Whole Heart Engineering: Advances and Challenges

2021 ◽  
pp. 1-11
Author(s):  
Jacquelynn Morrissey ◽  
Fernanda C.P. Mesquita ◽  
Camila Hochman-Mendez ◽  
Doris A. Taylor
Keyword(s):  
Unmet Need ◽  
Multiple Organ ◽  
Biologically Active ◽  
Solid Organ ◽  
Organ Engineering ◽  
Engineering Research ◽  
Organ Systems ◽  
Whole Organ Engineering ◽  
Whole Heart

Bioengineering a solid organ for organ replacement is a growing endeavor in regenerative medicine. Our approach – recellularization of a decellularized cadaveric organ scaffold with human cells – is currently the most promising approach to building a complex solid vascularized organ to be utilized in vivo, which remains the major unmet need and a key challenge. The 2008 publication of perfusion-based decellularization and partial recellularization of a rat heart revolutionized the tissue engineering field by showing that it was feasible to rebuild an organ using a decellularized extracellular matrix scaffold. Toward the goal of clinical translation of bioengineered tissues and organs, there is increasing recognition of the underlying need to better integrate basic science domains and industry. From the perspective of a research group focusing on whole heart engineering, we discuss the current approaches and advances in whole organ engineering research as they relate to this multidisciplinary field’s 3 major pillars: organ scaffolds, large numbers of cells, and biomimetic bioreactor systems. The success of whole organ engineering will require optimization of protocols to produce biologically-active scaffolds for multiple organ systems, and further technological innovation both to produce the massive quantities of high-quality cells needed for recellularization and to engineer a bioreactor with physiologic stimuli to recapitulate organ function. Also discussed are the challenges to building an implantable vascularized solid organ.

Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers

2021 ◽  
Author(s):  
Lara Cheslow ◽  
Adam E Snook ◽  
Scott A Waldman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Unmet Need ◽  
Multiple Organ ◽  
The Body ◽  
Organ Systems ◽  
Diagnostic Approaches ◽  
New Biomarkers

Parkinson’s disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.

scholarly journals Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Dominik Samotij ◽  
Adam Reich
Keyword(s):  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Unmet Need ◽  
Clinical Manifestations ◽  
Immunosuppressive Drugs ◽  
Multiple Organ ◽  
Biologic Agents ◽  
Drug Induced ◽  
Treatment Regimes ◽  
Organ Systems

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

scholarly journals Neuroinvasion of SARS-CoV-2 in human and mouse brain

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Eric Song ◽  
Ce Zhang ◽  
Benjamin Israelow ◽  
Alice Lu-Culligan ◽  
Alba Vieites Prado ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Immune Cell ◽  
Multiple Organ ◽  
Type I ◽  
Organ Systems ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
The Brain ◽  
Immune Cell Infiltrates

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

scholarly journals CCD Based Detector for Detection of Abrin Toxin Activity

Toxins ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 120
Author(s):  
Reuven Rasooly ◽  
Paula Do ◽  
Bradley Hernlem
Keyword(s):  
Hela Cells ◽  
Thermal Inactivation ◽  
Fluorescent Protein ◽  
Limit Of Detection ◽  
Colorimetric Assay ◽  
Low Cost ◽  
Vero Cells ◽  
Multiple Organ ◽  
Biologically Active ◽  
Organ Systems

Abrin is a highly potent and naturally occurring toxin produced in the seeds of Abrus precatorius (Rosary Pea) and is of concern as a potential bioterrorism weapon. There are many rapid and specific assay methods to detect this toxic plant protein, but few are based on detection of toxin activity, critical to discern biologically active toxin that disables ribosomes and thereby inhibits protein synthesis, producing cytotoxic effects in multiple organ systems, from degraded or inactivated toxin which is not a threat. A simple and low-cost CCD detector system was evaluated with colorimetric and fluorometric cell-based assays for abrin activity; in the first instance measuring the abrin suppression of mitochondrial dehydrogenase in Vero cells by the MTT-formazan method and in the second instance measuring the abrin suppression of green fluorescent protein (GFP) expression in transduced Vero and HeLa cells. The limit of detection using the colorimetric assay was 10 pg/mL which was comparable to the fluorometric assay using HeLa cells. However, with GFP transduced Vero cells a hundred-fold improvement in sensitivity was achieved. Results were comparable to those using a more expensive commercial plate reader. Thermal inactivation of abrin was studied in PBS and in milk using the GFP-Vero cell assay. Inactivation at 100 °C for 5 min in both media was complete only at the lowest concentration studied (0.1 ng/mL) while treatment at 63 °C for 30 min was effective in PBS but not milk.

