An experimental evaluation of host specificity: The role of encounter and compatibility filters for a rhizocephalan parasite of crabs

USGS Publications Warehouse

Kuris, Armand M.; Goddard, Jeffrey H. R.; Torchin, Mark E.; Murphy, Nicole; Gurney, Robert; Lafferty, Kevin D.

2007-01-01

The encounter/compatibility paradigm of host specificity provides three qualitative pathways to the success or failure of a potential host-parasite interaction. It is usually impossible to distinguish between two of these (encounter and compatibility filters closed versus encounter filter open and compatibility filter closed) because unsuccessful infection attempts are difficult to observe in nature. We were able to open the encounter filter under experimental laboratory conditions. Our analytical system used the rhizocephalan barnacle, Sacculina carcini, a parasitic castrator of the European green crab, Carcinus maenas, and Pachygrapsus marmoratus, a native European crab that occurs with C. maenas but is not parasitized by S. carcini in nature. Penetration followed by unsuccessful infection of P. marmoratus crabs by parasitic barnacle larvae leaves a uniquely permanent record in the thoracic ganglion of the crabs. This provided us with a novel tool to quantify the encounter filter in a host-parasite system in nature. We demonstrated, in the laboratory, that the compatibility filter was closed and that, in nature, even where barnacle larvae were present, the encounter filter was also effectively closed. The closure of both filters in nature explains the failure of this potential host-parasite interaction, an outcome favored by selection in both host and parasite.

The mitonuclear compatibility hypothesis of sexual selection

PubMed Central

Hill, Geoffrey E.; Johnson, James D.

2013-01-01

Why females assess ornaments when choosing mates remains a central question in evolutionary biology. We hypothesize that the imperative for a choosing female to find a mate with nuclear oxidative phosphorylation (OXPHOS) genes that are compatible with her mitochondrial OXPHOS genes drives the evolution of ornaments. Indicator traits are proposed to signal the efficiency of OXPHOS function thus enabling females to select mates with nuclear genes that are compatible with maternal mitochondrial genes in the formation of OXPHOS complexes. Species-typical pattern of ornamentation is proposed to serve as a marker of mitochondrial type ensuring that females assess prospective mates with a shared mitochondrial background. The mitonuclear compatibility hypothesis predicts that the production of ornaments will be closely linked to OXPHOS pathways, and that sexual selection for compatible mates will be strongest when genes for nuclear components of OXPHOS complexes are Z-linked. The implications of this hypothesis are that sexual selection may serve as a driver for the evolution of more efficient cellular respiration. PMID:23945683

Mitochondrial DNA transmission and confounding mitochondrial influences in cloned cattle and pigs.

PubMed

Takeda, Kumiko

2013-04-01

Although somatic cell nuclear transfer (SCNT) is a powerful tool for production of cloned animals, SCNT embryos generally have low developmental competency and many abnormalities. The interaction between the donor nucleus and the enucleated ooplasm plays an important role in early embryonic development, but the underlying mechanisms that negatively impact developmental competency remain unclear. Mitochondria have a broad range of critical functions in cellular energy supply, cell signaling, and programmed cell death; thus, affect embryonic and fetal development. This review focuses on mitochondrial considerations influencing SCNT techniques in farm animals. Donor somatic cell mitochondrial DNA (mtDNA) can be transmitted through what has been considered a "bottleneck" in mitochondrial genetics via the SCNT maternal lineage. This indicates that donor somatic cell mitochondria have a role in the reconstructed cytoplasm. However, foreign somatic cell mitochondria may affect the early development of SCNT embryos. Nuclear-mitochondrial interactions in interspecies/intergeneric SCNT (iSCNT) result in severe problems. A major biological selective pressure exists against survival of exogenous mtDNA in iSCNT. Yet, mtDNA differences in SCNT animals did not reflect transfer of proteomic components following proteomic analysis. Further study of nuclear-cytoplasmic interactions is needed to illuminate key developmental characteristics of SCNT animals associated with mitochondrial biology.

Fasciola hepatica in Cuba: compatibility of different isolates with two intermediate snail hosts, Galba cubensis and Pseudosuccinea columella.

PubMed

Vázquez, A A; Sánchez, J; Pointier, J-P; Théron, A; Hurtrez-Boussès, S

2014-12-01

In Cuba, only two lymnaeid snails, Galba cubensis and Pseudosuccinea columella, with different ecology and distribution patterns, are intermediate hosts for Fasciola hepatica. The compatibility of these two species as hosts was analysed through their rates of infection, the production of rediae and survivorship when exposed to F. hepatica miracidia. Ten populations of G. cubensis, eight of P. columella collected from various habitats and six isolates of F. hepatica sampled in slaughterhouses from different localities were tested. Our results clearly demonstrate that G. cubensis is a more compatible host for F. hepatica in Cuba when compared with P. columella. However, the role that P. columella may have in fascioliasis transmission under certain conditions should not be disregarded. Variation in infectivity among isolates of F. hepatica were also observed and may explain why some regions in Cuba are more commonly subjected to fascioliasis outbreaks.

Mating Compatibility and Restriction Analysis of Ganoderma Isolates from Oil Palm and Other Palm Hosts.

PubMed

Jing, Chan Jer; Seman, Idris Abu; Zakaria, Latiffah

2015-12-01

Mating compatibility and restriction analyses of Internal Transcribed Spacer (ITS) regions were performed to determine the relations between Ganoderma boninense, the most common species associated with basal stem rot in oil palm and Ganoderma isolates from infected oil palm, two ornamental palms, sealing wax palm (Cyrtostachys renda) and MacArthur palm (Ptychosperma macarthurii), an isolate from coconut stump (Cocos nucifera), Ganoderma miniatocinctum, Ganoderma zonatum and Ganoderma tornatum. The results showed that G. boninense was compatible with Ganoderma isolates from oil palm, G. miniatocinctum and G. zonatum, Ganoderma isolates from sealing wax palm, MacArthur palm and coconut stump. G. boninense was not compatible with G. tornatum. Therefore, the results suggested that the G. boninense, G. miniatocinctum, G. zonatum, and Ganoderma isolates from oil palm, ornamental palms and coconut stump could represent the same biological species. In performing a restriction analysis of the ITS regions, variations were observed in which five haplotypes were generated from the restriction patterns. An unweighted pair-group method with arithmetic averages (UPGMA) cluster analysis showed that all the Ganoderma isolates were grouped into five primary groups, and the similarity values of the isolates ranged from 97% to 100%. Thus, a restriction analysis of the ITS regions showed that G. boninense and the Ganoderma isolates from other palm hosts were closely related. On the basis of the mating compatibility test and the restriction analysis of the ITS regions performed in this study, a diverse group of Ganoderma species from oil palm and other palm hosts are closely related, except for G. tornatum and Ganoderma isolates from tea and rubber.

Is heart transplantation after circulatory death compatible with the dead donor rule?

PubMed

Nair-Collins, Michael; Miller, Franklin G

2016-05-01

Dalle Ave et al (2016) provide a valuable overview of several protocols for heart transplantation after circulatory death. However, their analysis of the compatibility of heart donation after circulatory death (DCD) with the dead donor rule (DDR) is flawed. Their permanence-based criteria for death, which depart substantially from established law and bioethics, are ad hoc and unfounded. Furthermore, their analysis is self-defeating, because it undercuts the central motivation for DDR as both a legal and a moral constraint, rendering the DDR vacuous and trivial. Rather than devise new and ad hoc criteria for death for the purpose of rendering DCD nominally consistent with DDR, we contend that the best approach is to explicitly abandon DDR. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Mating Compatibility and Restriction Analysis of Ganoderma Isolates from Oil Palm and Other Palm Hosts

PubMed Central

Jing, Chan Jer; Seman, Idris Abu; Zakaria, Latiffah

2015-01-01

Mating compatibility and restriction analyses of Internal Transcribed Spacer (ITS) regions were performed to determine the relations between Ganoderma boninense, the most common species associated with basal stem rot in oil palm and Ganoderma isolates from infected oil palm, two ornamental palms, sealing wax palm (Cyrtostachys renda) and MacArthur palm (Ptychosperma macarthurii), an isolate from coconut stump (Cocos nucifera), Ganoderma miniatocinctum, Ganoderma zonatum and Ganoderma tornatum. The results showed that G. boninense was compatible with Ganoderma isolates from oil palm, G. miniatocinctum and G. zonatum, Ganoderma isolates from sealing wax palm, MacArthur palm and coconut stump. G. boninense was not compatible with G. tornatum. Therefore, the results suggested that the G. boninense, G. miniatocinctum, G. zonatum, and Ganoderma isolates from oil palm, ornamental palms and coconut stump could represent the same biological species. In performing a restriction analysis of the ITS regions, variations were observed in which five haplotypes were generated from the restriction patterns. An unweighted pair-group method with arithmetic averages (UPGMA) cluster analysis showed that all the Ganoderma isolates were grouped into five primary groups, and the similarity values of the isolates ranged from 97% to 100%. Thus, a restriction analysis of the ITS regions showed that G. boninense and the Ganoderma isolates from other palm hosts were closely related. On the basis of the mating compatibility test and the restriction analysis of the ITS regions performed in this study, a diverse group of Ganoderma species from oil palm and other palm hosts are closely related, except for G. tornatum and Ganoderma isolates from tea and rubber. PMID:26868709

An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation outcomes.

PubMed

Ross, Julie A; Tolar, Jakub; Spector, Logan G; DeFor, Todd; Lund, Troy C; Weisdorf, Daniel J; Langer, Erica; Hooten, Anthony J; Thyagarajan, Bharat; Gleason, Michelle K; Wagner, John E; Robien, Kimberly; Verneris, Michael R

2015-01-01

Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

76 FR 23824 - Guidance for Industry: “Computer Crossmatch” (Computerized Analysis of the Compatibility Between...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-28

... the Compatibility Between the Donor's Cell Type and the Recipient's Serum or Plasma Type... Crossmatch' (Computerized Analysis of the Compatibility between the Donor's Cell Type and the Recipient's... donor's cell type and the recipient's serum or plasma type. The guidance describes practices that we...

A New Approximate Chimera Donor Cell Search Algorithm

NASA Technical Reports Server (NTRS)

Holst, Terry L.; Nixon, David (Technical Monitor)

1998-01-01

The objectives of this study were to develop chimera-based full potential methodology which is compatible with overflow (Euler/Navier-Stokes) chimera flow solver and to develop a fast donor cell search algorithm that is compatible with the chimera full potential approach. Results of this work included presenting a new donor cell search algorithm suitable for use with a chimera-based full potential solver. This algorithm was found to be extremely fast and simple producing donor cells as fast as 60,000 per second.

Host mitochondrial association evolved in the human parasite Toxoplasma gondii via neofunctionalization of a gene duplicate

USDA-ARS?s Scientific Manuscript database

In Toxoplasma gondii, an intracellular parasite of humans and other warm-blooded animals, the ability to associate with host mitochondria (HMA) is driven by a locally expanded gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. The importance of copy number in the e...

Binding of tetramethylammonium to polyether side-chained aromatic hosts. Evaluation of the binding contribution from ether oxygen donors.

PubMed

Bartoli, Sandra; De Nicola, Gina; Roelens, Stefano

2003-10-17

A set of macrocyclic and open-chain aromatic ligands endowed with polyether side chains has been prepared to assess the contribution of ether oxygen donors to the binding of tetramethylammonium (TMA), a cation believed incapable of interacting with oxygen donors. The open-chain hosts consisted of an aromatic binding site and side chains possessing a variable number of ether oxygen donors; the macrocyclic ligands were based on the structure of a previously investigated host, the dimeric cyclophane 1,4-xylylene-1,4-phenylene diacetate (DXPDA), implemented with polyether-type side chains in the backbone. Association to tetramethylammonium picrate (TMAP) was measured in CDCl(3) at T = 296 K by (1)H NMR titrations. Results confirm that the main contribution to the binding of TMA comes from the cation-pi interaction established with the aromatic binding sites, but they unequivocally show that polyether chains participate with cooperative contributions, although of markedly smaller entity. Water is also bound, but the two guests interact with aromatic rings and oxygen donors in an essentially noncompetitive way. An improved procedure for the preparation of cyclophanic tetraester derivatives has been developed that conveniently recycles the oligomeric ester byproducts formed in the one-pot cyclization reaction. An alternative entry to benzylic diketones has also been provided that makes use of a low-order cyanocuprate reagent to prepare in fair yields a class of compounds otherwise uneasily accessible.

(Cryptic) sex in the microsporidian Nosema granulosis--evidence from parasite rDNA and host mitochondrial DNA.

PubMed

Krebes, Lukas; Zeidler, Lisza; Frankowski, Jens; Bastrop, Ralf

2014-01-01

Microsporidia are single-celled, intracellular eukaryotes that parasitise a wide range of animals. The Nosema/Vairimorpha group includes some putative asexual species, and asexuality is proposed to have originated multiple times from sexual ancestors. Here, we studied the variation in the ribosomal DNA (rDNA) of 14 isolates of the presumed apomictic and vertically transmitted Nosema granulosis to evaluate its sexual status. The analysed DNA fragment contained a part of the small-subunit ribosomal gene (SSU) and the entire intergenic spacer (IGS). The mitochondrial cox1 gene of the host Gammarus duebeni (Crustacea) was analysed to temporally calibrate the system and to test the expectation of cophylogeny of host and parasite genealogies. Genetic variability of the SSU gene was very low within and between the isolates. In contrast, intraisolate (within a single host) variability of the IGS felt in two categories, because 12 isolates possess a very high IGS genetic diversity and two isolates were almost invariable in the IGS. This difference suggests variable models of rDNA evolution involving birth-and-death and unexpectedly concerted evolution. An alternative explanation could be a likewise unattended mixed infection of host individuals by more than one parasite strain. Despite considerable genetic divergence between associated host mitochondrial haplotypes, some N. granulosis 'IGS populations' seem not to belong to different gene pools; the relevant tests failed to show significant differences between populations. A set of recombinant IGS sequences made our data incompatible with the model of a solely maternally inherited, asexual species. In line with recent reports, our study supports the hypothesis that some assumed apomictic Microsporidia did not entirely abstain from the evolutionary advantages of sex. In addition, the presented data indicate that horizontal transmission may occur occasionally. This transmission mode could be a survival strategy of N

The innate immune system in host mice targets cells with allogenic mitochondrial DNA

PubMed Central

Ishikawa, Kaori; Nakada, Kazuto; Morimoto, Mami; Imanishi, Hirotake; Yoshizaki, Mariko; Sasawatari, Shigemi; Niikura, Mamoru; Takenaga, Keizo; Yonekawa, Hiromichi

2010-01-01

Mitochondrial DNA (mtDNA) has been proposed to be involved in respiratory function, and mtDNA mutations have been associated with aging, tumors, and various disorders, but the effects of mtDNA imported into transplants from different individuals or aged subjects have been unclear. We examined this issue by generating trans-mitochondrial tumor cells and embryonic stem cells that shared the syngenic C57BL/6 (B6) strain–derived nuclear DNA background but possessed mtDNA derived from allogenic mouse strains. We demonstrate that transplants with mtDNA from the NZB/B1NJ strain were rejected from the host B6 mice, not by the acquired immune system but by the innate immune system. This rejection was caused partly by NK cells and involved a MyD88-dependent pathway. These results introduce novel roles of mtDNA and innate immunity in tumor immunology and transplantation medicine. PMID:20937705

Mitochondrial-Associated Cell Death Mechanisms Are Reset to an Embryonic-Like State in Aged Donor-Derived iPS Cells Harboring Chromosomal Aberrations

PubMed Central

Prigione, Alessandro; Hossini, Amir M.; Lichtner, Björn; Serin, Akdes; Fauler, Beatrix; Megges, Matthias; Lurz, Rudi; Lehrach, Hans; Zouboulis, Christos C.

2011-01-01

Somatic cells reprogrammed into induced pluripotent stem cells (iPSCs) acquire features of human embryonic stem cells (hESCs) and thus represent a promising source for cellular therapy of debilitating diseases, such as age-related disorders. However, reprogrammed cell lines have been found to harbor various genomic alterations. In addition, we recently discovered that the mitochondrial DNA of human fibroblasts also undergoes random mutational events upon reprogramming. Aged somatic cells might possess high susceptibility to nuclear and mitochondrial genome instability. Hence, concerns over the oncogenic potential of reprogrammed cells due to the lack of genomic integrity may hinder the applicability of iPSC-based therapies for age-associated conditions. Here, we investigated whether aged reprogrammed cells harboring chromosomal abnormalities show resistance to apoptotic cell death or mitochondrial-associated oxidative stress, both hallmarks of cancer transformation. Four iPSC lines were generated from dermal fibroblasts derived from an 84-year-old woman, representing the oldest human donor so far reprogrammed to pluripotency. Despite the presence of karyotype aberrations, all aged-iPSCs were able to differentiate into neurons, re-establish telomerase activity, and reconfigure mitochondrial ultra-structure and functionality to a hESC-like state. Importantly, aged-iPSCs exhibited high sensitivity to drug-induced apoptosis and low levels of oxidative stress and DNA damage, in a similar fashion as iPSCs derived from young donors and hESCs. Thus, the occurrence of chromosomal abnormalities within aged reprogrammed cells might not be sufficient to over-ride the cellular surveillance machinery and induce malignant transformation through the alteration of mitochondrial-associated cell death. Taken together, we unveiled that cellular reprogramming is capable of reversing aging-related features in somatic cells from a very old subject, despite the presence of genomic

Evaluation of four methods for platelet compatibility testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

McFarland, J.G.; Aster, R.H.

1987-05-01

Four platelet compatibility assays were performed on serum and platelet or lymphocyte samples from 38 closely HLA-matched donor/recipient pairs involved in 55 single-donor platelet transfusions. The 22 patients studied were refractory to transfusions of pooled random-donor platelets. Of the four assays (platelet suspension immunofluorescence, PSIFT; /sup 51/Cr release; microlymphocytotoxicity; and a monoclonal anti-IgG assay, MAIA), the MAIA was most predictive of platelet transfusion outcome (predictability, 74% for one-hour posttransfusion platelet recovery and 76% for 24-hour recovery). The only other assay to reach statistical significance was the PSIFT (63% predictability for one-hour posttransfusion recovery). The degree of HLA compatibility between donormore » and recipient (exact matches v those utilizing cross-reactive associations) was unrelated to the ability of the MAIA to predict transfusion results. The MAIA may be capable of differentiating HLA antibodies, ABO antibodies, and platelet-specific antibodies responsible for failure of HLA-matched and selectively mismatched single-donor platelet transfusions.« less

Depletion of host CCR7(+) dendritic cells prevented donor T cell tissue tropism in anti-CD3-conditioned recipients.

PubMed

He, Wei; Racine, Jeremy J; Johnston, Heather F; Li, Xiaofan; Li, Nainong; Cassady, Kaniel; Liu, Can; Deng, Ruishu; Martin, Paul; Forman, Stephen; Zeng, Defu

2014-07-01

We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7(+), but not CCR7(-), DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but it was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7(+) but not CCR7(-) DCs by inducing sequential expansion and apoptosis of CCR7(+) DCs in MLN and PLN. Apoptosis of CCR7(+) DCs was associated with DC upregulation of Fas expression and natural killer cell but not T, B, or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7(+) host-type DCs, with subsequent inhibition of donor T cell migration into GVHD target tissues, can be an effective approach in prevention of acute GVHD and preservation of GVL effects. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Massive mitochondrial gene transfer in a parasitic flowering plant clade.

PubMed

Xi, Zhenxiang; Wang, Yuguo; Bradley, Robert K; Sugumaran, M; Marx, Christopher J; Rest, Joshua S; Davis, Charles C

2013-01-01

Recent studies have suggested that plant genomes have undergone potentially rampant horizontal gene transfer (HGT), especially in the mitochondrial genome. Parasitic plants have provided the strongest evidence of HGT, which appears to be facilitated by the intimate physical association between the parasites and their hosts. A recent phylogenomic study demonstrated that in the holoparasite Rafflesia cantleyi (Rafflesiaceae), whose close relatives possess the world's largest flowers, about 2.1% of nuclear gene transcripts were likely acquired from its obligate host. Here, we used next-generation sequencing to obtain the 38 protein-coding and ribosomal RNA genes common to the mitochondrial genomes of angiosperms from R. cantleyi and five additional species, including two of its closest relatives and two host species. Strikingly, our phylogenetic analyses conservatively indicate that 24%-41% of these gene sequences show evidence of HGT in Rafflesiaceae, depending on the species. Most of these transgenic sequences possess intact reading frames and are actively transcribed, indicating that they are potentially functional. Additionally, some of these transgenes maintain synteny with their donor and recipient lineages, suggesting that native genes have likely been displaced via homologous recombination. Our study is the first to comprehensively assess the magnitude of HGT in plants involving a genome (i.e., mitochondria) and a species interaction (i.e., parasitism) where it has been hypothesized to be potentially rampant. Our results establish for the first time that, although the magnitude of HGT involving nuclear genes is appreciable in these parasitic plants, HGT involving mitochondrial genes is substantially higher. This may represent a more general pattern for other parasitic plant clades and perhaps more broadly for angiosperms.

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

PubMed Central

Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

2016-01-01

To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy “3rd-party” donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

The Evolution of Host Mitochondrial Association and its Impact on Toxoplasma gondii Infection

NASA Astrophysics Data System (ADS)

English, Elizabeth D.

The association of intracellular pathogens with host mitochondria has been observed across taxa, from bacterial pathogens, such as Legionella pneumophila and Chlamydia trachomati, to the eukaryotic pathogen Toxoplasma gondii. However the functional impact of host mitochondrial association (HMA) remains difficult to assess in most of these species because in many cases the genes responsible for this phenomenon have not yet been identified. The recent discovery of the T. gondii gene responsible for HMA, Mitochondrial Association Factor 1 ( MAF1) has provided us with the tools to begin to understand the evolution and impact of HMA. Here we use multispecies sequence analysis to determine that the MAF1 locus is tandemly duplicated and diversified in both T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative Neospora caninum. Using cross-species complementation we find that T. gondii and H. hammondi harbor copies of MAF1 able to mediate HMA, while N. caninum does not. We have begun mutational analysis using naturally occurring HMA+ and HMA- paralogs of MAF1 in order to determine the portions of MAF1 protein necessary for HMA. Additionally, we have identified the first in vivo phenotypes associated with HMA using multiple mouse models, for both acute and chronic infection. Taken together these data indicate that HMA likely evolved via neofunctionalization of a duplicated ancestral MAF1 gene, and that the neofunctionalized, HMA competent copy of MAF1 provides a selective advantage.

Thermal Stress Promotes Host Mitochondrial Degradation in Symbiotic Cnidarians: Are the Batteries of the Reef Going to Run Out?

PubMed Central

Dunn, Simon R.; Pernice, Mathieu; Green, Kathryn; Hoegh-Guldberg, Ove; Dove, Sophie G.

