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Pubblicazioni recenti - cardiac stem
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Direct coculture of human pluripotent stem cell-derived cardiac progenitor cells with epicardial cells induces cardiomyocyte proliferation and reduces sarcomere organization.
J Mol Cell Cardiol2021 Sep;():. doi: S0022-2828(21)00181-4.
Floy Martha E, Dunn Kaitlin K, Mateyka Taylor D, Reichardt Isabella M, Steinberg Alexandra B, Palecek Sean P,
Abstract
Epicardial cells (EpiCs) are necessary for myocardium formation, yet little is known about crosstalk between EpiCs and cardiomyocytes (CMs) during development and the potential impact of EpiCs on CM maturation. To investigate the effects of EpiCs on CM commitment and maturation, we differentiated human pluripotent stem cells (hPSCs) to cardiac progenitor cells (CPCs) and EpiCs, and cocultured EpiCs and CPCs for two weeks. When EpiCs were allowed to form epicardial-derived cells, we observed increased expression of cTnI in developing CMs. In the presence of the TGF? inhibitor A83-01, EpiCs remained in the epicardial state and induced CM proliferation, increased MLC2v expression, and led to less organized sarcomeres. These effects were not observed if CPCs were treated with EpiC-conditioned medium or if CPCs were indirectly cocultured with EpiCs. Finally, single cell RNA sequencing identified that EpiC-CPC coculture had bi-directional effects on transcriptional programs in EpiCs and CMs, and biased EpiC lineages from a SFRP2-enriched population to a DLK1- or C3-enriched population. This work suggests important crosstalk between EpiCs and CMs during differentiation can be used to influence cell fate and improve the ability to generate cardiac cells and tissues for in vitro models and development of cardiac cellular therapies.
Copyright © 2018. Published by Elsevier Ltd.
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Novel Pharmacological Targets for Pulmonary Arterial Hypertension.
Compr Physiol2021 Sep;11(4):1-53. doi: 10.1002/cphy.c200015.
Klinger James R,
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by an obliterative vasculopathy of the distal pulmonary circulation that results in severe elevation in pulmonary pressure and pulmonary vascular resistance. PAH is a progressive and devastating disease that usually results in right heart failure and death. Currently available medications have only moderate effects and none are curative. Thus, there is a pressing need for new pharmacologic approaches to this disease. In order to meaningfully advance the treatment of PAH, new agents must target the underlying cause of disease induction and progression. This review discusses the extensive work that has been done in the areas of altered glucose metabolism, tyrosine kinase inhibitions, signaling pathways associated with disease causing gene mutations such as the bone morphogenic protein receptor 2, and inflammation and immunomodulation including the effects of mesenchymal stem cells and the extracellular vesicles they secrete. Epigenetic modifications including the roles of micro RNAs, DNA methylation, histone acetylation and transcription factors that modulate pulmonary vascular remodeling are also reviewed. A brief background of each area of interest is provided with emphasis on those components that have potential to be exploited for the treatment of PAH. Significant findings of cell-based and animal studies and, where available, the results of early clinical trials, are presented to illustrate the potential of these novel therapeutic targets. Current challenges to the development of small peptides and biologicals for the treatment of PAH and direction for future studies are also briefly discussed. © 2021 American Physiological Society. Compr Physiol 11:1-53, 2021.
Copyright © 2021 American Physiological Society. All rights reserved.
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High-output heart failure associated with primary plasma cell leukaemia due to arteriovenous shunting: a case report.
Eur Heart J Case Rep2021 Sep;5(9):ytab353. doi: 10.1093/ehjcr/ytab353.
Sudo Yuta, Inagaki Hiroshi,
Abstract
Background:
Primary plasma cell leukaemia is rarely associated with high-output heart failure, and the underlying mechanism is not well understood. We encountered a rare case of high-output heart failure caused by primary plasma cell leukaemia. Its underlying mechanism was clarified through imaging studies.
