scholarly journals Selective germline genome edited pigs and their long immune tolerance in Non Human Primates

2020 ◽  
Author(s):  
Lijin Zou ◽  
Youlai Zhang ◽  
Ying He ◽  
Hui Yu ◽  
Jun Chen ◽  
...  
Keyword(s):  
Organ Failure ◽  
Killer Cell ◽  
The Other ◽  
Regulatory Proteins ◽  
Coagulation System ◽  
Specific Gene ◽  
Organ Shortage ◽  
Burn Patients ◽  
Human Organ ◽  
Terminal Organ

AbstractOrgan transplantation is the only curative treatment for patients with terminal organ failure, however, there is a worldwide organ shortage. Genetically modified pig organs and tissues have become an attractive and practical alternative solution for the severe organ shortage, which has been made possible by significant progress in xenotransplantation in recent years. The past several decades witnessed an expanding list of genetically engineered pigs due to technology advancements, however, the necessary combination of genetic modifications in pig for human organ xenotransplantation has not been determined. In the current study, we created a selective germline genome edited pig (SGGEP). The first triple xenoantigens (GGTA, B4GAL, and CAMH) knockout somatic cells were generated to serve as a prototype cells and then human proteins were expressed in the xenoantigen knockout cells, which include human complement system negative regulatory proteins (CD46, CD55, and CD59); human coagulation system negative regulatory proteins thrombomodulin (THBD); tissue factor pathway inhibitor (TFPI); CD39; macrophage negative regulatory proteins (human CD47); and natural killer cell negative regulatory human HLA-E. After the successful establishment of SGGEP by the nuclear tranfer, we engrafted SGGEP skin to NHP, up to 25 days graft survival without immunosuppressive drugs was observed. Because a pig skin graft does not impact the success of a subsequent allograft or autograft or vice versa, thus our SGGEP could have a great potential for clinical value to save severe and large area burn patients and the other human organ failure. Therefore, this combination of specific gene modifications is a major milestone and provides proof of concept to initiate investigator-initiated clinical trials (IITs) in severe burn patients with defined processes and governance measures in place and the other clinical application.

scholarly journals Yeast repressor alpha 2 binds to its operator cooperatively with yeast protein Mcm1.

1989 ◽  
Vol 9 (11) ◽  
pp. 5228-5230 ◽  
Author(s):  
C A Keleher ◽  
S Passmore ◽  
A D Johnson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Product ◽  
Strong Evidence ◽  
Regulatory Proteins ◽  
Yeast Cells ◽  
Specific Gene ◽  
Yeast Gene ◽  
Yeast Protein ◽  
Transcriptional Regulatory

To bring about repression of a family fo genes in Saccharomyces cerevisiae called the a-specific genes, two transcriptional regulatory proteins, alpha 2 and GRM (general regulator of matin type), bind cooperatively to an operator found upstream of each a-specific gene. To date, GRM has been defined only biochemically. In this communication we show that the product of a single yeast gene (MCM1) is sufficient to bind cooperatively with alpha 2 to the operator. We also show that antiserum raised against the MCM1 gene product recognizes GRM from yeast cells. These results, in combination with previous observations, provide strong evidence that MCM1 encodes the GRM activity.

Der Mangel an Spenderorganen – Ursachen und Lösungsmöglichkeiten aus ökonomischer Sicht / The Shortage of Transplants – An Economic Analysis of Causes and Possible Solutions

2007 ◽  
Vol 227 (5-6) ◽  
Author(s):  
Friedrich Breyer ◽  
Hartmut Kliemt
Keyword(s):  
Intensive Care ◽  
Brain Death ◽  
Social Institutions ◽  
Organ Allocation ◽  
Organ Shortage ◽  
Organ Donors ◽  
Organ Transplants ◽  
Presumed Consent ◽  
Human Organ