2012-01-01

The symbiotic relationship between cnidarians and their dinoflagellate symbionts, Symbiodinium spp, which underpins the formation of tropical coral reefs, can be destabilized by rapid changes to environmental conditions. Although some studies have concluded that a breakdown in the symbiosis begins with increased reactive oxygen species (ROS) generation within the symbiont due to a decoupling of photosynthesis, others have reported the release of viable symbionts via a variety of host cell derived mechanisms. We explored an alternative model focused upon changes in host cnidarian mitochondrial integrity in response to thermal stress. Mitochondria are often likened to being batteries of the cell, providing energy in the form of ATP, and controlling cellular pathway activation and ROS generation. The overall morphology of host mitochondria was compared to that of associated symbionts under an experimental thermal stress using confocal and electron microscopy. The results demonstrate that hyperthermic stress induces the degradation of cnidarian host mitochondria that is independent of symbiont cellular deterioration. The potential sites of host mitochondrial disruption were also assessed by measuring changes in the expression of genes associated with electron transport and ATP synthesis using quantitative RT-PCR. The primary site of degradation appeared to be downstream of complex III of the electron transport chain with a significant reduction in host cytochrome c and ATP synthase expression. The consequences of reduced expression could limit the capacity of the host to mitigate ROS generation and maintain both organelle integrity and cellular energy supplies. The disruption of host mitochondria, cellular homeostasis, and subsequent cell death irrespective of symbiont integrity highlights the importance of the host response to thermal stress and in symbiosis dysfunction that has substantial implications for understanding how coral reefs will survive in the face of

Host heterogeneity affects both parasite transmission to and fitness on subsequent hosts

PubMed Central

Young, Kyle A.; Fox, Jordan; Jokela, Jukka

2017-01-01

Infectious disease dynamics depend on the speed, number and fitness of parasites transmitting from infected hosts (‘donors’) to parasite-naive ‘recipients’. Donor heterogeneity likely affects these three parameters, and may arise from variation between donors in traits including: (i) infection load, (ii) resistance, (iii) stage of infection, and (iv) previous experience of transmission. We used the Trinidadian guppy, Poecilia reticulata, and a directly transmitted monogenean ectoparasite, Gyrodactylus turnbulli, to experimentally explore how these sources of donor heterogeneity affect the three transmission parameters. We exposed parasite-naive recipients to donors (infected with a single parasite strain) differing in their infection traits, and found that donor infection traits had diverse and sometimes interactive effects on transmission. First, although transmission speed increased with donor infection load, the relationship was nonlinear. Second, while the number of parasites transmitted generally increased with donor infection load, more resistant donors transmitted more parasites, as did those with previous transmission experience. Finally, parasites transmitting from experienced donors exhibited lower population growth rates on recipients than those from inexperienced donors. Stage of infection had little effect on transmission parameters. These results suggest that a more holistic consideration of within-host processes will improve our understanding of between-host transmission and hence disease dynamics. This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’. PMID:28289260

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

PubMed Central

Kim, Byung-Su; Nishikii, Hidekazu; Baker, Jeanette; Pierini, Antonio; Schneidawind, Dominik; Pan, Yuqiong; Beilhack, Andreas; Park, Chung-Gyu

2015-01-01

The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (αDR3) expanded CD4+FoxP3+ Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4+ T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from αDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4+ T cells were maintained, resulting in improved survival. Conventional T cells derived from αDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNγ, IL-1β, and TNFα) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from αDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of αDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. PMID:26063163

Long-term engraftment, graft-vs.-host disease, and immunologic reconstitution after experimental transplantation of allogeneic peripheral blood cells from G-CSF-treated donors.

PubMed

Pan, L; Bressler, S; Cooke, K R; Krenger, W; Karandikar, M; Ferrara, J L

1996-10-01

Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated donors showed complete donor engraftment within 1 month, which was sustained until the end of the observation period. In contrast, recipients of T cell-depleted splenocytes showed slower donor engraftment and persistent donor/host chimerism. In addition, lymphocyte phenotype and function in mice receiving splenocytes from G-CSF-treated donors was significantly restored by day 100 after transplantation. Thus, the use of G-CSF-mobilized PBPC may provide significant advantages to conventional BMT by reducing GVHD without impairing long-term engraftment and immunologic reconstruction.

Which Donor for Uterus Transplants: Brain-Dead Donor or Living Donor? A Systematic Review.

PubMed

Lavoué, Vincent; Vigneau, Cécile; Duros, Solène; Boudjema, Karim; Levêque, Jean; Piver, Pascal; Aubard, Yves; Gauthier, Tristan

2017-02-01

The aim of this systematic review was to evaluate and compare the pros and cons of using living donors or brain-dead donors in uterus transplantation programs, 2 years after the first worldwide live birth after uterus transplantation. The Medline database and the Central Cochrane Library were used to locate uterine transplantation studies carried out in human or nonhuman primates. All types of articles (case reports, original studies, meta-analyses, reviews) in English or French were considered for inclusion. Overall, 92 articles were screened and 44 were retained for review. Proof of concept for human uterine transplantation was demonstrated in 2014 with a living donor. Compared with a brain-dead donor strategy, a living donor strategy offers greater possibilities for planning surgery and also decreases cold ischemia time, potentially translating into a higher success rate. However, this approach poses ethical problems, given that the donor is exposed to surgery risks but does not derive any direct benefit. A brain-dead donor strategy is more acceptable from an ethical viewpoint, but its feasibility is currently unproven, potentially owing to a lack of compatible donors, and is associated with a longer cold ischemia time and a potentially higher rejection rate. The systematic review demonstrates that uterine transplantation is a major surgical innovation for the treatment of absolute uterine factor infertility. Living and brain-dead donor strategies are not mutually exclusive and, in view of the current scarcity of uterine grafts and the anticipated future rise in demand, both will probably be necessary.

Donor recruitment and selection for adult-to-adult living donor liver transplantation in urgent and elective circumstances.

PubMed

Ben-Haim, Menahem; Carmiel, Michal; Lubezky, Nir; Keidar, Rivka; Katz, Paulina; Blachar, Arye; Nimrod, Adi; Sorkine, Patrick; Oren, Ran; Klausner, Joseph M; Nakache, Richard

2005-03-01

Adult-to-adult living donor liver transplantation is becoming an alternative to cadaveric transplantation in urgent and elective settings. Donor selection crucially affects donor safety and recipient outcome. To present our algorithm of urgent and elective donor selection. Urgent selection is expeditious and protocol-based. Elective selection permits a comprehensive process. Both include medical, psychosocial and surgical-anatomic evaluations. Liver volumes and vascular anatomy are evaluated with computerized tomographic angiography. Informed consent is obtained after painstaking explanations. Independent institutional committees review and approve all cases. Between July 2003 and June 2004 we evaluated 43 potential live donors for 12 potential recipients (fulminant hepatic failure, n = 5; chronic end-stage liver disease, n = 6; primary graft non-function, n = 1). Thirty-three candidates (76%) were excluded due to blood type incompatibility (n = 14, 42%), incompatible anatomy (n = 8, 24%)--including problematic volume distribution (n = 2) or vascular anatomy (n = 6)--psychosocial issues (n = 4, 12%), or medical co-morbidity (n = 7, 22%). Five recipients (FHF, n = 4; chronic ESLD, n = 1) were successfully transplanted from living donors. In the acute setting, two patients (FHF, PGNF) died in the absence of an appropriate donor (cadaveric or living donor). In the elective group, one patient died of unexpected variceal bleeding and one received a cadaveric graft just before the planned living donor transplantation was performed. One candidate was transplanted overseas and two cases are scheduled. The ratio of compatibility for donation was 34% (10/29) for blood type-compatible candidates. Donor selection for living donor liver transplantation is a complex, labor-intensive multidisciplinary process. Most exclusions are due to blood type incompatibility or anatomic details. Psychosocial aspects of these donations warrant special attention.

The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.

PubMed

King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K; Millender-Swain, Telisha; Dunham-Snary, Kimberly J; Oliva, Claudia R; Griguer, Corinne E; Bailey, Shannon M

2016-10-01

Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the

Mitochondrial replacement techniques: egg donation, genealogy and eugenics.

PubMed

Palacios-González, César

2016-03-01

Several objections against the morality of researching or employing mitochondrial replacement techniques have been advanced recently. In this paper, I examine three of these objections and show that they are found wanting. First I examine whether mitochondrial replacement techniques, research and clinical practice, should not be carried out because of possible harms to egg donors. Next I assess whether mitochondrial replacement techniques should be banned because they could affect the study of genealogical ancestry. Finally, I examine the claim that mitochondrial replacement techniques are not transferring mitochondrial DNA but nuclear DNA, and that this should be prohibited on ethical grounds.

A novel role of the ferric reductase Cfl1 in cell wall integrity, mitochondrial function, and invasion to host cells in Candida albicans.

PubMed

Yu, Qilin; Dong, Yijie; Xu, Ning; Qian, Kefan; Chen, Yulu; Zhang, Biao; Xing, Laijun; Li, Mingchun

2014-11-01

Candida albicans is an important opportunistic pathogen, causing both superficial mucosal infections and life-threatening systemic diseases. Iron acquisition is an important factor for pathogen-host interaction and also a significant element for the pathogenicity of this organism. Ferric reductases, which convert ferric iron into ferrous iron, are important components of the high-affinity iron uptake system. Sequence analyses have identified at least 17 putative ferric reductase genes in C. albicans genome. CFL1 was the first ferric reductase identified in C. albicans. However, little is known about its roles in C. albicans physiology and pathogenicity. In this study, we found that disruption of CFL1 led to hypersensitivity to chemical and physical cell wall stresses, activation of the cell wall integrity (CWI) pathway, abnormal cell wall composition, and enhanced secretion, indicating a defect in CWI in this mutant. Moreover, this mutant showed abnormal mitochondrial activity and morphology, suggesting a link between ferric reductases and mitochondrial function. In addition, this mutant displayed decreased ability of adhesion to both the polystyrene microplates and buccal epithelial cells and invasion of host epithelial cells. These findings revealed a novel role of C. albicans Cfl1 in maintenance of CWI, mitochondrial function, and interaction between this pathogen and the host. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Molecular cloning and characterization of Echinostoma caproni heat shock protein-70 and differential expression in the parasite derived from low- and high-compatible hosts.

PubMed

Higón, M; Monteagudo, C; Fried, B; Esteban, J G; Toledo, R; Marcilla, A

2008-10-01

We cloned and expressed Echinostoma caproni HSP70 in Escherichia coli. This molecule presents an open reading frame (ORF) of 655 amino acids, and a theoretical molecular weight of 71 kDa. E. caproni HSP70 protein showed a high homology to other helminth molecules, major differences being located in the C-terminal region of the molecule, with a hydrophobic portion. Studies of protein and messenger RNA (mRNA) expression revealed a distinct pattern, depending on the host (low- or high-compatible). Specific polyclonal antisera raised against the recombinant protein expressed in Escherichia coli demonstrated its selective presence in excretory/secretory products (ESP) of adult parasites obtained from high-compatible hosts. Immunological studies showed clearly the association of HSP70 with the parasite surface and other structures, including eggs.

Donor cross-linking for keratoplasty: a laboratory evaluation.

PubMed

Mukherjee, Achyut; Hayes, Sally; Aslanides, Ioannis; Lanchares, Elena; Meek, Keith M

2015-12-01

This laboratory-based investigation compares the topographic outcomes of conventional penetrating keratoplasty with that of a novel procedure in which donor corneas are cross-linked prior to keratoplasty. Penetrating keratoplasty procedures with continuous running sutures were carried out in a porcine whole globe model. Sixty eyes were randomly paired as 'donor' and 'host' tissue before being assigned to one of two groups. In the cross-linked group, donor corneas underwent riboflavin/UVA cross-linking prior to being trephined and sutured to untreated hosts. In the conventional keratoplasty group, both host and donor corneas remained untreated prior to keratoplasty. Topographic and corneal wavefront measurements were performed following surgery, and technical aspects of the procedure evaluated. Mean keratometric astigmatism was significantly lower in the cross-linked donor group at 3.67D (SD 1.8 D), vs. 8.43 D (SD 2.4 D) in the conventional keratoplasty group (p < 0.005). Mean wavefront astigmatism was also significantly reduced in the cross-linked donor group 4.71 D (SD 2.1) vs. 8.29D (SD 3.6) in the conventional keratoplasty group (p < 0.005). Mean RMS higher order aberration was significantly lower in the cross-linked donor group at 1.79 um (SD 0.98), vs. 3.05 um (SD 1.9) in the conventional keratoplasty group (P = 0.02). Qualitative analysis revealed less tissue distortion at the graft-host junction in the cross-linked group. Cross-linking of donor corneas prior to keratoplasty reduces intraoperative induced astigmatism and aberrations in an animal model. Further studies are indicated to evaluate the implications of this potential modification of keratoplasty surgery.

α-1-Antitrypsin (AAT)–modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

PubMed Central

Karoopongse, Ekapun; Lesnikova, Marina; Margineantu, Daciana; Welte, Tobias; Dinarello, Charles A.; Hockenbery, David; Janciauskiene, Sabina; Deeg, H. Joachim

2014-01-01

Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8+CD11c+CD205+ major histocompatibility complex class II+ dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4+CD25+FoxP3+ regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1+, CD49B+, CD122+, CD335+ NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis–high oxidative phosphorylation profile for NK1.1+ cells, CD4+CD25+FoxP3+ T cells, and CD11c+ DCs but not for effector T cells, suggesting a cell type–specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects. PMID:25224412

Corneal Tissue From Dry Eye Donors Leads to Enhanced Graft Rejection.

PubMed

Inomata, Takenori; Hua, Jing; Nakao, Takeshi; Shiang, Tina; Chiang, Homer; Amouzegar, Afsaneh; Dana, Reza

2018-01-01

To assess the effect of dry eye disease (DED) in graft donors on dendritic cell (DC) maturation, host T-cell sensitization, and corneal allograft rejection. Corneas of control (healthy donor) and DED mice (C57BL/6) were transplanted onto fully allogeneic naive BALB/c recipients (n = 10 mice/group). Long-term allograft survival was evaluated for 8 weeks. Corneas and draining lymph nodes (dLNs) were harvested at posttransplantation day 14 (n = 5 mice/group). The frequencies of MHCII CD11c DCs in the donor corneas and host dLNs and the frequencies of interferon (IFN)-γ and IL-17 CD4 T cells and Foxp3 expression by Tregs in host dLNs were investigated using flow cytometry. The enzyme-linked immunospot assay was used to assess host T-cell allosensitization through direct and indirect pathways (n = 3/group). Recipients of DED donor corneas showed significantly reduced graft survival (10%) compared with control mice (50% survival, P = 0.022), and had significantly increased frequencies of mature DCs in the grafted cornea (DED donor 44.0% ± 0.36% vs. healthy donor 35.4 ± 0.5%; P < 0.0001) and host dLNs (DED donor 25.1% ± 0.66% vs. healthy donor 13.7% ± 1.6%; P = 0.005). Frequencies of IFN-γ and IL-17 T cells were increased in the dLNs of recipients of DED corneas, whereas the expression (mean fluorescence intensity) of Foxp3 in Tregs was decreased significantly in these mice (DED donor 6004 ± 193 vs. healthy donor 6806 ± 81; P = 0.0002). Enzyme-linked immunospot analysis showed that the direct pathway of allosensitization was significantly amplified in recipients of grafts with DED (P = 0.0146). Our results indicate that DED in the donor is a significant risk factor for subsequent corneal allograft rejection.

Toxoplasma gondii Infection Is Associated with Mitochondrial Dysfunction in-Vitro

PubMed Central

Syn, Genevieve; Anderson, Denise; Blackwell, Jenefer M.; Jamieson, Sarra E.

2017-01-01

Upon invasion of host cells, the ubiquitous pathogen Toxoplasma gondii manipulates several host processes, including re-organization of host organelles, to create a replicative niche. Host mitochondrial association to T. gondii parasitophorous vacuoles is rapid and has roles in modulating host immune responses. Here gene expression profiling of T. gondii infected cells reveals enrichment of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial dysfunction 6 h post-infection. We identified 11 hub genes (HIF-1α, CASP8, FN1, POU5F1, CD44, ISG15, HNRNPA1, MDM2, RPL35, VHL, and NUPR1) and 10 predicted upstream regulators, including 4 endogenous regulators RICTOR, KDM5A, RB1, and D-glucose. We characterized a number of mitochondrial parameters in T. gondii infected human foreskin fibroblast cells over a 36 h time-course. In addition to the usual rapid recruitment and apparent enlargement of mitochondria around the parasitophorous vacuole we observed fragmented host mitochondria in infected cells, not linked to cellular apoptosis, from 24 h post-infection. An increase in mitochondrial superoxide levels in T. gondii infected cells was observed that required active parasite invasion and peaked at 30 h post-infection. Measurement of OXPHOS proteins showed decreased expression of Complex IV in infected cells at 24 h post-infection, followed by decreased expression of Complexes I and II at 36 h post-infection. No change occurred in Complex V. No difference in host mitochondrial membrane potential between infected and mock-infected cells was observed at any time. Our results show perturbation of host mitochondrial function following T. gondii infection that likely impacts on pathogenesis of disease. PMID:29312892

Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Sairafi, Darius; Stikvoort, Arwen; Gertow, Jens; Mattsson, Jonas; Uhlin, Michael

2016-01-01

Background . Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods . Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II-IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results . Samples from donors in the GVHD group contained significantly lower frequencies of naïve γδ T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naïve CD95 + T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69 + T-cells between the two patient groups, with the non-GVHD group showing higher frequencies of CD8 + and CD69 + T-cells. Conclusion . We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD.

Sustained Activation of Akt Elicits Mitochondrial Dysfunction to Block Plasmodium falciparum Infection in the Mosquito Host

PubMed Central

Drexler, Anna L.; Antonova-Koch, Yevgeniya; Sakaguchi, Danielle; Napoli, Eleonora; Wong, Sarah; Price, Mark S.; Eigenheer, Richard; Phinney, Brett S.; Pakpour, Nazzy; Pietri, Jose E.; Cheung, Kong; Georgis, Martha; Riehle, Michael

2013-01-01

The overexpression of activated, myristoylated Akt in the midgut of female transgenic Anopheles stephensi results in resistance to infection with the human malaria parasite Plasmodium falciparum but also decreased lifespan. In the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. Given that Akt signaling is essential for cell growth and survival, we hypothesized that sustained Akt activation in the mosquito midgut would alter the balance of critical pathways that control mitochondrial dynamics to enhance parasite killing at some cost to survivorship. Toxic reactive oxygen and nitrogen species (RNOS) rise to high levels in the midgut after blood feeding, due to a combination of high NO production and a decline in FOXO-dependent antioxidants. Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios. In addition, mitochondrial mass was lower and accompanied by the presence of stalled autophagosomes in the posterior midgut, a critical site for blood digestion and stem cell-mediated epithelial maintenance and repair, and by functional degradation of the epithelial barrier. By 18 d, the age at which An. stephensi would transmit P. falciparum to human hosts, mitochondrial dysfunction coupled to Akt-mediated repression of autophagy/mitophagy was more evident and midgut epithelial structure was markedly compromised. Inhibition of RNOS by co-feeding of the nitric-oxide synthase inhibitor L-NAME at infection abrogated Akt-dependent killing of P. falciparum that begins within 18 h of infection in 3–5 d old mosquitoes. Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan. Further, quality control of mitochondrial function in the

BLOODR: blood donor and requester mobile application

PubMed Central

Tatikonda, Vamsi Krishna

2017-01-01

Background With rapid increase in the usage of social networks sites across the world, there is also a steady increase in blood donation requests as being noticed in the number of posts on these sites such as Facebook and twitter seeking blood donors. Finding blood donor is a challenging issue in almost every country. There are some blood donor finder applications in the market such as Blood app by Red Cross and Blood Donor Finder application by Neologix. However, more reliable applications that meet the needs of users are prompted. Methods Several software technologies including languages and framework are used to develop our blood-donor web application known as BLOODR application. These technologies comprise Ruby programming language (simply known as Ruby) along with JavaScript and PostgreSQL for database are used. Ruby on Rails (simply known as Rails) is an open source Web framework that makes it possible to quickly and easily create data-based web applications. Results We show screenshots for the BLOODR application for different types of users including requester, donor, and administrator. Various features of the application are described and their needs of use are analyzed. If a patient needs a blood at a clinic, blood donors in vicinity can be contacted through using a clinic management service provided in this application. Registered donors will get notification for the blood requests only if their blood group is compatible with the requested blood type and in the same city/region. Then matching blood donors can go to the requesting clinic and donate. Conclusions BLOODR application provides a reliable platform to connect local blood donors with patients. BLOODR creates a communication channel through authenticated clinics whenever a patient needs blood donation. It is a useful tool to find compatible blood donors who can receive blood request posts in their local area. Clinics can use this web application to maintain the blood donation activity. Future

BLOODR: blood donor and requester mobile application.

PubMed

Tatikonda, Vamsi Krishna; El-Ocla, Hosam

2017-01-01

With rapid increase in the usage of social networks sites across the world, there is also a steady increase in blood donation requests as being noticed in the number of posts on these sites such as Facebook and twitter seeking blood donors. Finding blood donor is a challenging issue in almost every country. There are some blood donor finder applications in the market such as Blood app by Red Cross and Blood Donor Finder application by Neologix. However, more reliable applications that meet the needs of users are prompted. Several software technologies including languages and framework are used to develop our blood-donor web application known as BLOODR application. These technologies comprise Ruby programming language (simply known as Ruby) along with JavaScript and PostgreSQL for database are used. Ruby on Rails (simply known as Rails) is an open source Web framework that makes it possible to quickly and easily create data-based web applications. We show screenshots for the BLOODR application for different types of users including requester, donor, and administrator. Various features of the application are described and their needs of use are analyzed. If a patient needs a blood at a clinic, blood donors in vicinity can be contacted through using a clinic management service provided in this application. Registered donors will get notification for the blood requests only if their blood group is compatible with the requested blood type and in the same city/region. Then matching blood donors can go to the requesting clinic and donate. BLOODR application provides a reliable platform to connect local blood donors with patients. BLOODR creates a communication channel through authenticated clinics whenever a patient needs blood donation. It is a useful tool to find compatible blood donors who can receive blood request posts in their local area. Clinics can use this web application to maintain the blood donation activity. Future improvement of the BLOODR is explained.

Outcomes of Same-Size Host and Donor Trephine in Deep Anterior Lamellar Keratoplasty for Keratoconus.

PubMed

Huang, Ting; Ouyang, Chen; Hou, Chao; Wu, Qianni; Hu, Yunwei

2016-06-01

To evaluate the efficacy of the same-size host and donor trephine on reducing myopic refractive errors for patients with keratoconus when deep anterior lamellar keratoplasty (DALK) was used. Randomized controlled clinical trial. One hundred eighteen eyes of 118 patients with keratoconus were enrolled. Using stratified blocked randomization, eligible eyes were allocated into the same-size trephine group or oversize trephine group. Postoperative uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), spherical equivalent (SE), topography data, and eye axial length were compared at each year for 5 years. The same-size trephine group had comparable UCVA to the oversize trephine group through 5 years after surgery. But the former had better BSCVA than the latter after 3 years of follow-up. At 5 years, mean BSCVA was 0.17 ± 0.10 logMAR in the same-size trephine group vs 0.25 ± 0.13 logMAR in the oversize trephine group (P = .03). The same-size trephine group had lower topographic power than the oversize trephine group after 3 years of follow-up. At 5 years, mean topographic power was 45.30 ± 2.28 diopters (D) in the same-size trephine group vs 46.75 ± 2.60 D in the oversize trephine group (P = .006). Eye axial lengths at 5 years were longer than those preoperatively as well as at 1 year follow-up after surgery in both groups. The same-size host and donor trephine could reduce late-stage myopic refractive errors for the patients with keratoconus after DALK. The mechanism may be late-stage axial length increase with time. Copyright © 2016 Elsevier Inc. All rights reserved.

Mitochondrial NUDIX hydrolases: A metabolic link between NAD catabolism, GTP and mitochondrial dynamics.

PubMed

Long, Aaron; Klimova, Nina; Kristian, Tibor

2017-10-01

NAD + catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD + catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism. Mitochondrial and cytosolic NUDIX hydrolases (NUDT9α and NUDT9β) can affect mitochondrial and cellular AMP levels by hydrolyzing ADP- ribose (ADPr) and subsequently altering the levels of GTP and ATP. Poly (ADP-ribose) polymerase 1 (PARP1) is activated after DNA damage, which depletes NAD + pools and results in the PARylation of nuclear and mitochondrial proteins. In the mitochondria, ADP-ribosyl hydrolase-3 (ARH3) hydrolyzes PAR to ADPr, while NUDT9α metabolizes ADPr to AMP. Elevated AMP levels have been reported to reduce mitochondrial ATP production by inhibiting the adenine nucleotide translocase (ANT), allosterically activating AMPK by altering the cellular AMP: ATP ratio, and by depleting mitochondrial GTP pools by being phosphorylated by adenylate kinase 3 (AK3), which uses GTP as a phosphate donor. Recently, activated AMPK was reported to phosphorylate mitochondria fission factor (MFF), which increases Drp1 localization to the mitochondria and promotes mitochondrial fission. Moreover, the increased AK3 activity could deplete mitochondrial GTP pools and possibly inhibit normal activity of GTP-dependent fusion enzymes, thus altering mitochondrial dynamics. Published by Elsevier Ltd.

Is it ethical to invite compatible pairs to participate in exchange programmes?

PubMed

Fortin, Marie-Chantal

2013-12-01

Living kidney transplantation offers the best results for patients with end-stage renal disease (ESRD). This form of transplantation is no longer restricted to genetically or emotionally related donors, as shown by the acceptance of non-directed living anonymous donors, and the development of exchange programmes (EPs). EPs make it possible to perform living kidney transplantation among incompatible pairs, but while such programmes can help increase living organ donation, they can also create a degree of unfairness. Kidney transplant recipients in the O blood group are at a disadvantage when it comes to EPs because they can only receive organs from O donors, whereas O donors are universal donors. This poses a major challenge in terms of distributive justice and equity. A way to remedy this situation is through altruistic unbalanced paired kidney exchange (AUPKE), in which a compatible pair consisting of an O blood group donor and a non-O recipient is invited to participate in an EP. Although the AUPKE approach appears fairer for O recipients, it still raises ethical questions. How does this type of exchange affect the donor/recipient gift relationship? Should recipients in compatible pairs receive a 'better organ' than the one they would otherwise have received from their intended donor? Finally, what is the role of transplant teams in AUPKE? This article will examine the organisational and ethical challenges associated with EPs and AUPKE, and compare different EP policies in countries where such programmes exist.