Case summary:
A 49-year-old man with no specific medical history was admitted to our hospital because of heart failure that did not improve with diuretic therapy. His condition was diagnosed as high-output heart failure and primary plasma cell leukaemia after admission. Extensive bone involvement in primary plasma cell leukaemia and arteriovenous shunts in the same lesion were suspected after various imaging studies. The first cycle of chemotherapy with bortezomib, adriamycin, and dexamethasone led to remission of primary plasma cell leukaemia and improved heart failure symptoms. The patient received further chemotherapy in addition to autologous peripheral blood stem cell transplantation and maintenance therapy and had no recurrence of pPCL or heart failure for 1?year to date.
Discussion:
Primary plasma cell leukaemia can be associated with high-output heart failure, which is caused by arteriovenous shunting at the lesion site with diffuse bone involvement. Imaging studies may lead to the early diagnosis of aetiology and treatment of patients with high-output heart failure associated with primary plasma cell leukaemia.
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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A Three-Dimensional Imaging Method for the Quantification and Localization of Dynamic Cell Tracking Posttransplantation.
Front Cell Dev Biol2021 ;9():698795. doi: 10.3389/fcell.2021.698795.
Lu Fengfeng, Pan Xin, Zhang Wencheng, Su Xin, Gu Yuying, Qiu Hua, Shen Shengwei, Liu Changcheng, Liu Wei, Wang Xicheng, Zhan Zhenzhen, Liu Zhongmin, He Zhiying,
Abstract
Cell transplantation has been proposed as a promising therapeutic strategy for curing the diseases requiring tissue repairing and functional restoration. A preclinical method to systematically evaluate the fates of donor cells in recipients, spatially and temporally, is demanded for judging therapeutic potentials for the particularly designed cell transplantation. Yet, the dynamic cell tracking methodology for tracing transplanted cells is still at its early phase. Here, we created a practical protocol for dynamically tracking cell a three-dimensional (3D) technique which enabled us to localize, quantify, and overall evaluate the transplanted hepatocytes within a liver failure mouse model. First, the capacity of 3D bioluminescence imaging for quantifying transplanted hepatocytes was defined. Images obtained from the 3D bioluminescence imaging module were then combined with the CT scanner to reconstruct structure images of host mice. With those reconstructed images, precise locations of transplanted hepatocytes in the liver of the recipient were dynamically monitored. Immunohistochemistry staining of transplanted cells, and the serology assay of liver panel of the host mice were applied to verify the successful engraftment of donor cells in the host livers. Our protocol was practical for evaluating the engraftment efficiency of donor cells at their preclinical phases, which is also applicable as a referable standard for studying the fates of other transplanted cells, such as stem cell-derived cell types, during preclinical studies with cell transplantation therapy.
Copyright © 2021 Lu, Pan, Zhang, Su, Gu, Qiu, Shen, Liu, Liu, Wang, Zhan, Liu and He.
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Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis.
BMJ2021 Sep;374():n2231. doi: 10.1136/bmj.n2231.
Siemieniuk Reed Ac, Bartoszko Jessica J, Díaz Martinez Juan Pablo, Kum Elena, Qasim Anila, Zeraatkar Dena, Izcovich Ariel, Mangala Sophia, Ge Long, Han Mi Ah, Agoritsas Thomas, Arnold Donald, Ávila Camila, Chu Derek K, Couban Rachel, Cusano Ellen, Darzi Andrea J, Devji Tahira, Foroutan Farid, Ghadimi Maryam, Khamis Assem, Lamontagne Francois, Loeb Mark, Miroshnychenko Anna, Motaghi Sharhzad, Murthy Srinivas, Mustafa Reem A, Rada Gabriel, Rochwerg Bram, Switzer Charlotte, Vandvik Per O, Vernooij Robin Wm, Wang Ying, Yao Liang, Guyatt Gordon H, Brignardello-Petersen Romina,
Abstract
OBJECTIVE:
To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19).
DESIGN:
Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data.
DATA SOURCES:
WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021).
STUDY SELECTION:
Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate.
METHODS:
After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ?100 patients randomised or ?20 events per treatment arm.
RESULTS:
As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative.
CONCLUSION:
In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.
SYSTEMATIC REVIEW REGISTRATION:
This review was not registered. The protocol established a priori is included as a data supplement.
FUNDING:
This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321).