SummaryThere is an increasing shortage of human organ transplants in Germany. This paper aims at understanding the reasons for that shortage and discusses various ways to alleviate it by changing the rules of donation and procurement. In particular we consider creating adequate incentives for hospitals and individual donors to participate in the process. In Section 2 we provide a stylized account of the nature and extent of organ shortage in Germany in terms of some key data. Then, in Section 3 we will turn to the incentives of hospitals and their employees, in particular those of intensive care units. When they intend to participate in the process of procuring cadaveric human organ transplants, they may face some rather severe obstacles. In Section 4 we turn to the role of potential organ donors and their families. We discuss different strategies to increase consent to a donation of organs after brain-death has been diagnosed. We particularly consider monetary and other incentives as well as the introduction of the presumedconsent rule. In Section 5 we conclude that organ shortage is due not to natural constraints but to inappropriate social institutions. Introducing a presumed consent rule, reciprocity in organ allocation, better payments for hospitals and for donors are proposed as potential remedies.

scholarly journals Activated protein C protects against ventilator-induced pulmonary capillary leak

2009 ◽  
Vol 296 (6) ◽  
pp. L1002-L1011 ◽  
Author(s):  
James H. Finigan ◽  
Adel Boueiz ◽  
Emily Wilkinson ◽  
Rachel Damico ◽  
Jarrett Skirball ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation System ◽  
Blue Dye ◽  
Specific Gene ◽  
Capillary Leakage ◽  
Endothelial Protein C Receptor ◽  
Pulmonary Endothelium ◽  
Pulmonary Capillary

The coagulation system is central to the pathophysiology of acute lung injury. We have previously demonstrated that the anticoagulant activated protein C (APC) prevents increased endothelial permeability in response to edemagenic agonists in endothelial cells and that this protection is dependent on the endothelial protein C receptor (EPCR). We currently investigate the effect of APC in a mouse model of ventilator-induced lung injury (VILI). C57BL/6J mice received spontaneous ventilation (control) or mechanical ventilation (MV) with high (HVT; 20 ml/kg) or low (LVT; 7 ml/kg) tidal volumes for 2 h and were pretreated with APC or vehicle via jugular vein 1 h before MV. In separate experiments, mice were ventilated for 4 h and received APC 30 and 150 min after starting MV. Indices of capillary leakage included bronchoalveolar lavage (BAL) total protein and Evans blue dye (EBD) assay. Changes in pulmonary EPCR protein and Rho-associated kinase (ROCK) were assessed using SDS-PAGE. Thrombin generation was measured via plasma thrombin-antithrombin complexes. HVT induced pulmonary capillary leakage, as evidenced by significant increases in BAL protein and EBD extravasation, without significantly increasing thrombin production. HVT also caused significant decreases in pulmonary, membrane-bound EPCR protein levels and increases in pulmonary ROCK-1. APC treatment significantly decreased pulmonary leakage induced by MV when given either before or after initiation of MV. Protection from capillary leakage was associated with restoration of EPCR protein expression and attenuation of ROCK-1 expression. In addition, mice overexpressing EPCR on the pulmonary endothelium were protected from HVT-mediated injury. Finally, gene microarray analysis demonstrated that APC significantly altered the expression of genes relevant to vascular permeability at the ontology (e.g., blood vessel development) and specific gene (e.g., MAPK-associated kinase 2 and integrin-β6) levels. These findings indicate that APC is barrier-protective in VILI and that EPCR is a critical participant in APC-mediated protection.

scholarly journals Acute-on-chronic liver failure: definition, prognosis and management

2019 ◽  
Vol 11 (6) ◽  
pp. 458-467
Author(s):  
Ahmed Amin ◽  
Rajeshwar P Mookerjee
Keyword(s):  
Liver Transplantation ◽  
Liver Failure ◽  
Organ Failure ◽  
Limited Resource ◽  
Chronic Liver ◽  
Rapid Progression ◽  
Organ Shortage ◽  
Chronic Liver Failure ◽  
Hepatic Decompensation ◽  
Short Term Mortality