Material Exchange in Photoreceptor Transplantation: Updating Our Understanding of Donor/Host Communication and the Future of Cell Engraftment Science.

PubMed

Nickerson, Philip E B; Ortin-Martinez, Arturo; Wallace, Valerie A

2018-01-01

Considerable research effort has been invested into the transplantation of mammalian photoreceptors into healthy and degenerating mouse eyes. Several platforms of rod and cone fluorescent reporting have been central to refining the isolation, purification and transplantation of photoreceptors. The tracking of engrafted cells, including identifying the position, morphology and degree of donor cell integration post-transplant is highly dependent on the use of fluorescent protein reporters. Improvements in imaging and analysis of transplant recipients have revealed that donor cell fluorescent reporters can transfer into host tissue though a process termed material exchange (ME). This recent discovery has chaperoned a new era of interpretation when reviewing the field's use of dissociated donor cell preparations, and has prompted scientists to re-examine how we use and interpret the information derived from fluorescence-based tracking tools. In this review, we describe the status of our understanding of ME in photoreceptor transplantation. In addition, we discuss the impact of this discovery on several aspects of historical rod and cone transplantation data, and provide insight into future standards and approaches to advance the field of cell engraftment.

Sibling Donor and Recipient Immune Modulation With Atorvastatin for the Prophylaxis of Acute Graft-Versus-Host Disease

PubMed Central

Hamadani, Mehdi; Gibson, Laura F.; Remick, Scot C.; Wen, Sijin; Petros, William; Tse, William; Brundage, Kathleen M.; Vos, Jeffrey A.; Cumpston, Aaron; Bunner, Pamela; Craig, Michael D.

2013-01-01

Purpose Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis. Patients and Methods We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short-course methotrexate, and atorvastatin (40 mg per day orally). Results Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06). Conclusion A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD. PMID:24166529

Investigating Climate Compatible Development Outcomes and their Implications for Distributive Justice: Evidence from Malawi

NASA Astrophysics Data System (ADS)

Wood, Benjamin T.; Quinn, Claire H.; Stringer, Lindsay C.; Dougill, Andrew J.

2017-09-01

Governments and donors are investing in climate compatible development in order to reduce climate and development vulnerabilities. However, the rate at which climate compatible development is being operationalised has outpaced academic enquiry into the concept. Interventions aiming to achieve climate compatible development "wins" (for development, mitigation, adaptation) can also create negative side-effects. Moreover, benefits and negative side-effects may differ across time and space and have diverse consequences for individuals and groups. Assessments of the full range of outcomes created by climate compatible development projects and their implications for distributive justice are scarce. This article develops a framework using a systematic literature review that enables holistic climate compatible development outcome evaluation over seven parameters identified. Thereafter, we explore the outcomes of two donor-funded projects that pursue climate compatible development triple-wins in Malawi using this framework. Household surveys, semi-structured interviews and documentary material are analysed. Results reveal that uneven outcomes are experienced between stakeholder groups and change over time. Although climate compatible development triple-wins can be achieved through projects, they do not represent the full range of outcomes. Ecosystem—and community-based activities are becoming popularised as approaches for achieving climate compatible development goals. However, findings suggest that a strengthened evidence base is required to ensure that these approaches are able to meet climate compatible development goals and further distributive justice.

An Obvious Improvement in the Performance of Ternary Organic Solar Cells with "Guest" Donor Present at the "Host" Donor/Acceptor Interface.

PubMed

Bi, Peng-Qing; Wu, Bo; Zheng, Fei; Xu, Wei-Long; Yang, Xiao-Yu; Feng, Lin; Zhu, Furong; Hao, Xiao-Tao

2016-09-07

A small-molecule material, 7,7-(4,4-bis(2-ethylhexyl)-4H-silolo[3,2-b:4,5-b']dithiophene-2,6-diyl)bis(6-fluoro-4-(5'-hexyl-[2,2'-bithiophen]-5-yl)benzo-[c] [1,2,5]thiadiazole) (p-DTS(FBTTH2)2), was used to modify the morphology and electron-transport properties of the polymer blend of poly(3-hexythiophene) (P3HT) and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) bulk heterojunctions. As a result, a 24% increase in the power-conversion efficiency (PCE) of the p-DTS(FBTTH2)2:P3HT:PC71BM ternary organic solar cells (OSCs) is obtained. The improvement in the performance of OSCs is attributed to the constructive energy cascade path in the ternary system that benefits an efficient Förster resonance energy/charge transfer process between P3HT and p-DTS(FBTTH2)2, thereby improving photocurrent generation. It is shown that p-DTS(FBTTH2)2 molecules engage themselves at the P3HT/PC71BM interface. A combination of absorption enhancement, efficient energy transfer process, and ordered nanomorphology in the ternary system favors exciton dissociation and charge transportation in the polymer bulk heterojunction. The finding of this work reveals that distribution of the appropriate "guest" donor at the "host" donor/acceptor interface is an effective approach for attaining high-performance OSCs.

Significance of Ethnicity in the Risk of Acute Graft-versus-Host Disease and Leukemia Relapse after Unrelated Donor Hematopoietic Stem Cell Transplantation

PubMed Central

Morishima, Yasuo; Kawase, Takakazu; Malkki, Mari; Morishima, Satoko; Spellman, Stephen; Kashiwase, Koichi; Kato, Shunichi; Cesbron, Anne; Tiercy, Jean-Marie; Senitzer, David; Velardi, Andrea; Petersdorf, Effie W.

2014-01-01

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient/donor pairs from the International Histocompatibility Working Group in HCT met the following three criteria: (1) HLA-A, B, C, DRB1 and DQB1 allele matched donor; (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Post-transplant risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, Caucasian, African American, Hispanic, and Native American patients transplanted from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II-IV and 15.3% grades III-IV; non-Japanese Asian patients: 42.1% grades II-IV and 15.7% grades III-IV) compared to Caucasian patients (56.5% grades II-IV and 22.6% grades III-IV) (p< 0.001). The hazard ratio (HR) of acute GVHD for Caucasian patients was significantly higher than for Japanese patients. Unexpectedly, the HR of leukemia relapse in Caucasian patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background. PMID:23747601

Entire nucleotide sequences of Gossypium raimondii and G. arboreum mitochondrial genomes revealed A-genome species as cytoplasmic donor of the allotetraploid species.

PubMed

Chen, Z; Nie, H; Grover, C E; Wang, Y; Li, P; Wang, M; Pei, H; Zhao, Y; Li, S; Wendel, J F; Hua, J

2017-05-01

Cotton (Gossypium spp.) is commonly grouped into eight diploid genomic groups, designated A-G and K, and an allotetraploid genomic group, AD. Gossypium raimondii (D 5 ) and G. arboreum (A 2 ) are the putative contributors to the progenitor of G. hirsutum (AD 1 ), the economically important fibre-producing cotton species. Mitochondrial DNA from week-old etiolated seedlings was extracted from isolated organelles using discontinuous sucrose density gradient method. Mitochondrial genomes were sequenced, assembled, annotated and analysed in orderly. Gossypium raimondii (D 5 ) and G. arboreum (A 2 ) mitochondrial genomes were provided in this study. The mitochondrial genomes of two diploid species harboured circular genome of 643,914 bp (D 5 ) and 687,482 bp (A 2 ), respectively. They differ in size and number of repeat sequences, both contain illuminating triplicate sequences with 7317 and 10,246 bp, respectively, demonstrating dynamic difference and rearranged genome organisations. Comparing the D 5 and A 2 mitogenomes with mitogenomes of tetraploid Gossypium species (AD 1 , G. hirsutum; AD 2 , G. barbadense), a shared 11 kbp fragment loss was detected in allotetraploid species, three regions shared by G. arboreum (A 2 ), G. hirsutum (AD 1 ) and G. barbadense (AD 2 ), while eight regions were specific to G. raimondii (D 5 ). The presence/absence variations and gene-based phylogeny supported that A-genome is a cytoplasmic donor to the progenitor of allotetraploid species G. hirsutum and G. barbadense. The results present structure variations and phylogeny of Gossypium mitochondrial genome evolution. © 2017 The Authors. Plant Biology published by John Wiley & Sons Ltd on behalf of German Botanical Society, Royal Dutch Botanical Society.

Nuclear and mitochondrial rDNA variability in Crinipellis perniciosa from different geographic origins and hosts.

PubMed

de Arruda, Maricília C C; Ferreira, Marisa A S V; Miller, Robert N G; Resende, Mário Lúcio V; Felipe, Maria Sueli S

2003-01-01

Genetic variability in Crinipellis perniciosa, the causal organism of witches' broom disease in Theobroma cacao, was determined in strains originating from T. cacao and other susceptible host species Heteropterys acutifolia and Solanum lycocarpum in Brazil, in order to clarify host specificity and geographical variability. RFLP analysis of the ribosomal DNA ITS regions (rDNA ITS), and the mitochondrial DNA small subunit ribosomal DNA gene (mtDNA SSU rDNA) did not reveal any genetic variability in 120 tested strains, possibly serving only as species level markers. Genetic variability was observed in the ribosomal DNA IGS spacer region, in terms of IGS size, RFLPs and sequence data. Phylogenetic analyses (using CLUSTAL W, PHYLIP and TREEVIEW) indicated considerable differences between C. perniciosa strains from T. cacao and those from H. acutifolia (85-86%) and S. lycocarpum (95-96%). Sequence differences also indicated that C. perniciosa from T. cacao in Bahia is less variable (98%) when compared to the pathogen on T. cacao in Amazonas (97-98%), perhaps reflecting a recent introduction to T. cacao in Bahia.

Material Exchange in Photoreceptor Transplantation: Updating Our Understanding of Donor/Host Communication and the Future of Cell Engraftment Science

PubMed Central

Nickerson, Philip E. B.; Ortin-Martinez, Arturo; Wallace, Valerie A.

2018-01-01

Considerable research effort has been invested into the transplantation of mammalian photoreceptors into healthy and degenerating mouse eyes. Several platforms of rod and cone fluorescent reporting have been central to refining the isolation, purification and transplantation of photoreceptors. The tracking of engrafted cells, including identifying the position, morphology and degree of donor cell integration post-transplant is highly dependent on the use of fluorescent protein reporters. Improvements in imaging and analysis of transplant recipients have revealed that donor cell fluorescent reporters can transfer into host tissue though a process termed material exchange (ME). This recent discovery has chaperoned a new era of interpretation when reviewing the field’s use of dissociated donor cell preparations, and has prompted scientists to re-examine how we use and interpret the information derived from fluorescence-based tracking tools. In this review, we describe the status of our understanding of ME in photoreceptor transplantation. In addition, we discuss the impact of this discovery on several aspects of historical rod and cone transplantation data, and provide insight into future standards and approaches to advance the field of cell engraftment. PMID:29559897

Allocating Deceased Donor Kidneys to Candidates with High Panel-Reactive Antibodies.

PubMed

Gebel, Howard M; Kasiske, Bertram L; Gustafson, Sally K; Pyke, Joshua; Shteyn, Eugene; Israni, Ajay K; Bray, Robert A; Snyder, Jon J; Friedewald, John J; Segev, Dorry L

2016-03-07

In December of 2014, the Organ Procurement and Transplant Network implemented a new Kidney Allocation System (KAS) for deceased donor transplant, with increased priority for highly sensitized candidates (calculated panel-reactive antibody [cPRA] >99%). We used a modified version of the new KAS to address issues of access and equity for these candidates. In a simulation, 10,988 deceased donor kidneys transplanted into waitlisted recipients in 2010 were instead allocated to candidates with cPRA≥80% (n=18,004). Each candidate's unacceptable donor HLA antigens had been entered into the allocation system by the transplant center. In simulated match runs, kidneys were allocated sequentially to adult ABO identical or permissible candidates with cPRA 100%, 99%, 98%, etc. to 80%. Allocations were restricted to donor/recipient pairs with negative virtual crossmatches. The simulation indicated that 2111 of 10,988 kidneys (19.2%) would have been allocated to patients with cPRA 100% versus 74 of 10,988 (0.7%) that were actually transplanted. Of cPRA 100% candidates, 74% were predicted to be compatible with an average of six deceased donors; the remaining 26% seemed to be incompatible with every deceased donor organ that entered the system. Of kidneys actually allocated to cPRA 100% candidates in 2010, 66% (49 of 74) were six-antigen HLA matched/zero-antigen mismatched (HLA-A, -B, and -DR) with their recipients versus only 11% (237 of 2111) in the simulation. The simulation predicted that 10,356 of 14,433 (72%) candidates with cPRA 90%-100% could be allocated an organ compared with 7.3% who actually underwent transplant. Data in this simulation are consistent with early results of the new KAS; specifically, nearly 20% of deceased donor kidneys were (virtually) compatible with cPRA 100% candidates. Although most of these candidates were predicted to be compatible with multiple donors, approximately one-quarter are unlikely to receive a single offer. Copyright © 2016 by the

Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation.

PubMed

Tandra, Anand; Covut, Fahrettin; Cooper, Brenda; Creger, Richard; Brister, Lauren; McQuigg, Bernadette; Caimi, Paolo; Malek, Ehsan; Tomlinson, Ben; Lazarus, Hillard M; Otegbeye, Folashade; Kolk, Merle; de Lima, Marcos; Metheny, Leland

2017-12-04

Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD.

Expanding the live kidney donor pool: ethical considerations regarding altruistic donors, paired and pooled programs.

PubMed

Patel, Shaneel Rajendra; Chadha, Priyanka; Papalois, Vassilios

2011-06-01

In renal transplant, there is a well-known deficiency in organ supply relative to demand. Live donation provides superior results when compared with deceased donation including a better rate of graft success and fewer immunologic complications. This deficiency in organs leads to significant morbidity and mortality rates. Alternative avenues have been extensively explored that may expand the live donor pool. They include altruistic donation as well as paired and pooled exchange programs. Altruistic donation is a truly selfless act from a donor unknown to the recipient. Kidney paired donation involves 2 incompatible donor-recipient pairs swapping donors to produce compatibility. Pooled donation involves at least 2 pairs, and can take the form of domino chains in which altruistic input sets up a chain of transplants, in which each recipient's incompatible donor makes a donation for the next recipient. Despite application of these various methods, there lie extensive ethical issues surrounding them. Misconceptions frequently occur; for instance, the perceived benefit that donating an organ to a loved one is greater for a related donor than for an altruistic one. Additionally, it is frequently believed that immunologic incompatibility offers coerced donors liberation from surgery, and that overcoming these barriers by introducing exchange programs provides vulnerable donors less protection. This article explores these and other complex ethical issues surrounding the various methods of expanding the donor pool. The authors offer opinions that challenge the ethical issues and attempt to overcome those views that hinder progress in the field.

Posttransplant lymphoproliferative disorder in a kidney-pancreas transplanted recipient: simultaneous development of clonal lymphoid B-cell proliferation of host and donor origin.

PubMed

Heyny-von Haussen, Roland; Klingel, Karin; Riegel, Werner; Kandolf, Reinhard; Mall, Gerhard

2006-07-01

Posttransplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that develop as a consequence of immunosuppression after solid organ or bone marrow transplantation and are mostly associated with an Epstein-Barr virus infection. The morphologic categories include different types of benign and malignant lymphoid proliferations. The majority of PTLDs is of B-cell origin with clonal rearrangements of the immunoglobulin genes. The PTLDs in solid organ transplants are reported to be either of host or of donor origin. Donor-related PTLDs frequently involve the allograft. We report a case of a 52-year-old woman recipient who developed simultaneously PTLDs in several organs 5 month after receiving a sex-mismatched renal and pancreas allograft. Immunosuppression regimen comprised antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. Pathologic features appeared as polymorphic PTLDs in the renal allograft, liver, and central nervous system (CNS). Molecular genetic studies revealed different clonal immunoglobulin heavy chain gene rearrangements in all 3 organs as determined by polymerase chain reaction (PCR). Epstein-Barr virus were detected by nested PCR and in situ hybridization in all 3 tumors. The PTLDs in liver and CNS were of host origin whereas the allograft kidney PTLD was found to originate from the male donor as shown by the simultaneous detection of female and male sex chromosomes by PCR and fluorescence in situ hybridization. The recipient died in consequence of the CNS involvement, after intracerebral hemorrhage with uncal and tonsillar herniation.

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

PubMed

Cherry, Anne D; Piantadosi, Claude A

2015-04-20

Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Donor cornea preparation in partial big bubble deep anterior lamellar keratoplasty.

PubMed

Lim, Li; Lim, Samuel Wen Yan

2014-01-01

The purpose of this paper is to describe a technique of donor cornea preparation to ensure good graft-host apposition in incomplete big bubble deep anterior lamellar keratoplasty. Following a partial-thickness trephination, manual dissection and excision of corneal stroma was performed. Anwar's big-bubble technique involving a deep stromal air injection was then initiated. However, the big bubble could not extend to the trephination edge and the peripheral residual corneal stroma could not be removed. Donor cornea preparation involving trimming of the posterior lip of the corneal button was then performed and good graft-host apposition was obtained without graft over-ride. We performed peripheral donor cornea trimming prior to allograft placement in order to ensure good graft-host apposition. Postoperatively, best-corrected visual acuity in both eyes was 6/7.5. Donor cornea preparation involving trimming of the posterior lip of the corneal button is a useful technique in instances where the big bubble does not extend to the trephination edge and ensures good graft-host apposition.

Mitochondrial Replacement Therapy in Reproductive Medicine

PubMed Central

Wolf, Don P.; Mitalipov, Nargiz; Mitalipov, Shoukhrat

2015-01-01

Mitochondrial dysfunction is implicated in disease and in age-related infertility. Mitochondrial replacement therapies (MRT) in oocytes or zygotes such as pronuclear (PNT), spindle (ST) or polar body (PBT) transfer could prevent second generation transmission of mitochondrial DNA (mtDNA) defects. PNT, associated with high levels of mtDNA carryover in mice but low levels in human embryos, carries ethical issues secondary to donor embryo destruction. ST, developed in primates, supports normal development to adults and low mtDNA carryover. PBT in mice, coupled with PN or ST, may increase the yield of reconstructed embryos with low mtDNA carryover. MRT also offers replacement of the deficient cytoplasm in oocytes from older patients, with the expectation of high pregnancy rates following in vitro fertilization. PMID:25573721

Mitochondrial Evolution

PubMed Central

Gray, Michael W.

2012-01-01

Viewed through the lens of the genome it contains, the mitochondrion is of unquestioned bacterial ancestry, originating from within the bacterial phylum α-Proteobacteria (Alphaproteobacteria). Accordingly, the endosymbiont hypothesis—the idea that the mitochondrion evolved from a bacterial progenitor via symbiosis within an essentially eukaryotic host cell—has assumed the status of a theory. Yet mitochondrial genome evolution has taken radically different pathways in diverse eukaryotic lineages, and the organelle itself is increasingly viewed as a genetic and functional mosaic, with the bulk of the mitochondrial proteome having an evolutionary origin outside Alphaproteobacteria. New data continue to reshape our views regarding mitochondrial evolution, particularly raising the question of whether the mitochondrion originated after the eukaryotic cell arose, as assumed in the classical endosymbiont hypothesis, or whether this organelle had its beginning at the same time as the cell containing it. PMID:22952398

Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma gondii via Neofunctionalization of a Gene Duplicate

PubMed Central

Adomako-Ankomah, Yaw; English, Elizabeth D.; Danielson, Jeffrey J.; Pernas, Lena F.; Parker, Michelle L.; Boulanger, Martin J.; Dubey, Jitender P.; Boyle, Jon P.

2016-01-01

In Toxoplasma gondii, an intracellular parasite of humans and other animals, host mitochondrial association (HMA) is driven by a gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. However, the importance of MAF1 gene duplication in the evolution of HMA is not understood, nor is the impact of HMA on parasite biology. Here we used within- and between-species comparative analysis to determine that the MAF1 locus is duplicated in T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative, Neospora caninum. Using cross-species complementation, we determined that the MAF1 locus harbors multiple distinct paralogs that differ in their ability to mediate HMA, and that only T. gondii and H. hammondi harbor HMA+ paralogs. Additionally, we found that exogenous expression of an HMA+ paralog in T. gondii strains that do not normally exhibit HMA provides a competitive advantage over their wild-type counterparts during a mouse infection. These data indicate that HMA likely evolved by neofunctionalization of a duplicate MAF1 copy in the common ancestor of T. gondii and H. hammondi, and that the neofunctionalized gene duplicate is selectively advantageous. PMID:26920761

The Case for High Resolution Extended 6-Loci HLA Typing for Identifying Related Donors in the Indian Subcontinent.

PubMed

Agarwal, Rajat Kumar; Kumari, Ankita; Sedai, Amit; Parmar, Lalith; Dhanya, Rakesh; Faulkner, Lawrence

2017-09-01

Three-loci low-resolution (LR) or intermediate-resolution HLA typing is generally considered adequate in the related blood and marrow transplantation (BMT) context. However, a single high-resolution (HR) mismatch may have a similar adverse impact on BMT outcome as an LR one. We sought to determine the frequency of mismatches that may go undetected when standard typing (LR or 3-loci HR) is used compared with 6-loci HR typing for related donor compatibility testing, and to assess its impact on relevant BMT outcomes. We analyzed data from a total of 2554 6-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) HR sequence-based typing (full typing [FT]) from 754 patients, 1011 siblings, and 789 parents done at DKMS Germany (www.DKMS.de) between January 1, 2014, and June 21, 2016. We also studied 38 cases in which the family had undergone 3-loci HLA typing (standard typing [ST]). Patients were from India (70%), Pakistan (22%), and Sri Lanka (8%). The IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) was used to tease out nonpermissive DPB1 mismatches. HLA disparity-related outcomes, such as rejection and graft-versus-host disease (GVHD) were assessed in a retrospective matched-pair cohort of 50 patients (25 with ST and 25 with FT) who underwent BMT for severe thalassemia from compatible related donors. We found fully matched (either 12/12 HR matches or with a single permissive DPB1 mismatch) related donors for 285 patients (38%). Of these donors, 89% were siblings and 11% were parents. The likelihood of matching on an individual locus on LR but not on HR was found to be 5%. A total of 9 donors (3%; 7 siblings and 2 parents) who would have been considered a full match by HR typing on A, B, and DRB1 alone were not a match by extended 6-loci HR typing. Five of these 9 donors had a mismatch on C or DQB1, and 4 had a nonpermissive DPB1 mismatch. In this group, 5 donors (56%) belonged to a consanguineous family, in 2 donors (22%) there was no reported consanguinity, and in 2 donors (22

Lung Transplantation From Donors After Previous Cardiac Surgery: Ideal Graft in Marginal Donor?

PubMed

Palleschi, A; Mendogni, P; Tosi, D; Montoli, M; Carrinola, R; Mariolo, A V; Briganti, F; Nosotti, M

2017-05-01

Lung transplantation is a limited by donor pool shortage. Despite the efforts to extend the graft acceptability with recurrent donor criteria reformulations, previous cardiothoracic surgery is still considered a contraindication. A donor who underwent cardiac surgery could potentially provide an ideal lung but high intraoperative risks and intrinsic technical challenges are expected during the graft harvesting. The purpose of this study is to present our dedicated protocol and four clinical cases of successful lung procurements from donors who had a previous major cardiac surgery. One donor had ascending aortic root (AAR) substitution, another had mitral valve substitution, and two had coronary artery bypass surgery. The others' eligibility criteria for organ allocation, such as ABO compatibility, PaO 2 /FiO 2 ratio, absence of aspiration, or sepsis were respected. In one of the cases with previous coronary bypass grafting, the donor had a veno-arterial extracorporeal membrane oxygenation support. Consequently, the grafts required an ex vivo lung perfusion evaluation. We report the technical details of procurement and postoperative courses of recipients. All procurements were uneventful, without lung damage or waste of abdominal organs related to catastrophic intraoperative events. All recipients had a successful clinical outcome. We believe that successful transplantation is achievable even in a complicated setting, such as cases involving donors with previous cardiac surgery frequently are. Facing lung donor shortage, we strongly support any effort to avoid the loss of possible acceptable lungs. In particular, previous major cardiac surgery does not strictly imply a poor quality of lungs as well as unsustainable graft procurement. Copyright © 2017 Elsevier Inc. All rights reserved.