READERS' NOTE:
This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Comparison of Contemporary and Historical Outcomes of Elective and Ruptured Open Abdominal Aortic Aneurysm Repair.
J Vasc Surg2021 Sep;():. doi: S0741-5214(21)02130-3.
Pomy Benjamin J, Devlin Joseph, Lala Salim, Amdur Richard L, Ricotta John J, Sidawy Anton N, Nguyen Bao-Ngoc, Macsata Robyn A,
Abstract
INTRODUCTION:
Recently, open AAA repair (OSR) has become less common and is often reserved for more complex aortic anatomy. Despite improvement in patient management, reduced surgical volume raises concern for potentially worsened outcomes in the contemporary era (2014-2019) compared to an earlier era where open repair was more widely practiced (2005-2010). This study compares the 30-day outcomes of open AAA repair between these two eras.
METHODS:
The American College of Surgeons National Quality Improvement Program (ACS-NSQIP) general database was queried for open AAA repair based on procedure CPT and ICD-9/10 codes. Cases were stratified into two groups based on operation year: 2005-2010 (early) and 2014-2019 (contemporary). In each era, the cases were further divided into "elective" and "ruptured" groups. Thirty-day outcomes, including mortality, major morbidity, postoperative sepsis, and unplanned reoperation were compared between the contemporary era and early era in the elective and ruptured groups, respectively. Preoperative variables with p-value less than 0.25 were adjusted for in the multivariate analysis.
RESULTS:
There were 3749 patients in the contemporary and 3798 in the early era who underwent elective OSR; whereas there were 1148 contemporary and 907 early era patients who underwent ruptured repair. These samples are similar sizes due to the NSQIP sampling process and our relatively strict inclusion criteria. There were fewer elderly patients and patients that smoke, hypertensive, and with dyspnea in the contemporary era in the elective and rupture cohorts. There were more patients with ASA > 3 in the elective contemporary era (39% vs 24%, p
CONCLUSION:
Thirty-day mortality has worsened following open AAA repair in the elective and rupture settings despite the improvement in peri-operative management over the years. These complications likely stem from increased bleeding events and major cardiac events which are increased in the contemporary era.
Copyright © 2021. Published by Elsevier Inc.
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Reversing aging for heart repair.
Science2021 09;373(6562):1439-1440. doi: 10.1126/science.abl8679.
Wang Yu Xin, Blau Helen M,
Abstract
[Figure: see text].
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Apigenin increases radiosensitivity of glioma stem cells by attenuating HIF-1?-mediated glycolysis.
Med Oncol2021 Sep;38(11):131. doi: 10.1007/s12032-021-01586-8.
Zhao Ying, Huang Hui, Jia Chang-Hao, Fan Ke, Xie Tao, Zhu Zeng-Yan, Xie Mei-Lin,
Abstract
Apigenin, a natural flavonoid compound present in a variety of edible plants and health foods, has an anti-tumor effect and inhibits hypoxia inducible factor-l? (HIF-1?) expression in hypertrophic cardiac tissues. However, whether or not apigenin has a radiosensitization effect on glioma stem cells (GSCs) is unknown. Our present study aimed to investigate the effect of apigenin and its possible mechanisms. The human GSCs SU3 and its radioresistance line SU3-5R were treated with apigenin, radiation, or their combination, and the cell proliferation, migration, colony formation, and intracellular lactic acid and glycolytic related protein expressions were determined. Additionally, a cell model with hypoxia-induced HIF-1? expression was used and treated with apigenin. The current results displayed that the combination of apigenin and radiation could synergically reduce the viability, colony formation, and migration of the both GSCs. Moreover, this combination could also decrease the radiation-induced increments of glycolytic production lactic acid in the both GSCs and related protein expressions, including HIF-1?, glucose transporter (GLUT)-1/3, nuclear factor kappa B (NF-?B) p65, and pyruvate kinase isozyme type M2 (PKM2). Further study confirmed that after treatment of hypoxia-cultured SU3 or SU3-5R cells with apigenin, the expression levels of HIF-1?, GLUT-1/3, NF-?B p65, and PKM2 proteins were reduced. These results demonstrated that apigenin could increase the radiosensitivity of GSCs and its radiosensitization mechanisms were attributable to the attenuation of glycolysis, which might result from the inhibition of HIF-1? expression and subsequent reductions of GLUT-1/3, NF-?B, and PKM2 expressions.
