-46, 2014). NLE presenting with cardiac alterations not involving rhythm disturbances are described in the literature, but they are rare. Here, we report a case of a neonate with high anti-SSA antibodies who developed severe ventricular dysfunction in the absence of rhythm abnormalities, endocardial fibroelastosis, and dilated cardiomyopathy (Trucco et al. in J Am Coll Cardiol 57:715-723, https://doi.org/10.1016/j.jacc.2010.09.044 , 2011), the most common cardiac presentations of NLE. The patient developed severe multiorgan dysfunction syndrome that required prolonged critical care support but fully recovered and was discharged home. We highlight the unusual clinical features of this NLE case and the importance of timely treatment of NLE allowing complete recovery of a critically ill neonate.
© 2022. The Author(s).
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An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression.
Nat Commun2022 Dec;13(1):7448. doi: 10.1038/s41467-022-34991-2.
Dinh Thanh Theresa, Xiang Menglan, Rajaraman Anusha, Wang Yongzhi, Salazar Nicole, Zhu Yu, Roper Walter, Rhee Siyeon, Brulois Kevin, O'Hara Ed, Kiefel Helena, Dinh Truc M, Bi Yuhan, Gonzalez Dalila, Bao Evan P, Red-Horse Kristy, Balogh Peter, Gábris Fanni, Gaszner Balázs, Berta Gergely, Pan Junliang, Butcher Eugene C,
Abstract
Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. The Madcam1 element also integrates repressive signals from arterial/capillary Notch effectors. Pan-endothelial COUP-TFII overexpression induces ectopic addressin expression in NKX2-3 capillaries, while NKX2-3 deficiency abrogates expression by HEV. Phylogenetically conserved NCCE are enriched in genes involved in neuron migration and morphogenesis of the heart, kidney, pancreas and other organs. Our results define an NKX-COUP-TFII morphogenetic code that targets expression of mucosal vascular addressins.
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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A reference human induced pluripotent stem cell line for large-scale collaborative studies.
Cell Stem Cell2022 Dec;29(12):1685-1702.e22. doi: 10.1016/j.stem.2022.11.004.
Pantazis Caroline B, Yang Andrian, Lara Erika, McDonough Justin A, Blauwendraat Cornelis, Peng Lirong, Oguro Hideyuki, Kanaujiya Jitendra, Zou Jizhong, Sebesta David, Pratt Gretchen, Cross Erin, Blockwick Jeffrey, Buxton Philip, Kinner-Bibeau Lauren, Medura Constance, Tompkins Christopher, Hughes Stephen, Santiana Marianita, Faghri Faraz, Nalls Mike A, Vitale Daniel, Ballard Shannon, Qi Yue A, Ramos Daniel M, Anderson Kailyn M, Stadler Julia, Narayan Priyanka, Papademetriou Jason, Reilly Luke, Nelson Matthew P, Aggarwal Sanya, Rosen Leah U, Kirwan Peter, Pisupati Venkat, Coon Steven L, Scholz Sonja W, Priebe Theresa, Öttl Miriam, Dong Jian, Meijer Marieke, Janssen Lara J M, Lourenco Vanessa S, van der Kant Rik, Crusius Dennis, Paquet Dominik, Raulin Ana-Caroline, Bu Guojun, Held Aaron, Wainger Brian J, Gabriele Rebecca M C, Casey Jackie M, Wray Selina, Abu-Bonsrah Dad, Parish Clare L, Beccari Melinda S, Cleveland Don W, Li Emmy, Rose Indigo V L, Kampmann Martin, Calatayud Aristoy Carles, Verstreken Patrik, Heinrich Laurin, Chen Max Y, Schüle Birgitt, Dou Dan, Holzbaur Erika L F, Zanellati Maria Clara, Basundra Richa, Deshmukh Mohanish, Cohen Sarah, Khanna Richa, Raman Malavika, Nevin Zachary S, Matia Madeline, Van Lent Jonas, Timmerman Vincent, Conklin Bruce R, Johnson Chase Katherine, Zhang Ke, Funes Salome, Bosco Daryl A, Erlebach Lena, Welzer Marc, Kronenberg-Versteeg Deborah, Lyu Guochang, Arenas Ernest, Coccia Elena, Sarrafha Lily, Ahfeldt Tim, Marioni John C, Skarnes William C, Cookson Mark R, Ward Michael E, Merkle Florian T,
Abstract
Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.
Published by Elsevier Inc.
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Endothelial progenitor cell-derived small extracellular vesicles for myocardial angiogenesis and revascularization.
J Clin Transl Res2022 Dec;8(6):476-487.
Al-Omar Maher T, Alnajjar Mahmoud T, Ahmed Ziyad T, Salaas Faris M I, Alrefaei Tamim S M, Haider Khawaja H,
Abstract
BACKGROUND:
Endothelial progenitor cells (EPCs) have been well-studied for their differentiation potential and paracrine activity in vitro and in experimental animal studies. EPCs are the precursors of endothelial cells (ECs) and a rich source of pro-angiogenic factors, and hence, possess enormous potential to treat ischemic heart through myocardial angiogenesis. Their proven safety and efficacy observed during the pre-clinical and clinical studies have portrayed them as a near ideal cell type for cell-based therapy of ischemic heart disease.In response to the chemical cues from the ischemic heart, EPCs from the bone marrow and peripheral circulation home-in to the ischemic myocardium and participate in the intrinsic repair process at the molecular and cellular levels through paracrine activity and EC differentiation. EPCs also release small extracellular vesicles (sEVs) loaded with bioactive molecules as part of their paracrine activity for intercellular communication to participate in the reparative process in the heart.
AIM:
This literature review is based on the published data regarding the characteristic features of EPC-derived sEVs and their proteomic and genomic payload, besides facilitating safe and effective repair of the ischemic myocardium. In light of the encouraging published data, translational and clinical assessment of EPC-derived sEVs is warranted. We report the recent experimental animal studies and their findings using EPC-derived sEVs on cardiac angiogenesis and preservation of cardiac function.
RELEVANCE FOR PATIENTS:
With the promising results from pre-clinical studies, clinical trials should be conducted to assess the clinical utility of EPC-derived sEVs in the treatment of the ischemic myocardium.
Copyright: © 2022 Author(s).
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