The mitochondrial genome of Toxocara canis.

PubMed

Jex, Aaron R; Waeschenbach, Andrea; Littlewood, D Timothy J; Hu, Min; Gasser, Robin B

2008-08-06

Toxocara canis (Ascaridida: Nematoda), which parasitizes (at the adult stage) the small intestine of canids, can be transmitted to a range of other mammals, including humans, and can cause the disease toxocariasis. Despite its significance as a pathogen, the genetics, epidemiology and biology of this parasite remain poorly understood. In addition, the zoonotic potential of related species of Toxocara, such as T. cati and T. malaysiensis, is not well known. Mitochondrial DNA is known to provide genetic markers for investigations in these areas, but complete mitochondrial genomic data have been lacking for T. canis and its congeners. In the present study, the mitochondrial genome of T. canis was amplified by long-range polymerase chain reaction (long PCR) and sequenced using a primer-walking strategy. This circular mitochondrial genome was 14162 bp and contained 12 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes consistent for secementean nematodes, including Ascaris suum and Anisakis simplex (Ascaridida). The mitochondrial genome of T. canis provides genetic markers for studies into the systematics, population genetics and epidemiology of this zoonotic parasite and its congeners. Such markers can now be used in prospecting for cryptic species and for exploring host specificity and zoonotic potential, thus underpinning the prevention and control of toxocariasis in humans and other hosts.

The Mitochondrial Genome of Toxocara canis

PubMed Central

Littlewood, D. Timothy J.; Hu, Min; Gasser, Robin B.

2008-01-01

Toxocara canis (Ascaridida: Nematoda), which parasitizes (at the adult stage) the small intestine of canids, can be transmitted to a range of other mammals, including humans, and can cause the disease toxocariasis. Despite its significance as a pathogen, the genetics, epidemiology and biology of this parasite remain poorly understood. In addition, the zoonotic potential of related species of Toxocara, such as T. cati and T. malaysiensis, is not well known. Mitochondrial DNA is known to provide genetic markers for investigations in these areas, but complete mitochondrial genomic data have been lacking for T. canis and its congeners. In the present study, the mitochondrial genome of T. canis was amplified by long-range polymerase chain reaction (long PCR) and sequenced using a primer-walking strategy. This circular mitochondrial genome was 14162 bp and contained 12 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes consistent for secernentean nematodes, including Ascaris suum and Anisakis simplex (Ascaridida). The mitochondrial genome of T. canis provides genetic markers for studies into the systematics, population genetics and epidemiology of this zoonotic parasite and its congeners. Such markers can now be used in prospecting for cryptic species and for exploring host specificity and zoonotic potential, thus underpinning the prevention and control of toxocariasis in humans and other hosts. PMID:18682828

Dual RNA-Sequencing of Eucalyptus nitens during Phytophthora cinnamomi Challenge Reveals Pathogen and Host Factors Influencing Compatibility

PubMed Central

Meyer, Febé E.; Shuey, Louise S.; Naidoo, Sitha; Mamni, Thandekile; Berger, Dave K.; Myburg, Alexander A.; van den Berg, Noëlani; Naidoo, Sanushka

2016-01-01

Damage caused by Phytophthora cinnamomi Rands remains an important concern on forest tree species. The pathogen causes root and collar rot, stem cankers, and dieback of various economically important Eucalyptus spp. In South Africa, susceptible cold tolerant Eucalyptus plantations have been affected by various Phytophthora spp. with P. cinnamomi considered one of the most virulent. The molecular basis of this compatible interaction is poorly understood. In this study, susceptible Eucalyptus nitens plants were stem inoculated with P. cinnamomi and tissue was harvested five days post inoculation. Dual RNA-sequencing, a technique which allows the concurrent detection of both pathogen and host transcripts during infection, was performed. Approximately 1% of the reads mapped to the draft genome of P. cinnamomi while 78% of the reads mapped to the Eucalyptus grandis genome. The highest expressed P. cinnamomi gene in planta was a putative crinkler effector (CRN1). Phylogenetic analysis indicated the high similarity of this P. cinnamomi CRN1 to that of Phytophthora infestans. Some CRN effectors are known to target host nuclei to suppress defense. In the host, over 1400 genes were significantly differentially expressed in comparison to mock inoculated trees, including suites of pathogenesis related (PR) genes. In particular, a PR-9 peroxidase gene with a high similarity to a Carica papaya PR-9 ortholog previously shown to be suppressed upon infection by Phytophthora palmivora was down-regulated two-fold. This PR-9 gene may represent a cross-species effector target during P. cinnamomi infection. This study identified pathogenicity factors, potential manipulation targets, and attempted host defense mechanisms activated by E. nitens that contributed to the susceptible outcome of the interaction. PMID:26973660

The Course of Colonization of Two Different Vitis Genotypes by Plasmopara viticola Indicates Compatible and Incompatible Host-Pathogen Interactions.

PubMed

Unger, Sabine; Büche, Claudia; Boso, Susana; Kassemeyer, Hanns-Heinz

2007-07-01

ABSTRACT The course of colonization of leaf mesophyll by the causal agent of grapevine downy mildew, Plasmopara viticola, in a susceptible and a resistant grapevine genotype was examined in order to characterize the development of the pathogen in compatible and incompatible host-pathogen interactions. Within a few hours after inoculation, the pathogen was established in the susceptible Vitis vinifera cv. Müller-Thurgau and formed primary hyphae with a first haustorium. No further development occurred in the following 10 to 18 h. The next step, in which the hyphae grew and branched to colonize the intercellular space of the host tissue, was observed 1.5 days after inoculation. After 3 days, the intercostal fields were entirely filled with mycelium and sporulation was abundant under favorable environmental conditions. The first infection steps were essentially the same in the resistant V. rupestris. However, the invasive growth of P. viticola was delayed, and further development ceased before the intercostal fields were filled with mycelium.

Activity of xyloglucan endotransglucosylases/hydrolases suggests a role during host invasion by the parasitic plant Cuscuta reflexa

PubMed Central

2017-01-01

The parasitic vines of the genus Cuscuta form haustoria that grow into other plants and connect with their vascular system, thus allowing the parasite to feed on its host. A major obstacle that meets the infection organ as it penetrates the host tissue is the rigid plant cell wall. In the present study, we examined the activity of xyloglucan endotransglucosylases/hydrolases (XTHs) during the host-invasive growth of the haustorium. The level of xyloglucan endotransglucosylation (XET) activity was found to peak at the penetrating stage of Cuscuta reflexa on its host Pelargonium zonale. In vivo colocalization of XET activity and donor substrate demonstrated XET activity at the border between host and parasite. A test for secretion of XET-active enzymes from haustoria of C. reflexa corroborated this and further indicated that the xyloglucan-modifying enzymes originated from the parasite. A known inhibitor of XET, Coomassie Brilliant Blue R250, was shown to reduce the level of XET in penetrating haustoria of C. reflexa. Moreover, the coating of P. zonale petioles with the inhibitor compound lowered the number of successful haustorial invasions of this otherwise compatible host plant. The presented data indicate that the activity of Cuscuta XTHs at the host-parasite interface is essential to penetration of host plant tissue. PMID:28448560

Activity of xyloglucan endotransglucosylases/hydrolases suggests a role during host invasion by the parasitic plant Cuscuta reflexa.

PubMed

Olsen, Stian; Krause, Kirsten

2017-01-01

The parasitic vines of the genus Cuscuta form haustoria that grow into other plants and connect with their vascular system, thus allowing the parasite to feed on its host. A major obstacle that meets the infection organ as it penetrates the host tissue is the rigid plant cell wall. In the present study, we examined the activity of xyloglucan endotransglucosylases/hydrolases (XTHs) during the host-invasive growth of the haustorium. The level of xyloglucan endotransglucosylation (XET) activity was found to peak at the penetrating stage of Cuscuta reflexa on its host Pelargonium zonale. In vivo colocalization of XET activity and donor substrate demonstrated XET activity at the border between host and parasite. A test for secretion of XET-active enzymes from haustoria of C. reflexa corroborated this and further indicated that the xyloglucan-modifying enzymes originated from the parasite. A known inhibitor of XET, Coomassie Brilliant Blue R250, was shown to reduce the level of XET in penetrating haustoria of C. reflexa. Moreover, the coating of P. zonale petioles with the inhibitor compound lowered the number of successful haustorial invasions of this otherwise compatible host plant. The presented data indicate that the activity of Cuscuta XTHs at the host-parasite interface is essential to penetration of host plant tissue.

Alternative Donor Graft Sources for Adults with Hematologic Malignancies: A Donor for All Patients in 2017!

PubMed

Kindwall-Keller, Tamila L; Ballen, Karen K

2017-09-01

Hematopoietic stem cell transplant (HSCT) is potentially curative for a wide variety of malignant diseases, including acute and leukemias, lymphoma, and myelodysplasia. Choice of a stem cell donor is dependent on donor availability, donor compatibility and health, recipient disease type, and recipient condition. Current sources of stem cell donation for HSCT are matched sibling donors (MSDs), matched unrelated donors (MUDs), 1-antigen mismatched unrelated donors (MMUDs), haploidentical donors (haplo), and umbilical cord blood (UCB) units. Historically, preferred donors for HSCT have been human leukocyte antigen (HLA)-matched sibling donors; however, only about 30% of U.S. patients will have a MSD available. The majority of patients referred for HSCT will require an alternative donor graft: MUD, MMUD, UCB, or haplo. The likelihood of finding a MUD varies depending on the ethnicity of the recipient. White Caucasians of European descent have the greatest chance of finding a MUD. Chances of finding a MUD are significantly less for African-American or Hispanic recipients due to HLA polymorphisms. Therefore, MMUD, UCB, and haplo donor graft sources expand the donor pool for recipients who do not have a MSD or MUD available. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic HSCT has a potential donor in 2017. All transplant-eligible patients with hematologic malignancies should be evaluated by a transplant center to determine if HSCT is a viable treatment option for their underlying disease process. The goal of this review is to increase the awareness of oncology practitioners to the availability of alternative donor stem cell transplants for patients with hematologic malignancies. Despite new agents, stem cell transplant remains the only curative therapy for many patients with acute and chronic leukemia, myelodysplasia, and lymphoma. Given the variety of different donor stem cell sources available today

Impact of ABO-Identical vs ABO-Compatible Nonidentical Plasma Transfusion in Trauma Patients

DTIC Science & Technology

2010-09-01

and B patients in turn could receive AB donor plasma. Few studies have examined the im- pact of compatible nonidentical plasma transfusion . In platelet ... transfusion ,19 the administration of compatible nonidenti- cal platelets to patients undergoing coro- nary artery bypass grafting or valve re...significantly different (in boldface) and for the volume of packed red blood cells, plasma, platelets , cryoprecipitate, and factor VIIa transfused . cBecause

[Kidney allotransplantation from the AB0-incompatible donors].

PubMed

Goriaĭnov, V A; Kaabak, M M; Babenko, N N; Shishlo, L A; Morozova, M M; Ragimov, A A; Dazhkova, N G; Salimov, E L

2013-01-01

The experience of 28 kidney allotransplantations from the AB0-incompatible donors was analyzed. The comparative group consisted of 38 patients, who received the AB0-compatible organ. The results were assessed using the following parameters: renal function, morphology of the biopsy samples of the transplanted kidney and actuary survival of the recipients with functioning transplants in both groups. The comparative analysis showed no significant difference between the two groups, giving the right to consider the kidney allotransplantation from the AB0-incompatible donors safe and effective.

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

PubMed Central

Berro, Mariano; Mayor, Neema P.; Maldonado-Torres, Hazael; Cooke, Louise; Kusminsky, Gustavo; Marsh, Steven G.E.; Madrigal, J. Alejandro; Shaw, Bronwen E.

2010-01-01

Background Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. Design and Methods We investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor β1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors. Results Patients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients’ genotype, the incidences of both overall and grades II-IV acute graft-versus-host disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs. Conclusions We conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors. PMID:19713222

Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma gondii via Neofunctionalization of a Gene Duplicate.

PubMed

Adomako-Ankomah, Yaw; English, Elizabeth D; Danielson, Jeffrey J; Pernas, Lena F; Parker, Michelle L; Boulanger, Martin J; Dubey, Jitender P; Boyle, Jon P

2016-05-01

In Toxoplasma gondii, an intracellular parasite of humans and other animals, host mitochondrial association (HMA) is driven by a gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. However, the importance of MAF1 gene duplication in the evolution of HMA is not understood, nor is the impact of HMA on parasite biology. Here we used within- and between-species comparative analysis to determine that the MAF1 locus is duplicated in T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative, Neospora caninum Using cross-species complementation, we determined that the MAF1 locus harbors multiple distinct paralogs that differ in their ability to mediate HMA, and that only T. gondii and H. hammondi harbor HMA(+) paralogs. Additionally, we found that exogenous expression of an HMA(+) paralog in T. gondii strains that do not normally exhibit HMA provides a competitive advantage over their wild-type counterparts during a mouse infection. These data indicate that HMA likely evolved by neofunctionalization of a duplicate MAF1 copy in the common ancestor of T. gondii and H. hammondi, and that the neofunctionalized gene duplicate is selectively advantageous. Copyright © 2016 by the Genetics Society of America.

The Complete Moss Mitochondrial Genome in the Angiosperm Amborella Is a Chimera Derived from Two Moss Whole-Genome Transfers.

PubMed

Taylor, Z Nathan; Rice, Danny W; Palmer, Jeffrey D

2015-01-01

Sequencing of the 4-Mb mitochondrial genome of the angiosperm Amborella trichopoda has shown that it contains unprecedented amounts of foreign mitochondrial DNA, including four blocks of sequences that together correspond almost perfectly to one entire moss mitochondrial genome. This implies whole-genome transfer from a single moss donor but conflicts with phylogenetic results from an earlier, PCR-based study that suggested three different moss donors to Amborella. To resolve this conflict, we conducted an expanded set of phylogenetic analyses with respect to both moss lineages and mitochondrial loci. The moss DNA in Amborella was consistently placed in either of two positions, depending on the locus analyzed, as sister to the Ptychomniales or within the Hookeriales. This agrees with two of the three previously suggested donors, whereas the third is no longer supported. These results, combined with synteny analyses and other considerations, lead us to favor a model involving two successive moss-to-Amborella whole-genome transfers, followed by recombination that produced a single intact and chimeric moss mitochondrial genome integrated in the Amborella mitochondrial genome. Eight subsequent recombination events account for the state of fragmentation, rearrangement, duplication, and deletion of this chimeric moss mitochondrial genome as it currently exists in Amborella. Five of these events are associated with short-to-intermediate sized repeats. Two of the five probably occurred by reciprocal homologous recombination, whereas the other three probably occurred in a non-reciprocal manner via microhomology-mediated break-induced replication (MMBIR). These findings reinforce and extend recent evidence for an important role of MMBIR in plant mitochondrial DNA evolution.

The mitochondrial plasmid of the true slime mold Physarum polycephalum bypasses uniparental inheritance by promoting mitochondrial fusion.

PubMed

Sakurai, Rakusa; Nomura, Hideo; Moriyam, Yohsuke; Kawano, Shigeyuki

2004-08-01

Mitochondrial DNA (mtDNA) is inherited maternally in most eukaryotes. Linear mitochondrial plasmids in higher plants and fungi are also transmitted from the maternal parent to the progeny. However, mF, which is a mitochondrial linear plasmid of Physarum polycephalum, evades uniparental mitochondrial inheritance. We examined 36 myxamoebal strains of Physarum and isolated three novel mF+ strains (JE8, TU111, NG111) that harbored free mF plasmids. These strains were mated with the mF- strain KM88. Of the three mF- x mF+ crosses, only KM88 x JE8 displayed complete uniparental inheritance. However, in KM88 x TU111 and KM88 x NG111, the mtDNA of KM88 and mF of TU111 and NG111 were inherited by the plasmodia and showed recombination. For example, although the mtDNA of TU111 was eliminated, the mF of TU111 persisted and became inserted into the mtDNA of KM88, such that recombinant mtDNA represented 80% of the total mtDNA. The parental mitochondria fused to yield giant mitochondria with two or more mitochondrial nucleoids. The mF appears to exchange mitochondria from the recipient (paternal) to the donor (maternal) by promoting mitochondrial fusion.

Oral manifestations compatible with chronic graft-versus-host disease in patients with Fanconi anemia.

PubMed

Grein Cavalcanti, Laura; Fuentes Araújo, Renata L; Bonfim, Carmem; Torres-Pereira, Cassius C

2015-02-01

Fanconi anemia (FA) is a genetic disease that is characterized by several congenital abnormalities and progressive bone marrow failure and is associated with an increased susceptibility to malignant disorders. Currently, the only potential cure for hematological disorders is hematopoietic stem cell transplantation (HSCT). However, 1 of the most common complications after HSCT is the development of oral chronic graft-versus-host disease (cGVHD), which is also a risk factor for the development of cancer, particularly oral squamous cell carcinoma. Therefore, the purpose of this study was to describe the prevalence and characteristics of oral manifestations compatible with cGVHD in patients diagnosed with FA according to the National Institutes of Health (NIH) consensus criteria. A total of 96 patients (51 females, 45 males; median age, 16 years) with FA, who were in medical follow-up after HSCT at the outpatient clinic of the bone marrow transplantation unit (Hospital de Clínicas from the Universidade Federal do Paraná) underwent an oral evaluation between January 2013 and December 2013. Post-HSCT periods varied from 1 to 261 months and were divided into 3 periods: immediate post-HSCT period; intermediate post-HSC period, and late post-HSCT period. Among the evaluated patients, 40 of 96 (42%) presented with oral manifestations of cGVHD, with 29 of 40 (73%) of these patients in the late post-HSCT period. NIH scale scores varied from 0 to 10, and lichenoid and hyperkeratotic lesions were the abnormalities most frequently observed (100%). Overall, a high prevalence of oral manifestations was observed for cGVHD patients with FA. These data highlight the importance of monitoring oral manifestations compatible with cGVHD to identify and treat individuals with a higher risk of developing oral cancer. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Mitochondrial and Morphologic Alterations in Native Human Corneal Endothelial Cells Associated With Diabetes Mellitus.

PubMed

Aldrich, Benjamin T; Schlötzer-Schrehardt, Ursula; Skeie, Jessica M; Burckart, Kimberlee A; Schmidt, Gregory A; Reed, Cynthia R; Zimmerman, M Bridget; Kruse, Friedrich E; Greiner, Mark A

2017-04-01

To characterize changes in the energy-producing metabolic activity and morphologic ultrastructure of corneal endothelial cells associated with diabetes mellitus. Transplant suitable corneoscleral tissue was obtained from donors aged 50 to 75 years. We assayed 3-mm punches of endothelium-Descemet membrane for mitochondrial respiration and glycolysis activity using extracellular flux analysis of oxygen and pH, respectively. Transmission electron microscopy was used to assess qualitative and quantitative ultrastructural changes in corneal endothelial cells and associated Descemet membrane. For purposes of analysis, samples were divided into four groups based on a medical history of diabetes regardless of type: (1) nondiabetic, (2) noninsulin-dependent diabetic, (3) insulin-dependent diabetic, and (4) insulin-dependent diabetic with specified complications due to diabetes (advanced diabetic). In total, 229 corneas from 159 donors were analyzed. Insulin-dependent diabetic samples with complications due to diabetes displayed the lowest spare respiratory values compared to all other groups (P ≤ 0.002). The remaining mitochondrial respiration and glycolysis metrics did not differ significantly among groups. Compared to nondiabetic controls, the endothelium from advanced diabetic samples had alterations in mitochondrial morphology, pronounced Golgi bodies associated with abundant vesicles, accumulation of lysosomal bodies/autophagosomes, and focal production of abnormal long-spacing collagen. Extracellular flux analysis suggests that corneal endothelial cells of donors with advanced diabetes have impaired mitochondrial function. Metabolic findings are supported by observed differences in mitochondrial morphology of advanced diabetic samples but not controls. Additional studies are needed to determine the precise mechanism(s) by which mitochondria become impaired in diabetic corneal endothelial cells.

Incipient evolution of Wolbachia compatibility types.

PubMed

Charlat, Sylvain; Riegler, Markus; Baures, Isabelle; Poinsot, Denis; Stauffer, Christian; Merçot, Hervé

2004-09-01

Cytoplasmic incompatibility (CI) is induced in arthropods by the maternally inherited bacterium Wolbachia. When infected males mate with uninfected females or with females bearing a different Wolbachia variant, paternal chromosomes behave abnormally and embryos die. This pattern can be interpreted as resulting from two bacterial effects: One (usually termed mod, for modification) would affect sperm and induce embryo death, unless Wolbachia is also present in the egg, which implies the existence of a second effect, usually termed resc, for rescue. The fact that CI can occur in crosses between males and females infected by different Wolbachia shows that mod and resc interact in a specific manner. In other words, different compatibility types, or mod/resc pairs seem to have diverged from one (or a few) common ancestor(s). We are interested in the process allowing the evolution of mod/resc pairs. Here this question is addressed experimentally after cytoplasmic injection into a single host species (Drosophila simulans) by investigating compatibility relationships between closely related Wolbachia variants naturally evolving in different dipteran hosts: D. simulans, Drosophila melanogaster, and Rhagoletis cerasi. Our results suggest that closely related bacteria can be totally or partially incompatible. The compatibility relationships observed can be explained using a formal description of the mod and resc functions, implying both qualitative and quantitative variations.

Characterization, design, and function of the mitochondrial proteome: from organs to organisms.

PubMed

Lotz, Christopher; Lin, Amanda J; Black, Caitlin M; Zhang, Jun; Lau, Edward; Deng, Ning; Wang, Yueju; Zong, Nobel C; Choi, Jeong H; Xu, Tao; Liem, David A; Korge, Paavo; Weiss, James N; Hermjakob, Henning; Yates, John R; Apweiler, Rolf; Ping, Peipei

2014-02-07

Mitochondria are a common energy source for organs and organisms; their diverse functions are specialized according to the unique phenotypes of their hosting environment. Perturbation of mitochondrial homeostasis accompanies significant pathological phenotypes. However, the connections between mitochondrial proteome properties and function remain to be experimentally established on a systematic level. This uncertainty impedes the contextualization and translation of proteomic data to the molecular derivations of mitochondrial diseases. We present a collection of mitochondrial features and functions from four model systems, including two cardiac mitochondrial proteomes from distinct genomes (human and mouse), two unique organ mitochondrial proteomes from identical genetic codons (mouse heart and mouse liver), as well as a relevant metazoan out-group (drosophila). The data, composed of mitochondrial protein abundance and their biochemical activities, capture the core functionalities of these mitochondria. This investigation allowed us to redefine the core mitochondrial proteome from organs and organisms, as well as the relevant contributions from genetic information and hosting milieu. Our study has identified significant enrichment of disease-associated genes and their products. Furthermore, correlational analyses suggest that mitochondrial proteome design is primarily driven by cellular environment. Taken together, these results connect proteome feature with mitochondrial function, providing a prospective resource for mitochondrial pathophysiology and developing novel therapeutic targets in medicine.

Evolution of Compatibility Range in the Rice-Magnaporthe oryzae System: An Uneven Distribution of R Genes Between Rice Subspecies.

PubMed

Gallet, Romain; Fontaine, Colin; Bonnot, François; Milazzo, Joëlle; Tertois, Christophe; Adreit, Henri; Ravigné, Virginie; Fournier, Elisabeth; Tharreau, Didier

2016-04-01

Efficient strategies for limiting the impact of pathogens on crops require a good understanding of the factors underlying the evolution of compatibility range for the pathogens and host plants, i.e., the set of host genotypes that a particular pathogen genotype can infect and the set of pathogen genotypes that can infect a particular host genotype. Until now, little is known about the evolutionary and ecological factors driving compatibility ranges in systems implicating crop plants. We studied the evolution of host and pathogen compatibility ranges for rice blast disease, which is caused by the ascomycete Magnaporthe oryzae. We challenged 61 rice varieties from three rice subspecies with 31 strains of M. oryzae collected worldwide from all major known genetic groups. We determined the compatibility range of each plant variety and pathogen genotype and the severity of each plant-pathogen interaction. Compatibility ranges differed between rice subspecies, with the most resistant subspecies selecting for pathogens with broader compatibility ranges and the least resistant subspecies selecting for pathogens with narrower compatibility ranges. These results are consistent with a nested distribution of R genes between rice subspecies.

Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease.

PubMed

Fitzhugh, Courtney D; Abraham, Allistair; Hsieh, Matthew M

2017-01-01

Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source-with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expertise; there is no clear preferred choice over the other. Active research is ongoing in expanding cord blood progenitor cells to overcome the limitation of cell dose, including the options of small molecule inhibitor compounds added to ex vivo culture or co-culture with supportive cell lines. There are inconsistent data from using 7/8 or lower matched unrelated donors. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, GvHD prophylaxis, and/or other strategies.