© 2021. Springer Science+Business Media, LLC, part of Springer Nature.
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Application of Human Induced Pluripotent Stem Cell-Derived Cellular and Organoid Models for COVID-19 Research.
Front Cell Dev Biol2021 ;9():720099. doi: 10.3389/fcell.2021.720099.
Luo Yumei, Zhang Mimi, Chen Yapei, Chen Yaoyong, Zhu Detu,
Abstract
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid international spread has caused the coronavirus disease 2019 (COVID-19) pandemics, which is a global public health crisis. Thus, there is an urgent need to establish biological models to study the pathology of SARS-CoV-2 infection, which not only involves respiratory failure, but also includes dysregulation of other organs and systems, including the brain, heart, liver, intestines, pancreas, kidneys, eyes, and so on. Cellular and organoid models derived from human induced pluripotent stem cells (iPSCs) are ideal tools for simulation of viral life cycles and drug screening to prevent the reemergence of coronavirus. These iPSC-derived models could recapitulate the functions and physiology of various human cell types and assemble the complex microenvironments similar with those in the human organs; therefore, they can improve the study efficiency of viral infection mechanisms, mimic the natural host-virus interaction, and be suited for long-term experiments. In this review, we focus on the application of iPSC-derived cellular and organoid models in COVID-19 studies.
Copyright © 2021 Luo, Zhang, Chen, Chen and Zhu.
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Isochoric supercooled preservation and revival of human cardiac microtissues.
Commun Biol2021 Sep;4(1):1118. doi: 10.1038/s42003-021-02650-9.
Powell-Palm Matthew J, Charwat Verena, Charrez Berenice, Siemons Brian, Healy Kevin E, Rubinsky Boris,
Abstract
Low-temperature biopreservation and 3D tissue engineering present two differing routes towards eventual on-demand access to transplantable biologics, but recent advances in both fields present critical new opportunities for crossover between them. In this work, we demonstrate sub-zero centigrade preservation and revival of autonomously beating three-dimensional human induced pluripotent stem cell (hiPSC)-derived cardiac microtissues via isochoric supercooling, without the use of chemical cryoprotectants. We show that these tissues can cease autonomous beating during preservation and resume it after warming, that the supercooling process does not affect sarcomere structural integrity, and that the tissues maintain responsiveness to drug exposure following revival. Our work suggests both that functional three dimensional (3D) engineered tissues may provide an excellent high-content, low-risk testbed to study complex tissue biopreservation in a genetically human context, and that isochoric supercooling may provide a robust method for preserving and reviving engineered tissues themselves.
© 2021. The Author(s).
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Impact of Pediatric Primary Palliative Care Education and Mentoring in Practice.
J Hosp Palliat Nurs2021 Sep;():. doi: 10.1097/NJH.0000000000000802.
Lafond Deborah, Perko Kathy, Fisher Deborah, Mahmood Laila A, Hinds Pamela S,
Abstract
Primary palliative care education and mentoring strengthens frontline clinicians' confidence and competence in pediatric palliative care, and potentially mitigates their moral distress. The project aims were to improve the knowledge, attitudes, and skills of frontline intradisciplinary clinicians in caring for children with serious conditions and their families. We undertook an intensive educational initiative consisting of didactic and mentoring sessions, and mentored quality improvement projects. Outcomes included the following: 93.3% of participants reported comfort in discussing death, suffering, spirituality, and hope with families, and increased comfort in end-of-life care (89.5%), increased knowledge (94.7%) and skills (100%), improved communication (100%), and being better prepared to discuss and access palliative care resources (100%). Secondary outcomes included 33% increase in specialty pediatric palliative care consults and 98% increase in the integration of specialty palliative care for patients with high-risk cancers. Specialty pediatric palliative care referral became standard for patients with cystic fibrosis, high-risk solid and brain tumors, heart failure, and patients receiving a stem cell transplant. Clinician self-reported moral distress decreased by 30%. This project improved primary palliative care knowledge, attitudes, and confidence in skills, access to care, and family satisfaction, and decreased clinician self-reported moral distress. We report on the 4-year period of project implementation and sustainability.