Acute-on-chronic liver failure (ACLF) is a recently described entity in chronic liver disease defined by acute hepatic decompensation, organ failure and a high risk of short-term mortality (usually less than 4 weeks). This condition is distinct from acute liver failure and stable progression of cirrhosis in numerous ways, including triggering precipitant factors, systemic inflammation, rapid progression and a potential for recovery. While a clear definition of ACLF has been forwarded from a large European Consortium study, some heterogeneity remains in how patients present and the types of organ failure, depending on whether they are described in Asian or European studies. Active alcoholism, acute alcoholic hepatitis and infections are the most frequent precipitants for ACLF. Underpinning the pathophysiology of ACLF is a state of persistent inflammation and immune dysfunction, collectively driving a systematic inflammatory response syndrome and an increased propensity to sepsis. Prevention and early treatment of organ failure are key in influencing survival. Given increasing organ shortage and more marginal grafts, liver transplantation is a limited resource and emphasises the need for new therapies to improve ACLF outcomes. Recent data indicate that liver transplantation has encouraging outcomes even in patients with advanced ACLF if patients are carefully selected during the permissive window of clinical presentation. ACLF remains a significant challenge in the field of hepatology, with considerable research and resource being channelled to improve upon the definition, prognostication, treatment and unravelling of mechanistic drivers. This Review discusses updates in ACLF definition, prognosis and management.

scholarly journals Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes

2019 ◽  
Vol 151 (12) ◽  
pp. 1347-1356 ◽  
Author(s):  
Edward C. Twomey ◽  
Maria V. Yelshanskaya ◽  
Alexander I. Sobolevsky
Keyword(s):  
Protein Complexes ◽  
Regulatory Protein ◽  
Regulatory Proteins ◽  
Specific Gene ◽  
Modular Architecture ◽  
Auxiliary Subunits ◽  
Functional Studies ◽  
Excitatory Neurotransmission ◽  
Synaptic Complexes ◽  
The Brain

Fast excitatory neurotransmission is mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (AMPAR). AMPARs initiate depolarization of the postsynaptic neuron by allowing cations to enter through their ion channel pores in response to binding of the neurotransmitter glutamate. AMPAR function is dramatically affected by auxiliary subunits, which are regulatory proteins that form various complexes with AMPARs throughout the brain. The most well-studied auxiliary subunits are the transmembrane AMPAR regulatory proteins (TARPs), which alter the assembly, trafficking, localization, kinetics, and pharmacology of AMPARs. Recent structural and functional studies of TARPs and the TARP-fold germ cell-specific gene 1-like (GSG1L) subunit have provided important glimpses into how auxiliary subunits regulate the function of synaptic complexes. In this review, we put these recent structures in the context of new functional findings in order to gain insight into the determinants of AMPAR regulation by TARPs. We thus reveal why TARPs display a broad range of effects despite their conserved modular architecture.

Acquired Hemophagocytic Lymphohistiocytosis Among Adults: A Single Center Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2277-2277
Author(s):  
Muhammad Rizwan Khawaja ◽  
Naveen Manchanda
Keyword(s):  
Organ Failure ◽  
Clinical Features ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Organ Transplant ◽  
Multi Organ Failure ◽  
Killer Cell Activity ◽  
History Of ◽  
Histopathological Evidence