Grafting of a Single Donor Myofibre Promotes Hypertrophy in Dystrophic Mouse Muscle

PubMed Central

Boldrin, Luisa; Morgan, Jennifer E.

2013-01-01

Skeletal muscle has a remarkable capability of regeneration following injury. Satellite cells, the principal muscle stem cells, are responsible for this process. However, this regenerative capacity is reduced in muscular dystrophies or in old age: in both these situations, there is a net loss of muscle fibres. Promoting skeletal muscle muscle hypertrophy could therefore have potential applications for treating muscular dystrophies or sarcopenia. Here, we observed that muscles of dystrophic mdx nude host mice that had been acutely injured by myotoxin and grafted with a single myofibre derived from a normal donor mouse exhibited increased muscle area. Transplantation experiments revealed that the hypertrophic effect is mediated by the grafted fibre and does not require either an imposed injury to the host muscle, or the contribution of donor cells to the host muscle. These results suggest the presence of a crucial cross-talk between the donor fibre and the host muscle environment. PMID:23349935

Mixed Donor Chimerism Following Simultaneous Pancreas-Kidney Transplant.

PubMed

Rashidi, Armin; Brennan, Daniel C; Amarillo, Ina E; Wellen, Jason R; Cashen, Amanda

2018-06-01

Graft-versus-host disease after solid-organ transplant is exceedingly rare. Although the precise pathogenetic mechanisms are unknown, a progressive increase in donor chimerism is a requirement for its development. The incidence of mixed donor chimerism and its timeline after simultaneous pancreas-kidney transplant is unknown. After encountering 2 cases of graft-versus-host disease after simultaneous pancreas-kidney transplant at our institution over a period of < 2 years, a collaborative pilot study was conducted by the bone marrow transplant, nephrology, and abdominal transplant surgery teams. We enrolled all consecutive patients undergoing sex-mismatched simultaneous pancreas-kidney transplant over 1 year and longitudinally monitored donor chimerism using fluorescence in situ hybridization for sex chromosomes. We found no evidence for chimerism in our 7 patients. In a comprehensive literature review, we found a total of 25 previously reported cases of graft-versus-host disease after kidney, pancreas, and simultaneous pancreas-kidney transplants. The median onset of graft-versus-host disease was approximately 5 weeks after transplant, with a median of about 2 weeks of delay between first presentation and diagnosis. Skin, gut, and bone marrow were almost equally affected at initial presentation, and fever of unknown origin occurred in more than half of patients. The median survival measured from the first manifestation of graft-versus-host disease was only 48 days. Within the limitations related to small sample size, our results argue against an unusually high risk of graft-versus-host disease after simultaneous pancreas-kidney transplant. Collaboration between solid-organ and stem cell transplant investigators can be fruitful and can improve our understanding of the complications that are shared between the 2 fields.

Energy-cascade organic photovoltaic devices incorporating a host-guest architecture.

PubMed

Menke, S Matthew; Holmes, Russell J

2015-02-04

In planar heterojunction organic photovoltaic devices (OPVs), broad spectral coverage can be realized by incorporating multiple molecular absorbers in an energy-cascade architecture. Here, this approach is combined with a host-guest donor layer architecture previously shown to optimize exciton transport for the fluorescent organic semiconductor boron subphthalocyanine chloride (SubPc) when diluted in an optically transparent host. In order to maximize the absorption efficiency, energy-cascade OPVs that utilize both photoactive host and guest donor materials are examined using the pairing of SubPc and boron subnaphthalocyanine chloride (SubNc), respectively. In a planar heterojunction architecture, excitons generated on the SubPc host rapidly energy transfer to the SubNc guest, where they may migrate toward the dissociating, donor-acceptor interface. Overall, the incorporation of a photoactive host leads to a 13% enhancement in the short-circuit current density and a 20% enhancement in the power conversion efficiency relative to an optimized host-guest OPV combining SubNc with a nonabsorbing host. This work underscores the potential for further design refinements in planar heterojunction OPVs and demonstrates progress toward the effective separation of functionality between constituent OPV materials.

[Regulatory problems regarding bone marrow transplantation from non-consanguinous donors].

PubMed

Moratti, A

1999-01-01

The paper reports the normative rules and the Italian Ministry of Health administrative instructions concerning the bone marrow unrelated donor (MUD) search in the Italian Bone Marrow Donor Registry (IBMDR) and in international registries from the preliminary activation to a MUD bone marrow transplant (BMT), when a volunteer donor, perfectly compatible with a recipient lacking a HLA identical sibling, is found. The article describes all the expenses pertinent to the different stages of search and the documents necessary to obtain the reimbursement of these expenses. A very recent Ministry Decree establishing that all the search costs will be charged to the competent local sanitary authority is added.

Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist.

PubMed

Kekre, Natasha; Antin, Joseph H

2014-07-17

Most patients who require allogeneic stem cell transplantation do not have a matched sibling donor, and many patients do not have a matched unrelated donor. In an effort to increase the applicability of transplantation, alternative donors such as mismatched adult unrelated donors, haploidentical related donors, and umbilical cord blood stem cell products are frequently used when a well matched donor is unavailable. We do not yet have the benefit of randomized trials comparing alternative donor stem cell sources to inform the choice of donor; however, the existing data allow some inferences to be made on the basis of existing observational and phase 2 studies. All 3 alternative donor sources can provide effective lymphohematopoietic reconstitution, but time to engraftment, graft failure rate, graft-versus-host disease, transplant-related mortality, and relapse risk vary by donor source. These factors all contribute to survival outcomes and an understanding of them should help guide clinicians when choosing among alternative donor sources when a matched related or matched unrelated donor is not available. © 2014 by The American Society of Hematology.

Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis

PubMed Central

Moreira, Diana; Rodrigues, Vasco; Abengozar, Maria; Rivas, Luis; Rial, Eduardo; Laforge, Mireille; Li, Xiaoling; Foretz, Marc; Viollet, Benoit; Estaquier, Jérôme; Cordeiro da Silva, Anabela; Silvestre, Ricardo

2015-01-01

Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. PMID:25738568

Yeast mitochondria: an overview of mitochondrial biology and the potential of mitochondrial systems biology.

PubMed

Malina, Carl; Larsson, Christer; Nielsen, Jens

2018-08-01

Mitochondria are dynamic organelles of endosymbiotic origin that are essential components of eukaryal cells. They contain their own genetic machinery, have multicopy genomes and like their bacterial ancestors they consist of two membranes. However, the majority of the ancestral genome has been lost or transferred to the nuclear genome of the host, preserving only a core set of genes involved in oxidative phosphorylation. Mitochondria perform numerous biological tasks ranging from bioenergetics to production of protein co-factors, including heme and iron-sulfur clusters. Due to the importance of mitochondria in many cellular processes, mitochondrial dysfunction is implicated in a wide variety of human disorders. Much of our current knowledge on mitochondrial function and dysfunction comes from studies using Saccharomyces cerevisiae. This yeast has good fermenting capacity, rendering tolerance to mutations that inactivate oxidative phosphorylation and complete loss of mitochondrial DNA. Here, we review yeast mitochondrial metabolism and function with focus on S. cerevisiae and its contribution in understanding mitochondrial biology. We further review how systems biology studies, including mathematical modeling, has allowed gaining new insight into mitochondrial function, and argue that this approach may enable us to gain a holistic view on how mitochondrial function interacts with different cellular processes.

Mitochondrial rhodanese: membrane-bound and complexed activity.

PubMed

Ogata, K; Volini, M

1990-05-15

We have proposed that phosphorylated and dephosphorylated forms of the mitochondrial sulfurtransferase, rhodanese, function as converter enzymes that interact with membrane-bound iron-sulfur centers of the electron transport chain to modulate the rate of mitochondrial respiration (Ogata, K., Dai, X., and Volini, M. (1989) J. Biol. Chem. 204, 2718-2725). In the present studies, we have explored some structural aspects of the mitochondrial rhodanese system. By sequential extraction of lysed mitochondria with phosphate buffer and phosphate buffer containing 20 mM cholate, we have shown that 30% of the rhodanese activity of bovine liver is membrane-bound. Resolution of cholate extracts on Sephadex G-100 indicates that part of the bound rhodanese is complexed with other mitochondrial proteins. Tests with the complex show that it forms iron-sulfur centers when incubated with the rhodanese sulfur-donor substrate thiosulfate, iron ions, and a reducing agent. Experiments on the rhodanese activity of rat liver mitochondria give similar results. Taken together, the findings indicate that liver rhodanese is in part bound to the mitochondrial membrane as a component of a multiprotein complex that forms iron-sulfur centers. The findings are consistent with the role we propose for rhodanese in the modulation of mitochondrial respiratory activity.

Mitochondrial dysfunction and organophosphorus compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karami-Mohajeri, Somayyeh; Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman; Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca

2013-07-01

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen frommore » dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.« less

Betaine is a positive regulator of mitochondrial respiration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Icksoo, E-mail: icksoolee@dankook.ac.kr

2015-01-09

Highlights: • Betaine enhances cytochrome c oxidase activity and mitochondrial respiration. • Betaine increases mitochondrial membrane potential and cellular energy levels. • Betaine’s anti-tumorigenic effect might be due to a reversal of the Warburg effect. - Abstract: Betaine protects cells from environmental stress and serves as a methyl donor in several biochemical pathways. It reduces cardiovascular disease risk and protects liver cells from alcoholic liver damage and nonalcoholic steatohepatitis. Its pretreatment can rescue cells exposed to toxins such as rotenone, chloroform, and LiCl. Furthermore, it has been suggested that betaine can suppress cancer cell growth in vivo and in vitro.more » Mitochondrial electron transport chain (ETC) complexes generate the mitochondrial membrane potential, which is essential to produce cellular energy, ATP. Reduced mitochondrial respiration and energy status have been found in many human pathological conditions including aging, cancer, and neurodegenerative disease. In this study we investigated whether betaine directly targets mitochondria. We show that betaine treatment leads to an upregulation of mitochondrial respiration and cytochrome c oxidase activity in H2.35 cells, the proposed rate limiting enzyme of ETC in vivo. Following treatment, the mitochondrial membrane potential was increased and cellular energy levels were elevated. We propose that the anti-proliferative effects of betaine on cancer cells might be due to enhanced mitochondrial function contributing to a reversal of the Warburg effect.« less

Willingness of Directed Living Donors and Their Recipients to Participate in Kidney Paired Donation Programs.

PubMed

Hendren, Elizabeth; Gill, Jagbir; Landsberg, David; Dong, Jianghu; Rose, Caren; Gill, John S

2015-09-01

Participation of compatible living donors and recipients in kidney paired donation (KPD) could double the number of KPD transplants. We determined the willingness of previous directed donors and their recipients to participate in KPD and identified the association of various factors, including financial incentives, with willingness to participate. Survey of previous directed living kidney donors and their recipients in a single Canadian center between 2001 and 2009. Among 207 of 222 eligible living donors contacted, 86 (42%) completed the anonymous survey: 93% (78/86) of donors indicated willingness to participate in KPD if this option had been provided at the time of donation. An increased willingness to participate was reported among the majority of respondents if reimbursements for lost wages and travel expenses were provided; however, cash payments between $5 000 and $50 000 had little impact on willingness. Willingness was also increased with an advantage to the recipient (younger donor or better human leukocyte antigen match), whereas delays beyond 3 months and donor travel were associated with reduced willingness to participate. Among 38 recipients approached during routine clinical follow-up visits over a 3-month period, 100% completed the survey, and 36 of 38 (92%) reported they would have been willing to participate in KPD. Over 90% of directed donors and recipients were willing to participate in KPD. Reimbursement for the costs of participation and improved efficiency of KPD (i.e., eliminating travel and reducing transplant times), but not cash payments, may increase participation of compatible donors and recipients in KPD.

A photonic link for donor spin qubits in silicon

NASA Astrophysics Data System (ADS)

Simmons, Stephanie

Atomically identical donor spin qubits in silicon offer excellent native quantum properties, which match or outperform many qubit rivals. To scale up such systems it would be advantageous to connect silicon donor spin qubits in a cavity-QED architecture. Many proposals in this direction introduce strong electric dipole interactions to the otherwise largely isolated spin qubit ground state in order to couple to superconducting cavities. Here I present an alternative approach, which uses the built-in strong electric dipole (optical) transitions of singly-ionized double donors in silicon. These donors, such as chalcogen donors S +, Se + and Te +, have the same ground-state spin Hamiltonians as shallow donors yet offer mid-gap binding energies and mid-IR optical access to excited orbital states. This photonic link is spin-selective which could be harnessed to measure and couple donor qubits using photonic cavity-QED. This approach should be robust to device environments with variable strains and electric fields, and will allow for CMOS- compatible, bulk-like, spatially separated donor qubit placement, optical parity measurements, and 4.2K operation. I will present preliminary data in support of this approach, including 4.2K optical initialization/readout in Earth's magnetic field, where long T1 and T2 times have been measured.

Temporal manipulation of mitochondrial function by virulent Francisella tularensis to limit inflammation and control cell death.

PubMed

Jessop, Forrest; Schwarz, Benjamin; Heitmann, Emily; Buntyn, Robert; Wehrly, Tara; Bosio, Catharine M

2018-05-14

Francisella tularensis ssp tularensis (Ftt) is a highly pathogenic intracellular bacterium that suppresses host inflammation by impairing the metabolic shift from oxidative phosphorylation to glycolysis. Decreased mitochondrial metabolism is central to initiating a metabolic shift to glycolysis and regulating inflammation, but Ftt manipulation of host mitochondrial function has not been explored. We demonstrate using extracellular flux analysis that Ftt infection initially improves host macrophage mitochondrial bioenergetics in a capsule dependent manner. Enhancement of mitochondrial function by Ftt allowed for modest replication and inhibition of apoptosis early after infection. However, using live cell imaging we found that Ftt facilitated the loss of mitochondrial function at later time points during infection in a capsule independent fashion. This loss of function was paired with oncosis and rapid bacterial replication. Inhibition of oncosis reduced intracellular bacteria numbers, underscoring the requirement for this process during Ftt infection. These findings establish that temporal mitochondrial manipulation by Ftt is critical for maintenance of a non-inflammatory environment and subsequently aids in optimal replication and dissemination of this pathogenic organism. Copyright © 2018 American Society for Microbiology.

Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation.

PubMed

Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Choi, Eun Young; Min, Chang-Ki

2015-11-01

Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2(b)) → B6D2F1 (H-2(b/d)), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type (H-2(d)) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-γ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-γ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT.

Mitochondrial Haplogroups as a Risk Factor for Herpes Zoster.

PubMed

Levinson, Rebecca T; Hulgan, Todd; Kalams, Spyros A; Fessel, Joshua P; Samuels, David C

2016-10-01

Background.  Herpes zoster, or shingles, is a common, painful reactivation of latent varicella zoster virus infection. Understanding host factors that predispose to herpes zoster may permit development of more effective prevention strategies. Our objective was to examine mitochondrial haplogroups as a potential host factor related to herpes zoster incidence. Methods.  Study participants were drawn from BioVU, a deoxyribonucleic acid (DNA) biobank connected to deidentified electronic medical records (EMRs) from Vanderbilt University Medical Center. Our study used 9691 Caucasian individuals with herpes zoster status determined by International Classification of Diseases, Ninth Revision codes 053-053.9. Cases and controls were matched on sex and date of birth within 5 years. Mitochondrial haplogroups were defined from mitochondrial DNA variants genotyped on the Illumina 660W or Illumina Infinium Human-Exome Beadchip. Sex and date of birth were extracted from the EMR. Results.  European mitochondrial haplogroup H had a protective association with herpes zoster status (odds ratio [OR] = .82; 95% confidence interval [CI], .71-.94; P = .005), whereas haplogroup clade IWX was a risk factor for herpes zoster status (OR = 1.38; 95% CI, 1.07-1.77; P = .01). Conclusions.  Mitochondrial haplogroup influences herpes zoster risk. Knowledge of a patient's mitochondrial haplogroup could allow for a precision approach to the management of herpes zoster risk through vaccination strategies and management of other modifiable risk factors.

Dynamic intervention: pathogen disarmament of mitochondrial-based immune surveillance.

PubMed

Holland, Robin L; Blanke, Steven R

2014-11-12

In this issue of Cell Host & Microbe, Suzuki et al. (2014) describe a Vibrio cholerae Type-III-secreted effector that targets mitochondrial dynamics to dampen host innate immune signaling. This suggests that mammalian hosts possess surveillance mechanisms to monitor pathogen-mediated alterations in the integrity of normal cellular processes and organelles. Copyright © 2014 Elsevier Inc. All rights reserved.

Late acquisition of mitochondria by a host with chimeric prokaryotic ancestry

PubMed Central

Pittis, Alexandros A.; Gabaldón, Toni

2016-01-01

The origin of eukaryotes stands as a major conundrum in biology1. Current evidence indicates that the Last Eukaryotic Common Ancestor (LECA) already possessed many eukaryotic hallmarks, including a complex subcellular organization1–3. In addition, the lack of evolutionary intermediates challenges the elucidation of the relative order of emergence of eukaryotic traits. Mitochondria are ubiquitous organelles derived from an alpha-proteobacterial endosymbiont4. Different hypotheses disagree on whether mitochondria were acquired early or late during eukaryogenesis5. Similarly, the nature and complexity of the receiving host are debated, with models ranging from a simple prokaryotic host to an already complex proto-eukaryote1,3,6,7. Most competing scenarios can be roughly grouped into either mito-early, which consider the driving force of eukaryogenesis to be mitochondrial endosymbiosis into a simple host, or mito-late, which postulate that a significant complexity predated mitochondrial endosymbiosis3. Here we provide evidence for late mitochondrial endosymbiosis. We used phylogenomics to directly test whether proto-mitochondrial proteins were acquired earlier or later than other LECA proteins. We found that LECA protein families of alpha-proteobacterial ancestry and of mitochondrial localization show the shortest phylogenetic distances to their closest prokaryotic relatives, when compared to proteins of different prokaryotic origin or cellular localization. Altogether, our results shed new light on a long-standing question and provide compelling support for the late acquisition of mitochondria into a host that already had a proteome of chimeric phylogenetic origin. We argue that mitochondrial endosymbiosis was one of the ultimate steps in eukaryogenesis and that it provided the definitive selective advantage to mitochondria-bearing eukaryotes over less complex forms. PMID:26840490

Late acquisition of mitochondria by a host with chimaeric prokaryotic ancestry.

PubMed

Pittis, Alexandros A; Gabaldón, Toni

2016-03-03

The origin of eukaryotes stands as a major conundrum in biology. Current evidence indicates that the last eukaryotic common ancestor already possessed many eukaryotic hallmarks, including a complex subcellular organization. In addition, the lack of evolutionary intermediates challenges the elucidation of the relative order of emergence of eukaryotic traits. Mitochondria are ubiquitous organelles derived from an alphaproteobacterial endosymbiont. Different hypotheses disagree on whether mitochondria were acquired early or late during eukaryogenesis. Similarly, the nature and complexity of the receiving host are debated, with models ranging from a simple prokaryotic host to an already complex proto-eukaryote. Most competing scenarios can be roughly grouped into either mito-early, which consider the driving force of eukaryogenesis to be mitochondrial endosymbiosis into a simple host, or mito-late, which postulate that a significant complexity predated mitochondrial endosymbiosis. Here we provide evidence for late mitochondrial endosymbiosis. We use phylogenomics to directly test whether proto-mitochondrial proteins were acquired earlier or later than other proteins of the last eukaryotic common ancestor. We find that last eukaryotic common ancestor protein families of alphaproteobacterial ancestry and of mitochondrial localization show the shortest phylogenetic distances to their closest prokaryotic relatives, compared with proteins of different prokaryotic origin or cellular localization. Altogether, our results shed new light on a long-standing question and provide compelling support for the late acquisition of mitochondria into a host that already had a proteome of chimaeric phylogenetic origin. We argue that mitochondrial endosymbiosis was one of the ultimate steps in eukaryogenesis and that it provided the definitive selective advantage to mitochondria-bearing eukaryotes over less complex forms.

Induction of MHC-mismatched Mouse Lung Allograft Acceptance with Combined Donor Bone Marrow: Lung Transplant using a 12-Hour Nonmyeloablative Conditioning Regimen

PubMed Central

Vulic, Ante; Panoskaltsis-Mortari, Angela; McDyer, John F.; Luznik, Leo

2016-01-01

Background Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Methods Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low dose total body irradiation and posttransplant (donor) bone marrow and splenocyte infusion followed by posttransplantation cyclophosphamide (PTTT-PTB/PTCy). Results Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3+ T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of PTTT-PTB/PTCy following a chimerism-ablating secondary recipient lymphocyte infusion. Conclusion Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation (BMT) using a short-duration nonmyeloablative conditioning regimen and PTCy. PMID:27861294

Towards building artificial light harvesting complexes: enhanced singlet-singlet energy transfer between donor and acceptor pairs bound to albumins.

PubMed

Kumar, Challa V; Duff, Michael R

2008-12-01

Specific donor and acceptor pairs have been assembled in bovine serum albumin (BSA), at neutral pH and room temperature, and these dye-protein complexes indicated efficient donor to acceptor singlet-singlet energy transfer. For example, pyrene-1-butyric acid served as the donor and Coumarin 540A served as the acceptor. Both the donor and the acceptor bind to BSA with affinity constants in excess of 2x10(5) M(-1), as measured in absorption and circular dichroism (CD) spectral titrations. Simultaneous binding of both the donor and the acceptor chromophores was supported by CD spectra and one chromophore did not displace the other from the protein host, even when limited concentrations of the host were used. For example, a 1:1:1 complex between the donor, acceptor and the host can be readily formed, and spectral data clearly show that the binding sites are mutually exclusive. The ternary complexes (two different ligands bound to the same protein molecule) provided opportunities to examine singlet-singlet energy transfer between the protein-bound chromophores. Donor emission was quenched by the addition of the acceptor, in the presence of limited amounts of BSA, while no energy transfer was observed in the absence of the protein host, under the same conditions. The excitation spectra of the donor-acceptor-host complexes clearly show the sensitization of acceptor emission by the donor. Protein denaturation, as induced by the addition of urea or increasing the temperature to 360 K, inhibited energy transfer, which indicate that protein structure plays an important role. Sensitization also proceeded at low temperature (77 K) and diffusion of the donor or the acceptor is not required for energy transfer. Stern-Volmer quenching plots show that the quenching constant is (3.1+/-0.2)x10(4) M(-1), at low acceptor concentrations (<35 microM). Other albumins such as human and porcine proteins also served as good hosts for the above experiments. For the first time, non

Recipient-donor KIR ligand matching prevents CMV reactivation post-haploidentical T cell-replete transplantation.

PubMed

Zhao, Xiang-Yu; Luo, Xue-Yi; Yu, Xing-Xing; Zhao, Xiao-Su; Han, Ting-Ting; Chang, Ying-Jun; Huo, Ming-Rui; Xu, Lan-Ping; Zhang, Xiao-Hui; Liu, Kai-Yan; Li, Dan; Jiang, Zheng-Fan; Huang, Xiao-Jun

2017-06-01

Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation. Donor-recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post-transplantation. In addition, the percentage of γ-interferon expression on donor-derived NK cells was significantly higher in the recipients among the recipient-donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft-versus-host or host-versus-graft direction mismatch on days 30 and 100 post-transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor-recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation. © 2017 John Wiley & Sons Ltd.

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide

PubMed Central

Williams, Robert C.; Opelz, Gerhard; Weil, E. Jennifer; McGarvey, Chelsea J.; Chakkera, Harini A.

2017-01-01

Background Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Methods Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. Results There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. Conclusions These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible. PMID:28573187

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide.

PubMed

Williams, Robert C; Opelz, Gerhard; Weil, E Jennifer; McGarvey, Chelsea J; Chakkera, Harini A

2017-05-01

Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible.

Impact of HLA diversity on donor selection in organ and stem cell transplantation.