Copyright © 2021 by The Hospice and Palliative Nurses Association.
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8q21.11 microdeletion syndrome: Delineation of HEY1 as a candidate gene in neurodevelopmental and cardiac defects.
Mol Genet Genomic Med2021 Sep;():e1811. doi: 10.1002/mgg3.1811.
Ben Ayed Ikhlas, Bouzid Amal, Kammoun Fatma, Souissi Amal, Jallouli Olfa, Mallouli Salma, Guidara Souhir, Loukil Salma, Aloulou Hajer, Jbeli Fida, Aouichaoui Sahar, Abid Dorra, Abdelhedi Fatma, Triki Chahnez, Kamoun Hassen, Masmoudi Saber,
Abstract
BACKGROUND:
8q21.11 microdeletion syndrome is a rare chromosomal disorder characterized by recurrent dysmorphic features, a variable degree of intellectual disability and ocular, cardiac and hand/feet abnormalities. To date, ZFHX4 is the only candidate gene implicated in the ocular findings. In this study, we evaluated a patient with a de novo 8q21.13-21.3 deletion to define a new small region of overlap (SRO) for this entity.
METHODS:
We conducted a clinical evaluation and comparative genomic hybridization (CGH) 4x44K microarrays in a patient with de novo unbalanced translocation t(8;16)(q21; q11.2).
RESULTS:
The case, a 6-year-old boy, presented dysmorphic features including an elongated face, brachycephaly with a high forehead, an underdeveloped ala, thin upper lip, micrognathia, low-set ears, hypotonia, mild intellectual disability, cortical atrophy with thin corpus callosum defect, and an atrial septal defect. No ocular abnormalities were found. Microarray analysis revealed a 9.6 Mb interstitial 8q21.11-21.3 deletion, not including the ZFHX4 gene. This microdeletion was confirmed in our patient through qPCR analysis, and both parents had a normal profile. Alignment analysis of our case defined a new SRO encompassing five genes. Among them, the HEY1 gene is involved in the embryonic development of the heart, central nervous system, and vascular system. Hrt1/Hey1 null mice show perinatal lethality due to congenital malformations of the aortic arch and its branch arteries. HEY1 has also been linked to the maintenance of neural stem cells, inhibition of oligodendrocyte differentiation, and myelin gene expression.
CONCLUSION:
HEY1 is a candidate gene for both neurological and cardiac features of the 8q21.11 microdeletion syndrome and might, therefore, explain specific components of its pathophysiology.
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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Heart rate variability associated with acute exercise challenge in children with sickle cell anaemia.
Br J Haematol2021 Sep;():. doi: 10.1111/bjh.17834.
Kienzle Stephan L, Rodeghier Mark, Liem Robert I,
Abstract
We examined heart rate variability (HRV) during exercise testing in 20 children with sickle cell anaemia (SCA) and 12 controls. Subjects achieved lower median HRV at peak exercise [standard deviation of R-wave to R-wave intervals (SDNN), 2·3 vs 2·9 ms, P = 0·027; logarithmic transformation of high frequency power (lnHF), 0·9 vs 1·3 ln(ms ), P = 0·047] and had lower post-exercise HRV across minute-by-minute analysis of recovery. After adjustment for haemoglobin, fitness and SCA status, subjects had lower HRV at the end of recovery with differences increasing as baseline HRV increased. Further investigation of HRV and exercise safety in SCA is warranted.
© 2021 British Society for Haematology and John Wiley & Sons Ltd.
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An Intra-Cycle Optimal Control Framework for Ventricular Assist Devices Based on Atrioventricular Plane Displacement Modeling.
Ann Biomed Eng2021 Sep;():. doi: 10.1007/s10439-021-02848-2.