scholarly journals Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

2006 ◽  
Vol 26 (18) ◽  
pp. 6870-6879 ◽  
Author(s):  
Xinyan Huang ◽  
Ying Fu ◽  
Raelene A. Charbeneau ◽  
Thomas L. Saunders ◽  
Douglas K. Taylor ◽  
...  
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Cell Function ◽  
Immune Cell ◽  
Multiple Organ ◽  
Rgs Proteins ◽  
Total Contribution ◽  
Pleiotropic Phenotype ◽  
Organ Systems

ABSTRACT Signal transduction via guanine nucleotide binding proteins (G proteins) is involved in cardiovascular, neural, endocrine, and immune cell function. Regulators of G protein signaling (RGS proteins) speed the turn-off of G protein signals and inhibit signal transduction, but the in vivo roles of RGS proteins remain poorly defined. To overcome the redundancy of RGS functions and reveal the total contribution of RGS regulation at the Gαi2 subunit, we prepared a genomic knock-in of the RGS-insensitive G184S Gnai2 allele. The Gαi2 G184S knock-in mice show a dramatic and complex phenotype affecting multiple organ systems (heart, myeloid, skeletal, and central nervous system). Both homozygotes and heterozygotes demonstrate reduced viability and decreased body weight. Other phenotypes include shortened long bones, a markedly enlarged spleen, elevated neutrophil counts, an enlarged heart, and behavioral hyperactivity. Heterozygous Gαi2 +/G184S mice show some but not all of these abnormalities. Thus, loss of RGS actions at Gαi2 produces a dramatic and pleiotropic phenotype which is more evident than the phenotype seen for individual RGS protein knockouts.

scholarly journals mito-QC illuminates mitophagy and mitochondrial architecture in vivo

2016 ◽  
Vol 214 (3) ◽  
pp. 333-345 ◽  
Author(s):  
Thomas G. McWilliams ◽  
Alan R. Prescott ◽  
George F.G. Allen ◽  
Jevgenia Tamjar ◽  
Michael J. Munson ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Biology ◽  
Multiple Organ ◽  
Mitochondrial Morphology ◽  
In Vivo Detection ◽  
Developing Heart ◽  
Adult Kidney ◽  
Organ Systems ◽  
Essential Quality

Autophagic turnover of mitochondria, termed mitophagy, is proposed to be an essential quality-control (QC) mechanism of pathophysiological relevance in mammals. However, if and how mitophagy proceeds within specific cellular subtypes in vivo remains unclear, largely because of a lack of tractable tools and models. To address this, we have developed “mito-QC,” a transgenic mouse with a pH-sensitive fluorescent mitochondrial signal. This allows the assessment of mitophagy and mitochondrial architecture in vivo. Using confocal microscopy, we demonstrate that mito-QC is compatible with classical and contemporary techniques in histochemistry and allows unambiguous in vivo detection of mitophagy and mitochondrial morphology at single-cell resolution within multiple organ systems. Strikingly, our model uncovers highly enriched and differential zones of mitophagy in the developing heart and within specific cells of the adult kidney. mito-QC is an experimentally advantageous tool of broad relevance to cell biology researchers within both discovery-based and translational research communities.

scholarly journals Zinc Finger Protein Zbtb20 Is Essential for Postnatal Survival and Glucose Homeostasis

2009 ◽  
Vol 29 (10) ◽  
pp. 2804-2815 ◽  
Author(s):  
Andrew P. R. Sutherland ◽  
Hai Zhang ◽  
Ye Zhang ◽  
Monia Michaud ◽  
Zhifang Xie ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Glucose Homeostasis ◽  
Knockout Mice ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Postnatal Growth ◽  
Multiple Organ ◽  
Wild Type Littermate ◽  
Organ Systems