PubMed

Tiercy, Jean-Marie; Claas, Frans

2013-01-01

The human major histocompatibility complex is a multigene system encoding polymorphic human leucocyte antigens (HLA) that present peptides derived from pathogens to the immune system. The high diversity of HLA alleles and haplotypes in the worldwide populations represents a major barrier to organ and allogeneic hematopoietic stem cell transplantation, because HLA incompatibilities are efficiently recognized by T and B lymphocytes. In organ transplantation, pre-transplant anti-HLA antibodies need to be taken into account for organ allocation. Although HLA-incompatible transplants can be performed thanks to immunosuppressive drugs, the de novo production of anti-HLA antibodies still represents a major cause of graft failure. The HLAMatchmaker computer algorithm determines the immunogenicity of HLA mismatches and allows to define HLA antigens that will not induce an antibody response. Because of the much higher stringency of HLA compatibility criteria in stem cell transplantation, the best donor is a HLA genotypically identical sibling. However, more than 50% of the transplants are now performed with hematopoietic stem cells from volunteer donors selected from the international registry. The development of European national registries covering populations with different HLA haplotype frequencies is essential for optimizing donor search algorithms and providing the best chance for European patients to find a fully compatible donor.

[The kidney transplantation from the ABO-incompatible donors].

PubMed

Goriaĭnov, V A; Kaabak, M M; Babenko, N N; Shishlo, L A; Morozova, M M; Ragimov, A A; Dashkova, N G; Salimov, É L

2012-01-01

The experience of 28 allotransplantations of ABO-incompatible kidneys was compared with the treatment results of 38 ABO-compatible renal transplantations. The transplanted kidney function, morphological changes of the transplanted kidney and the comparative analysis of actuary survival in both groups showed no significant difference. The results of the study prove the validity of the kidney transplantation from the ABO-incompatible donors.

Using EasyMatch® to anticipate the identification of an HLA identical unrelated donor: A validated efficient time and cost saving method.

PubMed

Dubois, Valérie; Detrait, Marie; Sobh, Mohamad; Morisset, Stéphane; Labussière, Hélène; Giannoli, Catherine; Nicolini, Franck; Moskovtchenko, Philippe; Mialou, Valérie; Ducastelle, Sophie; Rey, Sylvie; Thomas, Xavier; Barraco, Fiorenza; Tedone, Nathalie; Marry, Evelyne; Garnier, Federico; Bertrand, Yves; Michallet, Mauricette

2016-11-01

In the absence of an HLA matched familial donor, a search for an unrelated donor or cord blood unit is initiated through worldwide registries. Although a first look-up on available HLA information of donors in the "book" at BMDW (Bone Marrow Donor Worldwide) can provide a good estimation of the number of compatible donors, the variety of resolution typing levels requires confirmatory typing (CT) which are expensive and time consuming. In order to help recipient centers in their work. The French donor registry (France Greffe de Moelle/Agence de la Biomedecine) has recently developed a software program called "EasyMatch®" that uses haplotype frequencies to compute the likelihood of phenotypic match in donors according to various typing resolution levels. The goal of our study is to report a single monocentric user-experience with EasyMatch®, demonstrating that its routine use reduced the cost and the delay of the donor search in our center, allowing the definition of a new strategy to search compatible unrelated donors. The strategy was first established on a retrospective cohort of 217 recipients (185 adults and 32 children=before score) and then validated on a prospective cohort of 171 recipients (160 adults and 11 children=after score). For all patients, we calculated the delay between the registration day and the donor identification day, and the number of CT requested to the donor centre. Considering both groups, we could observe a significant decrease of the number of CT from 8 to 2 (p<0,001), and a significant decrease of the median delay to identify a suitable donor from 43 to 31days (p<0.0001). EasyMatch® estimates the number of potentially identical donors, but doesn't foresee availability of the donors. It provides us an easy tracking of mismatches, an estimation of the number of potential donors, the selection of population following ethnic origin of patients and a high prediction when probability is high or low. It affords a new approach of donor

Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.

PubMed

Ghosh, Arnab; Smith, Melody; James, Scott E; Davila, Marco L; Velardi, Enrico; Argyropoulos, Kimon V; Gunset, Gertrude; Perna, Fabiana; Kreines, Fabiana M; Levy, Emily R; Lieberman, Sophie; Jay, Hillary V; Tuckett, Andrea Z; Zakrzewski, Johannes L; Tan, Lisa; Young, Lauren F; Takvorian, Kate; Dudakov, Jarrod A; Jenq, Robert R; Hanash, Alan M; Motta, Ana Carolina F; Murphy, George F; Liu, Chen; Schietinger, Andrea; Sadelain, Michel; van den Brink, Marcel R M

2017-02-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.

Hexameric oligomerization of mitochondrial peroxiredoxin PrxIIF and formation of an ultrahigh affinity complex with its electron donor thioredoxin Trx-o.

PubMed

Barranco-Medina, Sergio; Krell, Tino; Bernier-Villamor, Laura; Sevilla, Francisca; Lázaro, Juan-José; Dietz, Karl-Josef

2008-01-01

Mitochondria from plants, yeast, and animals each contain at least one peroxiredoxin (Prx) that is involved in peroxide detoxification and redox signalling. The supramolecular dynamics of atypical type II Prx targeted to the mitochondrion was addressed in pea. Microcalorimetric (ITC) titrations identified an extremely high-affinity binding between the mitochondrial PsPrxIIF and Trx-o with a K(D) of 126+/-14 pM. Binding was driven by a favourable enthalpy change (DeltaH= -60.6 kcal mol(-1)) which was counterbalanced by unfavourable entropy changes (TDeltaS= -47.1 kcal mol(-1)). This is consistent with the occurrence of large conformational changes during binding which was abolished upon site-directed mutaganesis of the catalytic C59S and C84S. The redox-dependent interaction was confirmed by gel filtration of mitochondrial extracts and co-immunoprecipitation from extracts. The heterocomplex of PsPrxIIF and Trx-o reduced peroxide substrates more efficiently than free PsPrxIIF suggesting that Trx-o serves as an efficient and specific electron donor to PsPrxIIF in vivo. Other Trx-s tested by ITC analysis failed to interact with PsPrxIIF indicating a specific recognition of PsPrxIIF by Trx-o. PsPrxIIF exists primarily as a dimer or a hexamer depending on the redox state. In addition to the well-characterized oligomerization of classical 2-Cys Prx the results also show that atypical Prx undergo large structural reorganization with implications for protein-protein interaction and function.

Development of a UNIX network compatible reactivity computer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez, R.F.; Edwards, R.M.

1996-12-31

A state-of-the-art UNIX network compatible controller and UNIX host workstation with MATLAB/SIMULINK software were used to develop, implement, and validate a digital reactivity calculation. An objective of the development was to determine why a Macintosh-based reactivity computer reactivity output drifted intolerably.

Reduction of fatal graft-versus-host disease by /sup 3/H--thymidine suicide of donor cells cultured with host cells. [Mice, gamma radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheever, M.A.; Einstein, A.B. Jr.; Kempf, R.A.

The effect of the tritiated thymidine (/sup 3/H-TdR) suicide technique on the ability of donor cells to induce fatal graft-versus-host disease (GVHD) was studied. C57BL/6 (H-2/sup b/) spleen cells were stimulated in vitro with irradiated BALB/c (H-2/sup d/) Moloney lymphoma cells in mixed culture and /sup 3/H-TdR of high-specific activity added to eliminate proliferating cells. The ability of such cells to induce fatal GVHD was assayed by injecting them i.v. into adult BALB/c mice immunosuppressed with cyclophosphamide (180 mg/kg). These cells induced fatal GVHD in fewer mice (52 percent) than did C57BL/6 cells cultured with BALB/c lymphoma cells but withoutmore » /sup 3/H-TdR (87 percent) and C57BL/6 cells cultured with irradiated C57BL/6 cells with (95 percent) or without /sup 3/H-TdR (86 percent). Thus, the /sup 3/H-TdR suicide technique greatly diminished the ability of cells to induce lethal GVHD.« less

[Mechanical strength and mechano-compatibility of tissue-engineered bones].

PubMed

Tanaka, Shigeo

2016-01-01

Current artificial bones made of metals and ceramics may be replaced around a decade after implantation due to its low durability, which is brought on by a large difference from the host bone in mechanical properties, i.e., low mechano-compatibility. On the other hand, tissue engineering could be a solution with regeneration of bone tissues from stem cells in vitro. However, there are still some problems to realize exactly the same mechanical properties as those of real bone. This paper introduces the technical background of bone tissue engineering and discusses possible methods for installation of mechano-compatibility into a regenerative bone. At the end, future directions toward the realization of ideal mechano-compatible regenerative bone are proposed.

Tunnel coupling tuning of a QD-donor S-T qubit

NASA Astrophysics Data System (ADS)

Jock, R. M.; Rudolph, M.; Harvey-Collard, P.; Jacobson, T.; Wendt, J.; Pluym, T.; Dominguez, J.; Manginell, R.; Lilly, M. P.; Carroll, M. S.

Coherent coupling between an electrostatic quantum dot (QD) and an implanted 31P donor has been recently demonstrated in a singlet-triplet qubit design. Controlling the tunnel coupling between the QD and donor is a key design challenge. We demonstrate the ability to voltage-tune the tunnel coupling between a QD and a donor in a new, implanted, MOS-QD design. The tunnel coupling is extracted from the frequency dependence of coherent singlet-triplet oscillations on detuning. By tailoring the electrostatic tuning of the QD, we observe a near-order-of-magnitude change in QD-donor tunnel coupling. Independent control of the QD-lead tunnel rates is also demonstrated. This new MOS foundry compatible QD-donor design shows promise for substantially relaxing fabrication requirements for donor based qubits. This work was performed, in part, at the Center for Integrated Nanotechnologies, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. DOE's National Nuclear Security Administration under contract DE-AC04-94AL85000.

Interactions of Seedborne Bacterial Pathogens with Host and Non-Host Plants in Relation to Seed Infestation and Seedling Transmission

PubMed Central

Dutta, Bhabesh; Gitaitis, Ronald; Smith, Samuel; Langston, David

2014-01-01

The ability of seed-borne bacterial pathogens (Acidovorax citrulli, Clavibacter michiganensis subsp. michiganensis, Pseudomonas syringae pv. tomato, Xanthomonas euvesicatoria, and Pseudomonas syringae pv. glycinea) to infest seeds of host and non-host plants (watermelon, tomato, pepper, and soybean) and subsequent pathogen transmission to seedlings was investigated. A non-pathogenic, pigmented strain of Serratia marcescens was also included to assess a null-interacting situation with the same plant species. Flowers of host and non-host plants were inoculated with 1×106 colony forming units (CFUs)/flower for each bacterial species and allowed to develop into fruits or umbels (in case of onion). Seeds harvested from each host/non-host bacterial species combination were assayed for respective bacteria by plating on semi-selective media. Additionally, seedlots for each host/non-host bacterial species combination were also assayed for pathogen transmission by seedling grow-out (SGO) assays under greenhouse conditions. The mean percentage of seedlots infested with compatible and incompatible pathogens was 31.7 and 30.9% (by plating), respectively and they were not significantly different (P = 0.67). The percentage of seedlots infested with null-interacting bacterial species was 16.8% (by plating) and it was significantly lower than the infested lots generated with compatible and incompatible bacterial pathogens (P = 0.03). None of the seedlots with incompatible/null-interacting bacteria developed symptoms on seedlings; however, when seedlings were assayed for epiphytic bacterial presence, 19.5 and 9.4% of the lots were positive, respectively. These results indicate that the seeds of non-host plants can become infested with incompatible and null-interacting bacterial species through flower colonization and they can be transmitted via epiphytic colonization of seedlings. In addition, it was also observed that flowers and seeds of non-host plants can be colonized

Effect of two intermediate electron donors, NADPH and FADH(2), on Spirulina Delta (6)-desaturase co-expressed with two different immediate electron donors, cytochrome b (5) and ferredoxin, in Escherichia coli.

PubMed

Kurdrid, Pavinee; Subudhi, Sanjukta; Cheevadhanarak, Supapon; Tanticharoen, Morakot; Hongsthong, Apiradee

2007-12-01

When the gene desD encoding Spirulina Delta(6)-desaturase was heterologously expressed in E. coli, the enzyme was expressed without the ability to function. However, when this enzyme was co-expressed with an immediate electron donor, i.e. the cytochrome b (5) domain from Mucor rouxii, the results showed the production of GLA (gamma-linolenic acid), the product of the reaction catalyzed by Delta(6)-desaturase. The results revealed that in E. coli cells, where cytochrome b (5) is absent and ferredoxin, a natural electron donor of Delta(6)-desaturase, is present at a very low level, the cytochrome b (5) domain can complement for the function of ferredoxin in the host cells. In the present study, the Spirulina-ferredoxin gene was cloned and co-expressed with the Delta(6)-desaturase in E. coli. In comparison to the co-expression of cytochrome b ( 5 ) with the Delta(6)-desaturase, the co-expression with ferredoxin did not cause any differences in the GLA level. Moreover, the cultures containing the Delta(6)-desaturase co-expressed with cytochrome b (5) and ferredoxin were exogenously supplied with the intermediate electron donors, NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and FADH(2) (flavin adenine dinucleotide, reduced form), respectively. The GLA level in these host cells increased drastically, by approximately 50%, compared to the cells without the intermediate electron donors. The data indicated that besides the level of immediate electron donors, the level of intermediate electron donors is also critical for GLA production. Therefore, if the pools of the immediate and intermediate electron donors in the cells are manipulated, the GLA production in the heterologous host will be affected.

A patient with congenital hyperlactataemia and Leigh syndrome: an uncommon mitochondrial variant.

PubMed

Ching, C K; Mak, Chloe M; Au, K M; Chan, K Y; Yuen, Y P; Yau, Eric K C; Ma, Louis C K; Chow, H L; Chan, Albert Y W

2013-08-01

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC_012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility.

PubMed

Doxiadis, Ilias I N; de Fijter, Johan W; Mallat, Marko J K; Haasnoot, Geert W; Ringers, Jan; Persijn, Guido G; Claas, Frans H J

2007-05-15

The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.

Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease.

PubMed

Krenger, W; Snyder, K M; Byon, J C; Falzarano, G; Ferrara, J L

1995-07-15

Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice after i.v. injection with LPS was significantly improved. Furthermore, cell-mixing experiments revealed that polarized type 2 T cells were able to inhibit type 1 cytokine responses induced by naive T cells after BMT. These data demonstrate that both polarized CD4+ and CD8+ type 2 alloreactive donor T cells can be generated in vitro from mature T cell populations. These cells function in vivo to inhibit type 1 T cell responses, and such inhibition attenuates the systemic morbidity of GVHD after BMT across both MHC class II or class I barriers in mice.

Post-zygotic sterility and cytonuclear compatibility limits in S. cerevisiae xenomitochondrial cybrids

PubMed Central

Špírek, Mário; Poláková, Silvia; Jatzová, Katarína; Sulo, Pavol

2015-01-01

Nucleo-mitochondrial interactions, particularly those determining the primary divergence of biological species, can be studied by means of xenomitochondrial cybrids, which are cells where the original mitochondria are substituted by their counterparts from related species. Saccharomyces cerevisiae cybrids are prepared simply by the mating of the ρ0 strain with impaired karyogamy and germinating spores from other Saccharomyces species and fall into three categories. Cybrids with compatible mitochondrial DNA (mtDNA) from Saccharomyces paradoxus CBS 432 and Saccharomyces cariocanus CBS 7994 are metabolically and genetically similar to cybrids containing mtDNA from various S. cerevisiae. Cybrids with mtDNA from other S. paradoxus strains, S. cariocanus, Saccharomyces kudriavzevii, and Saccharomyces mikatae require a period of adaptation to establish efficient oxidative phosphorylation. They exhibit a temperature-sensitive phenotype, slower growth rate on a non-fermentable carbon source and a long lag phase after the shift from glucose. Their decreased respiration capacity and reduced cytochrome aa3 content is associated with the inefficient splicing of cox1I3β, the intron found in all Saccharomyces species but not in S. cerevisiae. The splicing defect is compensated in cybrids by nuclear gain-of-function and can be alternatively suppressed by overexpression of MRP13 gene for mitochondrial ribosomal protein or the MRS2, MRS3, and MRS4 genes involved in intron splicing. S. cerevisiae with Saccharomyces bayanus mtDNA is unable to respire and the growth on ethanol–glycerol can be restored only after mating to some mit− strains. The nucleo-mitochondrial compatibility limit of S. cerevisiae and other Saccharomyces was set between S. kudriavzevii and S. bayanus at the divergence from S. cerevisiae about 15 MYA. The MRS1-cox1 S. cerevisiae/S. paradoxus cytonuclear Dobzhansky–Muller pair has a neglible impact on the separation of species since its imperfection is

Nanographenes as electron-deficient cores of donor-acceptor systems.

PubMed

Liu, Yu-Min; Hou, Hao; Zhou, Yan-Zhen; Zhao, Xin-Jing; Tang, Chun; Tan, Yuan-Zhi; Müllen, Klaus

2018-05-15

Conjugation of nanographenes (NGs) with electro-active molecules can establish donor-acceptor π-systems in which the former generally serve as the electron-donating moieties due to their electronic-rich nature. In contrast, here we report a series of reversed donor-acceptor structures are obtained by C-N coupling of electron-deficient perchlorinated NGs with electron-rich anilines. Selective amination at the vertexes of the NGs is unambiguously shown through X-ray crystallography. By varying the donating ability of the anilino groups, the optical and assembly properties of donor-acceptor NGs can be finely modulated. The electron-deficient concave core of the resulting conjugates can host electron-rich guest molecules by intermolecular donor-acceptor interactions and gives rise to charge-transfer supramolecular architectures.

Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

PubMed Central

Sun, Kaihua; Johnson, Brian S.; Gunn, Teresa M.

2007-01-01

Oxidative stress, ubiquitination defects and mitochondrial dysfunction are commonly associated with neurodegeneration. Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) develop age-dependent spongiform neurodegeneration through an unknown mechanism. It has been suggested that they act in a common pathway. As MGRN1 is an E3 ubiquitin ligase, proteomic analysis of Mgrn1 mutant and control brains was performed to explore the hypothesis that loss of MGRN1 causes neurodegeneration via accumulation of its substrates. Many mitochondrial proteins were reduced in Mgrn1 mutants. Subsequent assays confirmed significantly reduced mitochondrial complex IV expression and activity as well as increased oxidative stress in mutant brains. Mitochondrial dysfunction was obvious many months before onset of vacuolation, implicating this as a causative factor. Compatible with the hypothesis that ATRN and MGRN1 act in the same pathway, mitochondrial dysfunction and increased oxidative stress were also observed in the brains of Atrn mutants. Our results suggest that the study of Mgrn1 and Atrn mutant mice will provide insight into a causative molecular mechanism common to many neurodegenerative disorders. PMID:17720281

Survival and engraftment of dopaminergic neurons manufactured by a Good Manufacturing Practice-compatible process.

PubMed

Peng, Jun; Liu, Qiuyue; Rao, Mahendra S; Zeng, Xianmin

2014-09-01

We have previously reported a Good Manufacturing Practice (GMP)-compatible process for generating authentic dopaminergic neurons in defined media from human pluripotent stem cells and determined the time point at which dopaminergic precursors/neurons (day 14 after neuronal stem cell [NSC] stage) can be frozen, shipped and thawed without compromising their viability and ability to mature in vitro. One important issue we wished to address is whether dopaminergic precursors/neurons manufactured by our GMP-compatible process can be cryopreserved and engrafted in animal Parkinson disease (PD) models. In this study, we evaluated the efficacy of freshly prepared and cryopreserved dopaminergic neurons in the 6-hydroxydopamine-lesioned rat PD model. We showed functional recovery up to 6 months post-transplantation in rats transplanted with our cells, whether freshly prepared or cryopreserved. In contrast, no motor improvement was observed in two control groups receiving either medium or cells at a slightly earlier stage (day 10 after NSC stage). Histologic analysis at the end point of the study (6 months post-transplantation) showed robust long-term survival of donor-derived tyrosine hydroxylase (TH)(+) dopaminergic neurons in rats transplanted with day 14 dopaminergic neurons. Moreover, TH(+) fibers emanated from the graft core into the surrounding host striatum. Consistent with the behavioral analysis, no or few TH(+) neurons were detected in animals receiving day 10 cells, although human cells were present in the graft. Importantly, no tumors were detected in any grafted rats, but long-term tumorigenic studies will need to determine the safety of our products. Dopaminergic neurons manufactured by a GMP-compatible process from human ESC survived and engrafted efficiently in the 6-OHDA PD rat model. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors.

PubMed

Pham, Thomas A; Lee, Jacqueline I; Melcher, Marc L

2017-01-01

With organs in short supply, only a limited number of kidney transplants can be performed a year. Live donor donation accounts for 1/3rd of all kidney transplants performed in the United States. Unfortunately, not every donor recipient pair is feasible because of Human leukocyte antigen (HLA) sensitization and ABO incompatibility. To overcome these barriers to transplant, strategies such as kidney paired donation (KPD) and desensitization have been developed. KPD is the exchange of donors between at least two incompatible donor-recipient pairs such that they are now compatible. Desensitization is the removal of circulating donor specific antibodies to prevent graft rejection. Regardless of the treatment strategy, highly sensitized patients whose calculated panel reactive antibody (cPRA) is ≥95% remain difficult to transplant with match rates as low as 15% in KPD pools. Desensitization has proved to be difficult in those with high antibody titers. A novel approach is the combination of both KPD and desensitization to facilitate compatible and successful transplantation. A highly sensitized patient can be paired with a better immunological match in the KPD pool and subsequently desensitized to a lesser degree. This article reviews the current progress in KPD and desensitization and their use as a combined therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

The devil is in the details: retention of recipient group A type 5 years after a successful allogeneic bone marrow transplant from a group O donor.

PubMed

Cooling, Laura L W; Herrst, Michelle; Hugan, Sherri L

2018-01-01

ABO-incompatible (ABOi) hematopoietic stem cell transplants (HSCTs) can present challenges in the blood bank. During transplantation, patients receive components that are ABO-compatible with both the donor graft and recipient; this practice can strain group O red blood cell (RBC) inventories.1 In addition, there are risks for acute hemolysis at the time of infusion and in the early post-transplant period.1,2 In ABO major-incompatible bone marrow HSCTs, which contain significant quantities of donor RBCs that are ABOi with recipient plasma, it is common to perform a RBC depletion of the bone marrow in an effort to minimize hemolysis at the time of infusion.2 Furthermore, patients with high-titer ABO antibodies may undergo a prophylactic, pre-transplant plasma exchange to further reduce the risk of acute hemolysis, delayed RBC engraftment, and pure RBC aplasia.2-4 ABO minor-incompatible HSCTs, in which donor plasma is ABOi with the recipient, have less risk for hemolysis at the time of infusion but can result in transient hemolysis approximately 10-21 days post-transplant, especially in patients undergoing nonmyeloablative HSCT and/or patients who have not received methotrexate for graft-versus-host-disease (GVHD) prophylaxis.1-4 In these patients, viable donor B-lymphocytes in the graft may expand and produce ABO antibodies capable of hemolyzing patient RBCs.

Deficient mitochondrial biogenesis in IL-2 activated NK cells correlates with impaired PGC1-α upregulation in elderly humans.

PubMed

Miranda, Dante; Jara, Claudia; Mejias, Sophia; Ahumada, Viviana; Cortez-San Martin, Marcelo; Ibañez, Jorge; Hirsch, Sandra; Montoya, Margarita

2018-05-18

Immunosenescence has been described as age-associated changes in the immune function which are thought to be responsible for the increased morbidity with age. Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in immune defense against tumor and microbial diseases. Interestingly, aging-related NK cell dysfunction is associated with features of aging such as tumor incidence, reduced vaccination efficacy, and short survival due to infection. It is known that NK cell effector functions are critically dependent on cytokines and metabolic activity. Our aim was to determine whether there is a difference in purified human NK cell function in response to high concentration of IL-2 between young and elder donors. Here, we report that the stimulation of human NK cells with IL-2 (2000 U/mL) enhance NK cell cytotoxic activity from both young and elderly donors. However, while NK cells from young people responded to IL-2 signaling by increasing mitochondrial mass and mitochondrial membrane potential, no increase in these mitochondrial functional parameters was seen in purified NK cells from elderly subjects. Moreover, as purified NK cells from the young exhibited an almost three-fold increase in PGC-1α expression after IL-2 (2000 U/mL) stimulation, PGC-1α expression was inhibited in purified NK cells from elders. Furthermore, this response upon PGC-1α expression after IL-2 stimulation promoted an increase in ROS production in NK cells from elderly humans, while no increase in ROS production was observed in NK cells of young donors. Our data show that IL-2 stimulates NK cell effector function through a signaling pathway which involves a PGC-1α-dependent mitochondrial function in young NK cells, however it seems that NK cells from older donors exhibit an altered IL-2 signaling which affects mitochondrial function associated with an increased production of ROS which could represent a feature of NK cell senescence

Living unrelated donor kidney transplantation--a fourteen-year experience.