Zeile Clemens, Rauwolf Thomas, Schmeisser Alexander, Mizerski Jeremi Kaj, Braun-Dullaeus Rüdiger C, Sager Sebastian,
Abstract
A promising treatment for congestive heart failure is the implementation of a left ventricular assist device (LVAD) that works as a mechanical pump. Modern LVADs work with adjustable constant rotor speed and provide therefore continuous blood flow; however, recently undertaken efforts try to mimic pulsatile blood flow by oscillating the pump speed. This work proposes an algorithmic framework to construct and evaluate optimal pump speed policies with respect to generic objectives. We use a model that captures the atrioventricular plane displacement, which is a physiological indicator for heart failure. We employ mathematical optimization to adapt this model to patient specific data and to find optimal pump speed policies with respect to ventricular unloading and aortic valve opening. To this end, we reformulate the cardiovascular dynamics into a switched system and thereby reduce nonlinearities. We consider system switches that stem from varying the constant pump speed and that are state dependent such as valve opening or closing. As a proof of concept study, we personalize the model to a selected patient with respect to ventricular pressure. The model fitting results in a root-mean-square deviation of about 6 mmHg. The optimization that considers aortic valve opening and ventricular unloading results in speed modulation akin to counterpulsation. These in silico findings demonstrate the potential of personalized hemodynamical optimization for the LVAD therapy.
© 2021. The Author(s).
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Seq Your Destiny: Neural Crest Fate Determination in the Genomic Era.
Annu Rev Genet2021 Sep;():. doi: 10.1146/annurev-genet-071719-020954.
Gandhi Shashank, Bronner Marianne E,
Abstract
Neural crest stem/progenitor cells arise early during vertebrate embryogenesis at the border of the forming central nervous system. They subsequently migrate throughout the body, eventually differentiating into diverse cell types ranging from neurons and glia of the peripheral nervous system to bones of the face, portions of the heart, and pigmentation of the skin. Along the body axis, the neural crest is heterogeneous, with different subpopulations arising in the head, neck, trunk, and tail regions, each characterized by distinct migratory patterns and developmental potential. Modern genomic approaches like single-cell RNA- and ATAC-sequencing (seq) have greatly enhanced our understanding of cell lineage trajectories and gene regulatory circuitry underlying the developmental progression of neural crest cells. Here, we discuss how genomic approaches have provided new insights into old questions in neural crest biology by elucidating transcriptional and posttranscriptional mechanisms that govern neural crest formation and the establishment of axial level identity. Expected final online publication date for the , Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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The miR-182/Myadm axis regulates hypoxia-induced pulmonary hypertension by balancing the BMP- and TGF-?-signalling pathways in an SMC/EC-crosstalk-associated manner.
Basic Res Cardiol2021 Sep;116(1):53. doi: 10.1007/s00395-021-00892-6.
Bai Yongyi, Wang Jingrong, Chen Ying, Lv Tingting, Wang Xiaojian, Liu Chunlei, Xue Hao, He Kunlun, Sun Lan,
Abstract
We recently identified oncologic miR-182 as a new regulator of pulmonary artery hypertension (PAH) that targets myeloid-associated differentiation marker (Myadm), which is expressed in bone marrow stem cells and multipotent progenitors. Both miR-182 and Myadm are expressed in the cardiopulmonary system and correlated with the balance between the bone morphogenetic protein (BMP) and the transforming growth factor (TGF)-? signalling pathways, which are disturbed in PAH. We hypothesize that miR-182/Myadm are involved in BMP-TGF-?-signalling way in PAH. Hypoxia triggered pathological progression in cardiopulmonary PAH in vivo and in vitro; these changes were accompanied by strongly dowregulated BMP/SMAD1/5/8 expression and enhanced TGF-?/SMAD2/3 signalling pathway, favouring SMAD4/SMAD2 transcript formation and inhibiting the PAH negative regulator Id1 expression. miR-182 gain-of-function significantly inhibited the pathological progression in hypoxia-induced PAH (HPH) in vivo and in vitro, with a restoration of the balance in BMP-TGF-? signalling pathway. This recovery was abrogated by overexpression of Myadm. Conversely, loss-of-function of miR-182 increased the pathological progression of HPH followed by severe disturbance of BMP and TGF-? signal transduction and reduced Id1 expression, which was restored by Myadm knockdown. We also showed that the miR-182/Myadm relate BMP-TGF-? pathway is associated with NOS3/NO/cGMP via the crosstalk between endothelial cells and smooth muscle cells. Our findings further support the therapeutic significance of miR-182/Myadm in PAH via the balance of BMP- and TGF-?-associated mechanisms.
© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.
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Biallelic variants in YRDC cause a developmental disorder with progeroid features.
Hum Genet2021 Sep;():. doi: 10.1007/s00439-021-02347-3.
Schmidt Julia, Goergens Jonas, Pochechueva Tatiana, Kotter Annika, Schwenzer Niko, Sitte Maren, Werner Gesa, Altmüller Janine, Thiele Holger, Nürnberg Peter, Isensee Jörg, Li Yun, Müller Christian, Leube Barbara, Reinhardt H Christian, Hucho Tim, Salinas Gabriela, Helm Mark, Jachimowicz Ron D, Wieczorek Dagmar, Kohl Tobias, Lehnart Stephan E, Yigit Gökhan, Wollnik Bernd,
Abstract
The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T?>?C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced tA modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient's dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.
© 2021. The Author(s).
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Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.
Circulation2021 Sep;144(12):1000-1003. doi: 10.1161/CIRCULATIONAHA.121.054846.
Payumo Alexander Y, Chen Xi, Hirose Kentaro, Chen Xiaoxin, Hoang Alison, Khyeam Sheamin, Yu Hongyao, Wang Jiajia, Chen Qing, Powers Nevan, Chen Li, Bigley Rachel B, Lovas Jonathan, Hu Guang, Huang Guo N,
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Sensitivity of Quails (Coturnix coturnix), Siskins (Carduelis spinus), and Frogs (Rana ridibunda) to West Nile Virus.
Bull Exp Biol Med2021 Sep;():. doi: 10.1007/s10517-021-05250-z.
Molchanova E V, Prilepskaya D R, Negodenko A O, Luchinin D N, Khabarova I A,
Abstract
The level of viremia and features of the course of experimental infection caused by West Nile virus were studied in two species of migratory birds, siskins ?arduelis spinus and quails Coturnix coturnix, and in one species of amphibians, frogs Rana ridibunda. In quails, the virus caused a fatal disease; histological analysis revealed pathological changes in the heart, kidneys, liver, and brain stem. In siskins and frogs, virus antigen was detected in cloacal smears despite the absence of clinical manifestations, the level of viremia was sufficient to infect insect vectors during bloodsucking. These findings suggest that siskins and frogs can be potential reservoirs of West Nile virus and play a role in its circulation.
© 2021. Springer Science+Business Media, LLC, part of Springer Nature.
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Lead Optimization and Structure-Activity Relationship Studies on Myeloid Ecotropic Viral Integration Site 1 Inhibitor.
J Med Chem2021 Sep;():. doi: 10.1021/acs.jmedchem.1c00972.
Turgutalp Bengisu, Uslu Merve, Helvacioglu Sinem, Charehsaz Mohammad, Gurdal Enise Ece, Sippl Wolfgang, Kocabas Fatih, Yarim Mine,
Abstract
The pivotal role of the myeloid ecotropic viral integration site 1 (MEIS1) transcriptional factor was reported in cardiac regeneration and hematopoietic stem-cell (HSC) regulation with our previous findings. MEIS1 as a promising target in the context of pharmacological inhibition, we identified a potent myeloid ecotropic viral integration site (MEIS) inhibitor, MEISi-1, to induce murine and human HSC expansion and . In this work, we performed lead optimization on MEISi-1 by synthesizing 45 novel analogues. Structure-activity relationship studies revealed the significance of a -methoxy group on ring and a hydrophobic moiety at the position of ring . Obtained biological data were supported by inhibitor docking and molecular dynamics simulation studies. Eleven compounds were depicted as potent inhibitors demonstrating a better inhibitory profile on MEIS1 and target genes , ?, and . Among those, , , and were the most potent inhibitors. The predicted pharmacokinetics properties fulfill drug-likeness criteria. In addition, compounds exerted neither cytotoxicity on human dermal fibroblasts nor mutagenicity.
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