ABSTRACT Zbtb20 is a member of the POK family of proteins, which function primarily as transcriptional repressors via interactions mediated by their conserved C2H2 Krüppel type zinc finger and BTB/POZ domains. To define the function of Zbtb20 in vivo, we generated knockout mice by homologous recombination. Zbtb20 null mice display a stark phenotype characterized by postnatal growth retardation, metabolic dysfunction, and lethality. Zbtb20 knockout mice displayed abnormal glucose homeostasis, hormonal responses, and depletion of energy stores, consistent with an energetic deficit. Additionally, increased serum bilirubin and alanine aminotransferase levels were suggestive of liver dysfunction. To identify potential liver-specific Zbtb20 target genes, we performed transcript profiling studies on liver tissue from Zbtb20 knockout mice and wild-type littermate controls. These studies identified sets of genes involved in growth, metabolism, and detoxification that were differentially regulated in Zbtb20 knockout liver. Transgenic mice expressing Zbtb20 in the liver were generated and crossed onto the Zbtb20 knockout background, which resulted in no significant normalization of growth or glucose metabolism but a significant increase in life span compared to controls. These data indicate that the phenotype of Zbtb20 knockout mice results from liver-dependent and -independent defects, suggesting that Zbtb20 plays nonredundant roles in multiple organ systems.

scholarly journals Lysophospholipid (S1P) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Hirotaka Mizuno ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Radioligand Binding ◽  
Cell Types ◽  
Receptor Activation ◽  
Multiple Organ ◽  
S1p Receptors ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
Heterologous Expression Systems

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [70]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [52]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [15, 39]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [74, 76]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [48, 14]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [26]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [107, 28, 43, 44].

scholarly journals Searching for Clinically Relevant Biomarkers in Geriatric Oncology

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Theodora Katsila ◽  
George P. Patrinos ◽  
Dimitrios Kardamakis
Keyword(s):  
Decision Making ◽  
Ethical Issues ◽  
Unmet Need ◽  
Geriatric Oncology ◽  
Cost Effective ◽  
Multiple Organ ◽  
Health Concern ◽  
Policy Makers ◽  
Mortality And Morbidity ◽  
Organ Systems

Ageing, which is associated with a progressive decline and functional deterioration in multiple organ systems, is highly heterogeneous, both inter- and intraindividually. For this, tailored-made theranostics and optimum patient stratification become fundamental, when decision-making in elderly patients is considered. In particular, when cancer incidence and cancer-related mortality and morbidity are taken into account, elderly patient care is a public health concern. In this review, we focus on oncogeriatrics and highlight current opportunities and challenges with an emphasis on the unmet need of clinically relevant biomarkers in elderly cancer patients. We performed a literature search on PubMed and Scopus databases for articles published in English between 2000 and 2017 coupled to text mining and analysis. Considering the top insights, we derived from our literature analysis that information knowledge needs to turn into knowledge growth in oncogeriatrics towards clinically relevant biomarkers, cost-effective practices, updated educational schemes for health professionals (in particular, geriatricians and oncologists), and awareness of ethical issues. We conclude with an interdisciplinary call to omics, geriatricians, oncologists, informatics, and policy-makers communities that Big Data should be translated into decision-making in the clinic.

scholarly journals HIF1α is a direct regulator of steroidogenesis in the adrenal gland

2021 ◽  
Author(s):  
Deepika Watts ◽  
Johanna Stein ◽  
Ana Meneses ◽  
Nicole Bechmann ◽  
Ales Neuwirth ◽  
...  
Keyword(s):  
Multiple Organ ◽  
Hypoxia Inducible Factors ◽  
Adrenocortical Cells ◽  
Steroid Production ◽  
Hormone Synthesis ◽  
Organ Systems ◽  
Direct Regulator ◽  
Endogenous Steroid ◽  
Endogenous Steroid Hormones

AbstractEndogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.

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