PubMed

Ignjatović, Ljiljana; Jovanović, Dragan; Kronja, Goran; Dujić, Aleksandar; Marić, Mihailo; Ignjatović, Dragan; Hrvacević, Rajko; Kovacević, Zoran; Petrović, Milija; Elaković, Dejan; Marenović, Tomislav; Lukić, Zoran; Trkuljić, Miroljub; Stanković, Bratislav; Maksić, Doko; Butorajac, Josip; Colić, Miodrag; Drasković-Pavlović, Biljana; Kapulica-Kuljić, Nada; Drasković, Nada; Misović, Sidor; Stijelja, Borislav; Milović, Novak; Tosevski, Perica; Filipović, Nikola; Romić, Predrag; Jevtić, Miodrag; Drasković, Miroljub; Vavić, Neven; Rabrenović, Violeta; Paunić, Zoran; Radojević, Milorad; Bjelanović, Zoran; Tomić, Aleksandar; Aleksić, Predrag; Kosević, Branko; Mocović, Dejan; Bancević, Vladimir; Magić, Zvonko; Vojvodić, Danilo; Balint, Bela; Ostojić, Gordana; Tukić, Ljiljana; Murgić, Jadranka; Pervulov, Svetozar; Rusović, Sinisa; Sjenicić, Goran; Vesna, Bućan; Milavić-Vujković, Merica; Jandrić, Dusan; Raicević, Ranko; Mijusković, Mirjana; Obrencević, Katarina; Pilcević, Dejan; Cukić, Zoran; Petrović, Marijana; Petrović, Milica; Tadić, Jelena; Terzić, Brankica; Karan, Zeljko; Bokonjić, Dubravko; Dobrić, Silva; Antunović, Mirjana; Bokun, Radmila; Dimitrijević, Jovan; Vukomanović-Djurdjević, Biserka

2010-12-01

In countries without a national organization for retrieval and distribution of organs of the deceased donors, problem of organ shortage is still not resolved. In order to increase the number of kidney transplantations we started with the program of living unrelated - spousal donors. The aim of this study was to compare treatment outcome and renal graft function in patients receiving the graft from spousal and those receiving ghe graft from living related donors. We retrospectively identified 14 patients who received renal allograft from spousal donors between 1996 and 2009 (group I). The control group consisted of 14 patients who got graft from related donor retrieved from the database and matched than with respect to sex, age, kidney disease, immunological and viral pretransplant status, the initial method of the end stage renal disease treatment and ABO compatibility. In the follow-up period of 41 +/- 38 months we recorded immunosuppressive therapy, surgical complications, episodes of acute rejection, CMV infection and graft function, assessed by serum creatinine levels at the beginning and in the end of the follow-up period. All patients had pretransplant negative cross-match. In ABO incompatible patients pretransplant isoagglutinine titer was zero. The patients with a spousal donor had worse HLA matching. There were no significant differences between the groups in surgical, infective, immunological complications and graft function. Two patients from the group I returned to hemodialysis after 82 and 22 months due to serious comorbidities. In spite of the worse HLA matching, graft survival and function of renal grafts from spousal donors were as good as those retrieved from related donors.

[Clinical impact of HLA disparities in transplants from unrelated donors].

PubMed

Gallardo, D

2010-12-01

The search for an unrelated donor must be based on the HLA typing of the donor and the host. PCR techniques have facilitated high-resolution HLA typing, but they have also elicited questions about the real impact of the various disparities on the progress of the graft Thus, whereas a donor used to be accepted based on HLA-A and B Identity determined by serology and HLA-DRB1 through molecular biology techniques, now a donor is required to have a 70/70 Identity for loci HLA-A, B, C, DRB7, and DQB7. Furthermore, the real effect of the disparities in the sixth locus of the major histocompatibility complex-HLA-DPBT-is still in doubt. This study intends to conduct a literature review of the clinical impact of the various HLA disparities In transplants from unrelated donors.

Loss of compatibility might explain resistance of the Arabidopsis thaliana accession Te-0 to Golovinomyces cichoracearum.

PubMed

Fabro, Georgina; Alvarez, María Elena

2012-08-11

The establishment of compatibility between plants and pathogens requires compliance with various conditions, such as recognition of the right host, suppression of defence mechanisms, and maintenance of an environment allowing pathogen reproduction. To date, most of the plant factors required to sustain compatibility remain unknown, with the few best characterized being those interfering with defence responses. A suitable system to study host compatibility factors is the interaction between Arabidopsis thaliana and the powdery mildew (PM) Golovinomyces cichoracearum. As an obligate biotrophic pathogen, this fungus must establish compatibility in order to perpetuate. In turn, A. thaliana displays natural variation for susceptibility to this invader, with some accessions showing full susceptibility (Col-0), and others monogenic dominant resistance (Kas-1). Interestingly, Te-0, among other accessions, displays recessive partial resistance to this PM. In this study, we characterized the interaction of G. cichoracearum with Te-0 plants to investigate the basis of this plant resistance. We found that Te-0's incompatibility was not associated with hyper-activation of host inducible defences. Te-0 plants allowed germination of conidia and development of functional haustoria, but could not support the formation of mature conidiophores. Using a suppressive subtractive hybridization technique, we identified plant genes showing differential expression between resistant Te-0 and susceptible Col-0 plants at the fungal pre-conidiation stage. Te-0 resistance is likely caused by loss of host compatibility and not by stimulation of inducible defences. Conidiophores formation is the main constraint for completion of fungal life cycle in Te-0 plants. The system here described allowed the identification of genes proposed as markers for susceptibility to this PM.

Loss of compatibility might explain resistance of the Arabidopsis thaliana accession Te-0 to Golovinomyces cichoracearum

PubMed Central

2012-01-01

Background The establishment of compatibility between plants and pathogens requires compliance with various conditions, such as recognition of the right host, suppression of defence mechanisms, and maintenance of an environment allowing pathogen reproduction. To date, most of the plant factors required to sustain compatibility remain unknown, with the few best characterized being those interfering with defence responses. A suitable system to study host compatibility factors is the interaction between Arabidopsis thaliana and the powdery mildew (PM) Golovinomyces cichoracearum. As an obligate biotrophic pathogen, this fungus must establish compatibility in order to perpetuate. In turn, A. thaliana displays natural variation for susceptibility to this invader, with some accessions showing full susceptibility (Col-0), and others monogenic dominant resistance (Kas-1). Interestingly, Te-0, among other accessions, displays recessive partial resistance to this PM. Results In this study, we characterized the interaction of G. cichoracearum with Te-0 plants to investigate the basis of this plant resistance. We found that Te-0´s incompatibility was not associated with hyper-activation of host inducible defences. Te-0 plants allowed germination of conidia and development of functional haustoria, but could not support the formation of mature conidiophores. Using a suppressive subtractive hybridization technique, we identified plant genes showing differential expression between resistant Te-0 and susceptible Col-0 plants at the fungal pre-conidiation stage. Conclusions Te-0 resistance is likely caused by loss of host compatibility and not by stimulation of inducible defences. Conidiophores formation is the main constraint for completion of fungal life cycle in Te-0 plants. The system here described allowed the identification of genes proposed as markers for susceptibility to this PM. PMID:22883024

Donor cycle and donor segmentation: new tools for improving blood donor management.

PubMed

Veldhuizen, I; Folléa, G; de Kort, W

2013-07-01

An adequate donor population is of key importance for the entire blood transfusion chain. For good donor management, a detailed overview of the donor database is therefore imperative. This study offers a new description of the donor cycle related to the donor management process. It also presents the outcomes of a European Project, Donor Management IN Europe (DOMAINE), regarding the segmentation of the donor population into donor types. Blood establishments (BEs) from 18 European countries, the Thalassaemia International Federation and a representative from the South-Eastern Europe Health Network joined forces in DOMAINE. A questionnaire assessed blood donor management practices and the composition of the donor population using the newly proposed DOMAINE donor segmentation. 48 BEs in 34 European countries were invited to participate. The response rate was high (88%). However, only 14 BEs could deliver data on the composition of their donor population. The data showed large variations and major imbalances in the donor population. In 79% of the countries, inactive donors formed the dominant donor type. Only in 21%, regular donors were the largest subgroup, and in 29%, the proportion of first-time donors was higher than the proportion of regular donors. Good donor management depends on a thorough insight into the flow of donors through their donor career. Segmentation of the donor database is an essential tool to understand the influx and efflux of donors. The DOMAINE donor segmentation helps BEs in understanding their donor database and to adapt their donor recruitment and retention practices accordingly. Ways to use this new tool are proposed. © 2013 International Society of Blood Transfusion.

Advanced Donation Programs and Deceased Donor-Initiated Chains-2 Innovations in Kidney Paired Donation.

PubMed

Wall, Anji E; Veale, Jeffrey L; Melcher, Marc L

2017-12-01

Kidney paired donation (KPD) strategies have facilitated compatible living-donor kidney transplants for end-stage renal disease patients with willing but incompatible living donors. Success has inspired further innovations that expand opportunities for kidney-paired donation. Two such innovations are the advanced donation strategy in which a donor provides a kidney before their recipient is matched, or even in need of, a kidney transplant, and deceased donor initiated chains in which chains are started with deceased donors rather than altruistic living donors. Although these innovations may expand KPD, they raise several ethical issues. Specific concerns raised by advanced donation include the management of uncertainty, the extent of donor and recipient consent, the scope of the obligation that the organization has to the kidney exchange paired recipient, the naming of alternative recipients, and the potential to unfairly advantage the recipient. Use of deceased donors for chain-initiating kidneys raises ethical issues concerning the consent process for each involved party, the prioritization of deceased donor kidneys, the allocation of chain ending kidneys, and the value of a living donor kidney versus a deceased donor kidney. We outline each ethical issue and discuss how it can be conceptualized and managed so that these KPD innovations programs are ultimately successful.

BARTERING FOR A COMPATIBLE KIDNEY USING YOUR INCOMPATIBLE, LIVE KIDNEY DONOR: LEGAL AND ETHICAL ISSUES RELATED TO KIDNEY CHAINS.

PubMed

Tenenbaum, Evelyn M

2016-01-01

Kidney chains are a recent and novel method of increasing the number of available kidneys for transplantation and have the potential to save thousands of lives. However, because they are novel, kidney chains do not fit neatly within existing legal and ethicalframeworks, raising potential barriers to their full implementation. Kidney chains are an extension of paired kidney donation, which began in the United States in 2000. Paired kidney donations allow kidney patients with willing, but incompatible, donors to swap donors to increase the number of donor/recipient pairs and consequently, the number of transplants. More recently, transplant centers have been using non-simultaneous, extended, altruistic donor ("NEAD") kidney chains--which consist of a sequence of donations by incompatible donors--to further expand the number of donations. This Article fully explains paired kidney donation and kidney chains and focuses on whether NEAD chains are more coercive than traditional kidney donation to a family member or close friend and whether NEAD chains violate the National Organ Transplant Act's prohibition on the transfer of organs for valuable consideration.

A Mitochondrial Story: Mitochondrial Replacement, Identity and Narrative.

PubMed

Scully, Jackie Leach

2017-01-01

Mitochondrial replacement techniques (MRT) are intended to avoid the transmission of mitochondrial diseases from mother to child. MRT represent a potentially powerful new biomedical technology with ethical, policy, economic and social implications. Among other ethical questions raised are concerns about the possible effects on the identity of children born from MRT, their families, and the providers or donors of mitochondria. It has been suggested that MRT can influence identity (i) directly, through altering the genetic makeup and physical characteristics of the child, or (ii) indirectly through changing the child's experience of disease, and by generating novel intrafamilial relationships that shape the sense of self. In this article I consider the plausibility and ethical implications of these proposed identity effects, but I focus instead on a third way in which identity may be affected, through the mediating influence of the wider social world on MRT effects on identity. By taking a narrative approach, and examining the nature and availability of identity narratives, I conclude that while neither direct genetic nor indirect experiential effects can be excluded, social responses to MRT are more likely to have a significant and potentially damaging influence on the generation of MRT children's narratives of identity. This conclusion carries some implications for the collective moral responsibility we hold to ensure that MRT, if implemented, are practised in ethically justifiable ways. © 2017 John Wiley & Sons Ltd.

The evolution of sex: A new hypothesis based on mitochondrial mutational erosion: Mitochondrial mutational erosion in ancestral eukaryotes would favor the evolution of sex, harnessing nuclear recombination to optimize compensatory nuclear coadaptation.

PubMed

Havird, Justin C; Hall, Matthew D; Dowling, Damian K

2015-09-01

The evolution of sex in eukaryotes represents a paradox, given the "twofold" fitness cost it incurs. We hypothesize that the mutational dynamics of the mitochondrial genome would have favored the evolution of sexual reproduction. Mitochondrial DNA (mtDNA) exhibits a high-mutation rate across most eukaryote taxa, and several lines of evidence suggest that this high rate is an ancestral character. This seems inexplicable given that mtDNA-encoded genes underlie the expression of life's most salient functions, including energy conversion. We propose that negative metabolic effects linked to mitochondrial mutation accumulation would have invoked selection for sexual recombination between divergent host nuclear genomes in early eukaryote lineages. This would provide a mechanism by which recombinant host genotypes could be rapidly shuffled and screened for the presence of compensatory modifiers that offset mtDNA-induced harm. Under this hypothesis, recombination provides the genetic variation necessary for compensatory nuclear coadaptation to keep pace with mitochondrial mutation accumulation. © 2015 WILEY Periodicals, Inc.

Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.

PubMed

Yoon, Young-In; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin; Kim, Ki-Hun; Kim, Seok-Hwan; Kang, Woo-Hyoung; Cho, Hwui-Dong; Jwa, Eun-Kyoung; Kwon, Jae-Hyun; Tak, Eun-Young; Kirchner, Varvara A

2018-06-01

Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m 2 /body surface area). We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO

Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue.

PubMed

Devall, Matthew; Smith, Rebecca G; Jeffries, Aaron; Hannon, Eilis; Davies, Matthew N; Schalkwyk, Leonard; Mill, Jonathan; Weedon, Michael; Lunnon, Katie

2017-01-01

DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions ( p  < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples ( N  = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex. Our study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation

Mitochondrial Dynamics in Mitochondrial Diseases

PubMed Central

Suárez-Rivero, Juan M.; Villanueva-Paz, Marina; de la Cruz-Ojeda, Patricia; de la Mata, Mario; Cotán, David; Oropesa-Ávila, Manuel; de Lavera, Isabel; Álvarez-Córdoba, Mónica; Luzón-Hidalgo, Raquel; Sánchez-Alcázar, José A.

2016-01-01

Mitochondria are very versatile organelles in continuous fusion and fission processes in response to various cellular signals. Mitochondrial dynamics, including mitochondrial fission/fusion, movements and turnover, are essential for the mitochondrial network quality control. Alterations in mitochondrial dynamics can cause neuropathies such as Charcot-Marie-Tooth disease in which mitochondrial fusion and transport are impaired, or dominant optic atrophy which is caused by a reduced mitochondrial fusion. On the other hand, mitochondrial dysfunction in primary mitochondrial diseases promotes reactive oxygen species production that impairs its own function and dynamics, causing a continuous vicious cycle that aggravates the pathological phenotype. Mitochondrial dynamics provides a new way to understand the pathophysiology of mitochondrial disorders and other diseases related to mitochondria dysfunction such as diabetes, heart failure, or Hungtinton’s disease. The knowledge about mitochondrial dynamics also offers new therapeutics targets in mitochondrial diseases. PMID:28933354

Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health☆☆☆

PubMed Central

Kotiadis, Vassilios N.; Duchen, Michael R.; Osellame, Laura D.

2014-01-01

Background The maintenance of cell metabolism and homeostasis is a fundamental characteristic of living organisms. In eukaryotes, mitochondria are the cornerstone of these life supporting processes, playing leading roles in a host of core cellular functions, including energy transduction, metabolic and calcium signalling, and supporting roles in a number of biosynthetic pathways. The possession of a discrete mitochondrial genome dictates that the maintenance of mitochondrial ‘fitness’ requires quality control mechanisms which involve close communication with the nucleus. Scope of review This review explores the synergistic mechanisms that control mitochondrial quality and function and ensure cellular bioenergetic homeostasis. These include antioxidant defence mechanisms that protect against oxidative damage caused by reactive oxygen species, while regulating signals transduced through such free radicals. Protein homeostasis controls import, folding, and degradation of proteins underpinned by mechanisms that regulate bioenergetic capacity through the mitochondrial unfolded protein response. Autophagic machinery is recruited for mitochondrial turnover through the process of mitophagy. Mitochondria also communicate with the nucleus to exact specific transcriptional responses through retrograde signalling pathways. Major conclusions The outcome of mitochondrial quality control is not only reliant on the efficient operation of the core homeostatic mechanisms but also in the effective interaction of mitochondria with other cellular components, namely the nucleus. General significance Understanding mitochondrial quality control and the interactions between the organelle and the nucleus will be crucial in developing therapies for the plethora of diseases in which the pathophysiology is determined by mitochondrial dysfunction. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID:24211250

A rhomboid gene controls speciation through regulation of nuclear-mitochondrial compatibility in Triticum

USDA-ARS?s Scientific Manuscript database

The nuclear encoded species cytoplasm specific (scs) genes control nuclear-cytoplasmic compatibility in Triticum. Alloplasmic cells, which have nucleus and cytoplasm derived from different species, produce vigorous and vital organisms only when the correct version of scs is present in their nucleus....

Use of octogenarian donors for liver transplantation: a survival analysis.

PubMed

Ghinolfi, D; Marti, J; De Simone, P; Lai, Q; Pezzati, D; Coletti, L; Tartaglia, D; Catalano, G; Tincani, G; Carrai, P; Campani, D; Miccoli, M; Biancofiore, G; Filipponi, F

2014-09-01

Use of very old donors in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk for graft dysfunction and worse long-term results, especially for hepatitis C virus (HCV)-positive recipients. This was a retrospective, single-center review of primary, ABO-compatible LT performed between 2001 and 2010. Recipients were stratified in four groups based on donor age (<60 years; 60-69 years; 70-79 years and ≥80 years) and their outcomes were compared. A total of 842 patients were included: 348 (41.3%) with donors <60 years; 176 (20.9%) with donors 60-69 years; 233 (27.7%) with donors 70-79 years and 85 (10.1%) with donors ≥80 years. There was no difference across groups in terms of early (≤30 days) graft loss, and graft survival at 1 and 5 years was 90.5% and 78.6% for grafts <60 years; 88.6% and 81.3% for grafts 60-69 years; 87.6% and 75.1% for grafts 70-79 years and 84.7% and 77.1% for grafts ≥80 years (p = 0.065). In the group ≥80 years, the 5-year graft survival was lower for HCV-positive versus HCV-negative recipients (62.4% vs. 85.6%, p = 0.034). Based on our experience, grafts from donors ≥80 years may provide favorable results but require appropriate selection and allocation policies. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Mitochondrial DNA content and 4977 bp deletion in unfertilized oocytes.

PubMed

Chan, C C W; Liu, V W S; Lau, E Y L; Yeung, W S B; Ng, E H Y; Ho, P C

2005-12-01

Previous studies analysing the incidences of mitochondrial DNA (mtDNA) deletions and mtDNA content in unfertilized oocytes in relation to donors' age have been controversial. The objective of the study was to compare these two parameters in unfertilized oocytes and relate them to the donors' age. Fifty-two women donated 155 unfertilized metaphase II (MII) oocytes. The incidence of 4977 bp deletion was 34.6%, and the mtDNA copy number was 598 350 +/- 265 862. Women >or=35 years of age had a significantly higher incidence of 4977 bp deletion, lower mtDNA copy number, higher FSH level and poorer ovarian response when compared with younger women. The mtDNA copy number was negatively correlated with the donor's age. The higher incidence of mtDNA deletion and lower mtDNA copy number in older women suggested that these two parameters may reflect ovarian ageing.

Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes.

PubMed

Goodwin, Jodi; Tinckam, Kathryn; denHollander, Neal; Haroon, Ayesha; Keshavjee, Shaf; Cserti-Gazdewich, Christine M

2010-09-01

It is unknown the extent to which transfusion-related acute lung injury (TRALI) contributes to primary graft dysfunction (PGD), the leading cause of death after lung transplantation. In this case of suspected transfusion-associated acute bilateral graft injury in a 61-year-old idiopathic pulmonary fibrosis patient, recipient sera from before and after transplantation/transfusion, as well as the sera of 22 of the 24 implicated blood donors, were individually screened by Luminex bead assay for the presence of human leukocyte antigen (HLA) antibodies, with recipient and lung donor HLA typing to explore for cognate relationships. A red-cell-unit donor-source anti-Cw6 antibody, cognate with the HLA type of the recipient, was identified. This is the second reported case of TRALI in the setting of lung transplantation, and the first to show an associated interaction between donor antibodies (in a low-plasma volume product) with recipient leukocytes (rather than graft antigens); therefore, it should be considered in the differential diagnosis of PGD. Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions.

PubMed

Lobb, I; Jiang, J; Lian, D; Liu, W; Haig, A; Saha, M N; Torregrossa, R; Wood, M E; Whiteman, M; Sener, A

2017-02-01

Ischemia-reperfusion injury is unavoidably caused by loss and subsequent restoration of blood flow during organ procurement, and prolonged ischemia-reperfusion injury IRI results in increased rates of delayed graft function and early graft loss. The endogenously produced gasotransmitter, hydrogen sulfide (H 2 S), is a novel molecule that mitigates hypoxic tissue injury. The current study investigates the protective mitochondrial effects of H 2 S during in vivo cold storage and subsequent renal transplantation (RTx) and in vitro cold hypoxic renal injury. Donor allografts from Brown Norway rats treated with University of Wisconsin (UW) solution + H 2 S (150 μM NaSH) during prolonged (24-h) cold (4°C) storage exhibited significantly (p < 0.05) decreased acute necrotic/apoptotic injury and significantly (p < 0.05) improved function and recipient Lewis rat survival compared to UW solution alone. Treatment of rat kidney epithelial cells (NRK-52E) with the mitochondrial-targeted H 2 S donor, AP39, during in vitro cold hypoxic injury improved the protective capacity of H 2 S >1000-fold compared to similar levels of the nonspecific H 2 S donor, GYY4137 and also improved syngraft function and survival following prolonged cold storage compared to UW solution. H 2 S treatment mitigates cold IRI-associated renal injury via mitochondrial actions and could represent a novel therapeutic strategy to minimize the detrimental clinical outcomes of prolonged cold IRI during RTx. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Penicillium expansum (compatible) and Penicillium digitatum (non-host) pathogen infection differentially alter ethylene biosynthesis in apple fruit.

PubMed

Vilanova, Laura; Vall-Llaura, Núria; Torres, Rosario; Usall, Josep; Teixidó, Neus; Larrigaudière, Christian; Giné-Bordonaba, Jordi

2017-11-01

The role of ethylene on inducing plant resistance or susceptibility to certain fungal pathogens clearly depends on the plant pathogen interaction with little or no-information available focused on the apple-Penicillium interaction. Taken advantage that Penicillium expansum is the compatible pathogen and P. digitatum is the non-host of apples, the present study aimed at deciphering how each Penicillium spp. could interfere in the fruit ethylene biosynthesis at the biochemical and molecular level. The infection capacity and different aspects related to the ethylene biosynthesis were conducted at different times post-inoculation. The results show that the fruit ethylene biosynthesis was differently altered during the P. expansum infection than in response to other biotic (non-host pathogen P. digitatum) or abiotic stresses (wounding). The first symptoms of the disease due to P. expansum were visible before the initiation of the fruit ethylene climacteric burst. Indeed, the ethylene climacteric burst was reduced in response to P. expansum concomitant to an important induction of MdACO3 gene expression and an inhibition (ca. 3-fold) and overexpression (ca. 2-fold) of ACO (1-Aminocyclopropane-1-carboxylic acid oxidase) and ACS (1-Aminocyclopropane-1-carboxylic acid synthase) enzyme activities, indicating a putative role of MdACO3 in the P. expansum-apple interaction which may, in turn, be related to System-1 ethylene biosynthesis. System-1 is auto-inhibited by ethylene and is characteristic of non-climateric or pre-climacteric fruit. Accordingly, we hypothesise that P. expansum may 'manipulate' the endogenous ethylene biosynthesis in apples, leading to the circumvention or suppression of effective defences hence facilitating its colonization. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The redox state of endogenous pyridine nucleotides can determine both the degree of mitochondrial oxidative stress and the solute selectivity of the permeability transition pore.