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life threatening syndrome characterized by an uncontrolled inflammatory reaction and is often associated with poor outcomes. The current study was conducted to characterize clinical features and outcomes of acquired HLH among adults. Methods Thirteen consecutive patients with HLH presenting to Indiana University Medical Center (IU) between January 2010 and June 2013 were analyzed retrospectively. The criteria described by Henter et al (Pediatr Blood Cancer 2007; 48:124-131) were used for diagnosis. Results Median age was 45 years (range 30-73), 8 patients were female and 12 patients were Caucasians. Four patients had a malignancy (one in remission), 2 had history of a solid organ transplant, 6 had an underlying infection (3 viral, 1 bacterial, 2 fungal), 2 had an underlying autoimmune illness and 3 patients had idiopathic HLH. Four patients were on immunosuppressants for their history of organ transplant (n=2), autoimmunity (n=1) or as part of their chemotherapy for a malignancy (n=1). All patients had fevers and 2 or more cytopenias. Multi-organ failure was frequent with liver failure (bilirubin >2.0; 11 patients), renal failure (Cr >2.0; 11 patients), respiratory failure requiring mechanical ventilation (10 patients), hemodynamic instability requiring vasopressor support (8 patients) and encephalopthy or generalized weakness (all patients). Other commonly seen clinical features included rash (6 patients), hyponatremia (Na <135; 11 patients), steatosis (5 patients), hepatomegaly (2 patients) and venous thromboembolism (5 patients). Seven of 12 patients had elevated triglycerides (≥265 mg/dL). Of 11 patients for whom fibrinogen was checked, 7 had a low fibrinogen (≤ 150mg/dL); two had undetectable fibrinogen in the absence of coagulopathy. All patients had markedly elevated ferritin levels (median 16500 ng/mL; range 2002-138705). Twelve of 13 patients had histopathological evidence of HLH on biopsy or autopsy. Soluble IL-2 receptor level was elevated (>2400 U/mL) in 9 patients (available for 11 patients) and all 6 patients (available for 6 patients) had decreased or absent natural killer cell activity. All patients received steroids as part of treatment (modified HLH 2004 protocol); 4 patients were too unstable to receive standard treatment and received only steroids. Eight patients died of HLH (6 at initial hospitalization; 2 later) at a median of 27 days (range 4-131). Multi-organ failure was the cause of death in 7 patients. Time to establishment of diagnosis was similar for patients who died at initial admission vs. those discharged alive (median 7 vs. 10 days). Conclusion Acquired HLH among adults is a systemic syndrome with diverse and sometimes unknown etiology. Most clinical features are nonspecific; incorporation of markedly high ferritin (≥2000 ng/mL), high soluble IL-2 receptor level, decreased/absent natural killer cell activity and histopathological evidence of HLH as major criteria for diagnosis may enhance specificity. Rash, steatosis/hepatomegaly, hyponatremia, thromboembolism and hypofibrinoginemia in the absence of coagulopathy can also be seen. Mortality is high due to multi-organ failure. Time to diagnosis does not seem to be a predictor of in-hospital mortality suggesting that the biology of underlying disease might be a more important factor. Disclosures: No relevant conflicts of interest to declare.

The bacterial Kdp K + -ATPase and its relation to other transport ATPases, such as the Na + /K + - and Ca 2+ -ATPases in higher organisms

1990 ◽  
Vol 326 (1236) ◽  
pp. 479-487 ◽  
Keyword(s):  
Turgor Pressure ◽  
The Other ◽  
Regulatory Proteins ◽  
Nodule Formation ◽  
Similar Function ◽  
Genetic Studies ◽  
High Affinity ◽  
Transmembrane Channel ◽  
Transport Atpases ◽  
Phosphate Regulon

The Kdp system is a three-subunit member of the Ej—E2 family of transport ATPases. There is sequence homology of the 72 kDa KdpB protein, the largest subunit of Kdp, with the other members of this family. The predicted structure of the 21 kDa KdpC subunit resembles that of the |3 subunit of the Na + ,K + -ATPase, suggesting that these subunits may have a similar function. The 59 kDa KdpA subunit has no known homologue; it is very hydrophobic and is predicted to cross the membrane 10-12 times. Genetic studies implicate this subunit in the binding of K + . As the binding site must be close to the beginning of the transmembrane channel, we suggest that KdpA also forms most or all of the latter. KdpA may have evolved from a K + /H + antiporter that was recruited by the KdpB precursor to achieve the high affinity and specificity for K + , and the activation of transport by low turgor pressure characteristic of Kdp. Turgor pressure controls the expression of Kdp. This action is dependent on the 70 kDa KdpD and 23 kDa KdpE proteins. We are in the process of sequencing these genes. KdpE is homologous to the smaller protein of other members of a family of pairs of regulatory proteins implicated in control of a variety of bacterial processes such as porin synthesis, phosphate regulon expression, nitrogen metabolism, chemotaxis and nodule formation.

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