PubMed

Zago, E B; Castilho, R F; Vercesi, A E

2000-07-28

Acetoacetate, an NADH oxidant, stimulated the ruthenium red-insensitive rat liver mitochondrial Ca(2+) efflux without significant release of state-4 respiration, disruption of membrane potential (Deltapsi) or mitochondrial swelling. This process is compatible with the opening of the currently designated low conductance state of the permeability transition pore (PTP) and, under our experimental conditions, was associated with a partial oxidation of the mitochondrial pyridine nucleotides. In contrast, diamide, a thiol oxidant, induced a fast mitochondrial Ca(2+) efflux associated with a release of state-4 respiration, a disruption of Deltapsi and a large amplitude mitochondrial swelling. This is compatible with the opening of the high conductance state of the PTP and was associated with extensive oxidation of pyridine nucleotides. Interestingly, the addition of carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone to the acetoacetate experiment promoted a fast shift from the low to the high conductance state of the PTP. Both acetoacetate and diamide-induced mitochondrial permeabilization were inhibited by exogenous catalase. We propose that the shift from a low to a high conductance state of the PTP can be promoted by the oxidation of NADPH. This impairs the antioxidant function of the glutathione reductase/peroxidase system, strongly strengthening the state of mitochondrial oxidative stress.

Mitochondrial genome sequencing reveals potential origins of the scabies mite Sarcoptes scabiei infesting two iconic Australian marsupials.

PubMed

Fraser, Tamieka A; Shao, Renfu; Fountain-Jones, Nicholas M; Charleston, Michael; Martin, Alynn; Whiteley, Pam; Holme, Roz; Carver, Scott; Polkinghorne, Adam

2017-11-28

Debilitating skin infestations caused by the mite, Sarcoptes scabiei, have a profound impact on human and animal health globally. In Australia, this impact is evident across different segments of Australian society, with a growing recognition that it can contribute to rapid declines of native Australian marsupials. Cross-host transmission has been suggested to play a significant role in the epidemiology and origin of mite infestations in different species but a chronic lack of genetic resources has made further inferences difficult. To investigate the origins and molecular epidemiology of S. scabiei in Australian wildlife, we sequenced the mitochondrial genomes of S. scabiei from diseased wombats (Vombatus ursinus) and koalas (Phascolarctos cinereus) spanning New South Wales, Victoria and Tasmania, and compared them with the recently sequenced mitochondrial genome sequences of S. scabiei from humans. We found unique S. scabiei haplotypes among individual wombat and koala hosts with high sequence similarity (99.1% - 100%). Phylogenetic analysis of near full-length mitochondrial genomes revealed three clades of S. scabiei (one human and two marsupial), with no apparent geographic or host species pattern, suggestive of multiple introductions. The availability of additional mitochondrial gene sequences also enabled a re-evaluation of a range of putative molecular markers of S. scabiei, revealing that cox1 is the most informative gene for molecular epidemiological investigations. Utilising this gene target, we provide additional evidence to support cross-host transmission between different animal hosts. Our results suggest a history of parasite invasion through colonisation of Australia from hosts across the globe and the potential for cross-host transmission being a common feature of the epidemiology of this neglected pathogen. If this is the case, comparable patterns may exist elsewhere in the 'New World'. This work provides a basis for expanded molecular studies into

Mechanism for Prevention of Alcohol-Induced Liver Injury by Dietary Methyl Donors

PubMed Central

Powell, Christine L.; Bradford, Blair U.; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O’Connell, Thomas M.; Pogribny, Igor P.; Melnyk, Stepan; Koop, Dennis R.; Bleyle, Lisa; Threadgill, David W.; Rusyn, Ivan

2010-01-01

Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI. PMID:20118189

Toxic money or paid altruism: the meaning of payments for identity-release gamete donors.

PubMed

Gilman, Leah

2018-05-01

Public discourses commonly frame gamete, organ and other forms of bodily donation as altruistic 'gifts'. However, despite on-going debates about the ethics of payments to donors, few studies have examined the views of donors themselves regarding the meaning of payments and their compatibility (or not) with understandings of these practices as gifts. This article addresses this issue, analysing 24 in-depth interviews with UK identity-release gamete donors. It was crucial to all participants that their donation be viewed as fundamentally other-oriented, motivated by the desire to help others. However, whilst egg donors often accommodated payment within this narrative, male participants explained that any money would taint the gift they had given. I argue that sperm donors faced particular challenges to incorporating payment within a gift narrative for two key reasons: first, sperm donors relied on a discourse of 'pure altruism', including absolute opposition between gifts and market exchange, in order to present their donation as other-oriented. In contrast, egg donors were also able to mobilise a discourse of relational giving to present their donations as a personal gift. Second, according to a continued stereotype of sperm donors as financially motivated students, their payments have already been culturally earmarked as side-line earnings. © 2018 Foundation for the Sociology of Health & Illness.

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions.

PubMed

Mailloux, Ryan J; Jin, Xiaolei; Willmore, William G

2014-01-01

Mitochondria have a myriad of essential functions including metabolism and apoptosis. These chief functions are reliant on electron transfer reactions and the production of ATP and reactive oxygen species (ROS). The production of ATP and ROS are intimately linked to the electron transport chain (ETC). Electrons from nutrients are passed through the ETC via a series of acceptor and donor molecules to the terminal electron acceptor molecular oxygen (O2) which ultimately drives the synthesis of ATP. Electron transfer through the respiratory chain and nutrient oxidation also produces ROS. At high enough concentrations ROS can activate mitochondrial apoptotic machinery which ultimately leads to cell death. However, if maintained at low enough concentrations ROS can serve as important signaling molecules. Various regulatory mechanisms converge upon mitochondria to modulate ATP synthesis and ROS production. Given that mitochondrial function depends on redox reactions, it is important to consider how redox signals modulate mitochondrial processes. Here, we provide the first comprehensive review on how redox signals mediated through cysteine oxidation, namely S-oxidation (sulfenylation, sulfinylation), S-glutathionylation, and S-nitrosylation, regulate key mitochondrial functions including nutrient oxidation, oxidative phosphorylation, ROS production, mitochondrial permeability transition (MPT), apoptosis, and mitochondrial fission and fusion. We also consider the chemistry behind these reactions and how they are modulated in mitochondria. In addition, we also discuss emerging knowledge on disorders and disease states that are associated with deregulated redox signaling in mitochondria and how mitochondria-targeted medicines can be utilized to restore mitochondrial redox signaling.

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

PubMed Central

Chen, Michael L.; Logan, T. Daniel; Hochberg, Maryann L.; Shelat, Suresh G.; Yu, Xiang; Wilding, Gregory E.; Tan, Wei; Kujoth, Gregory C.; Prolla, Tomas A.; Selak, Mary A.; Kundu, Mondira; Carroll, Martin

2009-01-01

Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bone-marrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function. PMID:19734452

Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile.

PubMed

Kim, Yongsung; Zheng, Xinde; Ansari, Zoya; Bunnell, Mark C; Herdy, Joseph R; Traxler, Larissa; Lee, Hyungjun; Paquola, Apua C M; Blithikioti, Chrysanthi; Ku, Manching; Schlachetzki, Johannes C M; Winkler, Jürgen; Edenhofer, Frank; Glass, Christopher K; Paucar, Andres A; Jaeger, Baptiste N; Pham, Son; Boyer, Leah; Campbell, Benjamin C; Hunter, Tony; Mertens, Jerome; Gage, Fred H

2018-05-29

Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Infectious Complications after Umbilical Cord-Blood Transplantation from Unrelated Donors

PubMed Central

Montoro, Juan; Piñana, José Luis; Moscardó, Federico; Sanz, Jaime

2016-01-01

Umbilical cord-blood (UCB) is a well-recognized alternative source of stem cells for unrelated donor hematopoietic stem cell transplantation (HSCT). As compared with other stem cell sources from adult donors, it has the advantages of immediate availability of cells, absence of risk to the donor and reduced risk of graft-versus-host disease despite donor-recipient HLA disparity. However, the use of UCB is limited by the delayed post-transplant hematologic recovery due, at least in part, to the reduced number of hematopoietic cells in the graft and the delayed or incomplete immune reconstitution. As a result, severe infectious complications continue to be a leading cause of morbidity and mortality following UCB transplantation (UCBT). We will address the complex differences in the immune properties of UCB and review the incidence, characteristics, risk factors, and severity of bacterial, fungal and viral infectious complications in patients undergoing UCBT. PMID:27872731

Donor parity no longer a barrier for female-to-male hematopoietic stem cell transplantation.

PubMed

van Halteren, Astrid G S; Dierselhuis, Miranda P; Netelenbos, Tanja; Fechter, Mirjam

2014-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely applied treatment for disorders mainly involving the hematopoietic system. The success of this treatment depends on many different patient- and donor-specific factors. Based on higher CD34+ yields and superior clinical outcomes associated with the use of male donors, males are generally seen as the preferred HSCT donor. In addition, female donors are notorious for bearing memory type lymphocytes induced by previous pregnancies; such alloimmune cells may provoke unwanted immune reactions such as graft-vs.-host disease in transplant recipients. Consequently, many transplant centers try to avoid parous donors, particularly when searching the best unrelated donor for a male patient. We recently showed that parous women with female offspring have an anti-male directed tolerogenic immune status comparable to that of nulliparous donors. As discussed in this article addendum, the sex of the donor's offspring combined with the presence of HY-specific T regulator cells are possibly better selection criteria than parity status per se.

Plasticity in host utilization by two host-associated populations of Aphis gossypii Glover.

PubMed

Barman, A K; Gadhave, K R; Dutta, B; Srinivasan, R

2018-06-01

Biological and morphological plasticity in polyphagous insect herbivores allow them to exploit diverse host plant species. Geographical differences in resource availability can lead to preferential host exploitation and result in inconsistent host specialization. Biological and molecular data provide insights into specialization and plasticity of such herbivore populations. In agricultural landscapes, Aphis gossypii encounters several crop and non-crop hosts, which exist in temporal and spatial proximity. We investigated the host-specialization of two A. gossypii host-associated populations (HAPs), which were field collected from cotton and squash (cotton-associated population and melon-associated population), and later maintained separately in the greenhouse. The two aphid populations were exposed to seven plant species (cotton, okra, watermelon, squash, cucumber, pigweed, and morning glory), and evaluated for their host utilization plasticity by estimating aphid's fitness parameters (nymphal period, adult period, fecundity, and intrinsic rate of increase). Four phenotypical characters (body length, head capsule width, hind tibia length and cornicle length) were also measured from the resulting 14 different HAP × host plant combinations. Phylogenetic analysis of mitochondrial COI sequences showed no genetic variation between the two HAPs. Fitness parameters indicated a significant variation between the two aphid populations, and the variation was influenced by host plants. The performance of melon-aphids was poor (up to 89% reduction in fecundity) on malvaceous hosts, cotton and okra. However, cotton-aphids performed better on cucurbitaceous hosts, squash and watermelon (up to 66% increased fecundity) compared with the natal host, cotton. Both HAPs were able to reproduce on two weed hosts. Cotton-aphids were smaller than melon-aphids irrespective of their host plants. Results from this study suggest that the two HAPs in the study area do not have strict host

Germline replacement by blastula cell transplantation in the fish medaka.

PubMed

Li, Mingyou; Hong, Ni; Xu, Hongyan; Song, Jianxing; Hong, Yunhan

2016-07-13

Primordial germ cell (PGC) specification early in development establishes the germline for reproduction and reproductive technologies. Germline replacement (GR) is a powerful tool for conservation of valuable or endangered animals. GR is achievable by germ cell transplantation into the PGC migration pathway or gonads. Blastula cell transplantation (BCT) can also lead to the chimeric germline containing PGCs of both donor and host origins. It has remained largely unknown whether BCT is able to achieve GR at a high efficiency. Here we report efficient GR by BCT into blastula embryos in the fish medaka (Oryzias latipes). Specifically, dnd depletion completely ablated host PGCs and fertility, and dnd overexpression remarkably boosted PGCs in donor blastulae. BCT between normal donor and host produced a germline transmission rate of ~4%. This rate was enhanced up to ~30% upon PGC boosting in donors. Most importantly, BCT between PGC-boosted donors and PGC-ablated hosts led to more than 90% fertility restoration and 100% GR. Therefore, BCT features an extremely high efficiency of fertility recovery and GR in medaka. This finding makes medaka an ideal model to analyze genetic and physiological donor-host compatibilities for BCT-mediated surrogate production and propagation of endangered lower vertebrates and biodiversity.

Germline replacement by blastula cell transplantation in the fish medaka

PubMed Central

Li, Mingyou; Hong, Ni; Xu, Hongyan; Song, Jianxing; Hong, Yunhan

2016-01-01

Primordial germ cell (PGC) specification early in development establishes the germline for reproduction and reproductive technologies. Germline replacement (GR) is a powerful tool for conservation of valuable or endangered animals. GR is achievable by germ cell transplantation into the PGC migration pathway or gonads. Blastula cell transplantation (BCT) can also lead to the chimeric germline containing PGCs of both donor and host origins. It has remained largely unknown whether BCT is able to achieve GR at a high efficiency. Here we report efficient GR by BCT into blastula embryos in the fish medaka (Oryzias latipes). Specifically, dnd depletion completely ablated host PGCs and fertility, and dnd overexpression remarkably boosted PGCs in donor blastulae. BCT between normal donor and host produced a germline transmission rate of ~4%. This rate was enhanced up to ~30% upon PGC boosting in donors. Most importantly, BCT between PGC-boosted donors and PGC-ablated hosts led to more than 90% fertility restoration and 100% GR. Therefore, BCT features an extremely high efficiency of fertility recovery and GR in medaka. This finding makes medaka an ideal model to analyze genetic and physiological donor-host compatibilities for BCT-mediated surrogate production and propagation of endangered lower vertebrates and biodiversity. PMID:27406328

CSFV induced mitochondrial fission and mitophagy to inhibit apoptosis

PubMed Central

Xu, Hailuan; Yuan, Jin; He, Wencheng; Zhu, Mengjiao; Ding, Hongxing; Yi, Lin; Chen, Jinding

2017-01-01

Classical swine fever virus (CSFV), which causes typical clinical characteristics in piglets, including hemorrhagic syndrome and immunosuppression, is linked to hepatitis C and dengue virus. Oxidative stress and a reduced mitochondrial transmembrane potential are disturbed in CSFV-infected cells. The balance of mitochondrial dynamics is essential for cellular homeostasis. In this study, we offer the first evidence that CSFV induces mitochondrial fission and mitophagy to inhibit host cell apoptosis for persistent infection. The formation of mitophagosomes and decline in mitochondrial mass relevant to mitophagy were detected in CSFV-infected cells. CSFV infection increased the expression and mitochondrial translocation of Pink and Parkin. Upon activation of the PINK1 and Parkin pathways, Mitofusin 2 (MFN2), a mitochondrial fusion mediator, was ubiquitinated and degraded in CSFV-infected cells. Mitophagosomes and mitophagolysosomes induced by CSFV were, respectively, observed by the colocalization of LC3-associated mitochondria with Parkin or lysosomes. In addition, a sensitive dual fluorescence reporter (mito-mRFP-EGFP) was utilized to analyze the delivery of mitophagosomes to lysosomes. Mitochondrial fission caused by CSFV infection was further determined by mitochondrial fragmentation and Drp1 translocation into mitochondria using a confocal microscope. The preservation of mitochondrial proteins, upregulated apoptotic signals and decline of viral replication resulting from the silencing of Drp1 and Parkin in CSFV-infected cells suggested that CSFV induced mitochondrial fission and mitophagy to enhance cell survival and viral persistence. Our data for mitochondrial fission and selective mitophagy in CSFV-infected cells reveal a unique view of the pathogenesis of CSFV infection and provide new avenues for the development of antiviral strategies. PMID:28455958

Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment.

PubMed

Lopez-Cruzan, M; Sharma, R; Tiwari, M; Karbach, S; Holstein, D; Martin, C R; Lechleiter, J D; Herman, B

2016-02-15

Caspase-2 plays an important role in apoptosis induced by several stimuli, including oxidative stress. However, the subcellular localization of caspase-2, particularly its presence in the mitochondria, is unclear. It is also not known if cytosolic caspase-2 translocates to the mitochondria to trigger the intrinsic pathway of apoptosis or if caspase-2 is constitutively present in the mitochondria that then selectively mediates this apoptotic effect. Here, we demonstrate the presence of caspase-2 in purified mitochondrial fractions from in vitro -cultured cells and in liver hepatocytes using immunoblots and confocal microscopy. We show that mitochondrial caspase-2 is functionally active by performing fluorescence resonance energy transfer analyses using a mitochondrially targeted substrate flanked by donor and acceptor fluorophores. Cell-free apoptotic assays involving recombination of nuclear, cytosolic and mitochondrial fractions from the livers of wild type and Casp2 -/- mice clearly point to a direct functional role for mitochondrial caspase-2 in apoptosis. Furthermore, cytochrome c release from Casp2 -/- cells is decreased as compared with controls upon treatment with agents inducing mitochondrial dysfunction. Finally, we show that Casp2 -/- primary skin fibroblasts are protected from oxidants that target the mitochondrial electron transport chain. Taken together, our results demonstrate that caspase-2 exists in the mitochondria and that it is essential for mitochondrial oxidative stress-induced apoptosis.

Exchange donor transplantation: ethical option for living renal transplantation.

PubMed

Gürkan, A; Kaçar, S; Varılsuha, C; Tilif, S; Turunç, V; Doǧan, M; Dheir, H; Sahin, S

2011-04-01

Taking in consideration the opinion of our team, which necessitates obligation of a relative relation between donors and recipients (genetic or matrimonial), we performed donor exchanges as an ethical alternative in living donor transplantations. We reviewed the outcomes of our exchange series. Between July 2003 and August 2010 we performed 110 exchange donor transplantations in four hospitals: one four-way, two three-way, and 100 two-way cases. Donors were mostly spouses (n = 71) or mothers (n = 15). The mean age of the donors was 48.8 (range = 23-69) and the recipients 41.4 years (range = 5-66). Two were transplanted preemptively and the others had a mean dialysis duration of 43 months (range = 1-120). Among 110 patients, three compatible pairs joined the group voluntarily; 71, due to ABO incompatibility and 36, due to crossmatch positivity. Induction therapy was used in 92 patients. HLA mismatches (MM) were: one MM in three; two MM in three; three MM in 18, four MM in 36; five MM in 34; and six MM in 18. Among 90 patients tested for panel-reactive antibodies PRA, five showed class I and 10, class II positivity. In 11 patients, B-cell positivity was detected by flow cytometry. Delayed graft function (n = 2), acute rejection (n = 11), BK virus infection (n = 1), and cytomegalovirus infection (n = 3) were seen postoperatively. Three (2.7%) patients died due to sepsis. Five patients returned to dialysis program due to interstitial fibrosis tubular atrophy (IFTA) (n = 2), renal vein thrombosis (n = 1), de novo glomerulopathy (n = 1), or primary nonfunction (n = 1). The 1- and 5-year patient and graft survival rates were 96% and 96%, 95% and 89%, respectively. We believe that exchange donor transplantation is as successful as direct transplants; it is a good, ethical alternative to unrelated living transplantations. Copyright © 2011 Elsevier Inc. All rights reserved.

Animal inference on human mitochondrial diseases.

PubMed

Nardi, Francesco; Frati, Francesco; Liò, Pietro

2016-06-01

Several pathological mutations in the human mitochondrial genome have been characterized based on medical, genetic and biochemical evidence. The observation that the structure and core functions of the mitochondrial genome are conserved from animals to man suggests that the analysis of animal variation may be informative to further characterize, and possibly predict, human pathological variants. We studied the distribution of sequence site-wise diversity and structural heterogeneity (based on several scales of hydrophobicity and supercomplex classification of mitochondrial genes) at different taxonomic levels in ∼15,000 human and animal genomes. We found that human pathological mutations tend to lay in regions of low diversity and that states that are pathological in humans appear to be extremely rare in animals, with two noticeable exceptions (T10663C and C14568T). Focusing on hydrophobicity, as possibly the most general site-wise functional parameter of a protein, we deploy the observed range of hydrophobicity in mammals as a proxy for the range of permissible states compatible with an efficient functioning of the mitochondrial machinery. We show that, while non pathological human variants tend to fall within the hypothesized range, pathological mutations generally fall outside this range. We further analyzed this distribution quantitatively to show that the estimated probability of observed states can indeed be used to predict the pathogenicity of a mutation in humans. This study provides a proof of principle that animal data can indeed be informative to predict the pathogenicity of a human mutation alongside, or in the absence of, additional evidence. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analyses of mitochondrial amino acid sequence datasets support the proposal that specimens of Hypodontus macropi from three species of macropodid hosts represent distinct species

PubMed Central

2013-01-01

Background Hypodontus macropi is a common intestinal nematode of a range of kangaroos and wallabies (macropodid marsupials). Based on previous multilocus enzyme electrophoresis (MEE) and nuclear ribosomal DNA sequence data sets, H. macropi has been proposed to be complex of species. To test this proposal using independent molecular data, we sequenced the whole mitochondrial (mt) genomes of individuals of H. macropi from three different species of hosts (Macropus robustus robustus, Thylogale billardierii and Macropus [Wallabia] bicolor) as well as that of Macropicola ocydromi (a related nematode), and undertook a comparative analysis of the amino acid sequence datasets derived from these genomes. Results The mt genomes sequenced by next-generation (454) technology from H. macropi from the three host species varied from 13,634 bp to 13,699 bp in size. Pairwise comparisons of the amino acid sequences predicted from these three mt genomes revealed differences of 5.8% to 18%. Phylogenetic analysis of the amino acid sequence data sets using Bayesian Inference (BI) showed that H. macropi from the three different host species formed distinct, well-supported clades. In addition, sliding window analysis of the mt genomes defined variable regions for future population genetic studies of H. macropi in different macropodid hosts and geographical regions around Australia. Conclusions The present analyses of inferred mt protein sequence datasets clearly supported the hypothesis that H. macropi from M. robustus robustus, M. bicolor and T. billardierii represent distinct species. PMID:24261823

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells

PubMed Central

Bacchetta, Rosa; Lucarelli, Barbarella; Sartirana, Claudia; Gregori, Silvia; Lupo Stanghellini, Maria T.; Miqueu, Patrick; Tomiuk, Stefan; Hernandez-Fuentes, Maria; Gianolini, Monica E.; Greco, Raffaella; Bernardi, Massimo; Zappone, Elisabetta; Rossini, Silvano; Janssen, Uwe; Ambrosi, Alessandro; Salomoni, Monica; Peccatori, Jacopo; Ciceri, Fabio; Roncarolo, Maria-Grazia

2013-01-01

T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders. PMID:24550909

Process Improvement in Thoracic Donor Organ Procurement: Implementation of a Donor Assessment Checklist.

PubMed

Loor, Gabriel; Shumway, Sara J; McCurry, Kenneth R; Keshavamurthy, Suresh; Hussain, Syed; Weide, Garry D; Spratt, John R; Al Salihi, Mazin; Koch, Colleen G

2016-12-01

Donor organs are often procured by junior staff in stressful, unfamiliar environments where a single adverse event can be catastrophic. A formalized checklist focused on preprocedural processes related to thoracic donor organ procurement could improve detection and prevention of near miss events. A checklist was developed centered on patient identifiers, organ compatibility and quality, and team readiness. It went through five cycles of feedback and revision using a panel of expert procurement surgeons. Educational in-service sessions were held on the use of the checklist as well as best organ assessment practices. Near miss events before the survey were tallied by retrospective review of 20 procurements, and near misses after checklist implementation were prospectively recorded. We implemented the checklist for 40 donor lung and heart procurements: 20 from Cleveland Clinic and 20 from the University of Minnesota. A final survey assessment was used to determine ease of use. Nine near miss events were reported in 20 procurements before use of the checklist. Thirty-one near miss events of 40 organ procurements were identified and potentially prevented by the checklist. Eighty-seven percent of fellows found the checklist to be unobtrusive to work flow, and 100% believed its use should be mandatory. Mortality was the same before and after implementation of the checklist despite increased patient volumes. Implementation of a simple checklist for use during thoracic organ procurement uncovered a substantial number of near miss events. A preprocedural checklist for all thoracic organ transplants in the United States and abroad is feasible and would likely reduce adverse events. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Analysis of host preference and geographical distribution of Anastrepha suspensa (Diptera: Tephritidae) using phylogenetic analyses of mitochondrial cytochrome oxidase I DNA sequence data.

PubMed

Boykin, L M; Shatters, R G; Hall, D G; Burns, R E; Franqui, R A

2006-10-01

Anastrepha suspensa (Loew) is an economically important pest, restricted to the Greater Antilles and southern Florida. It infests a wide variety of hosts and is of quarantine importance in citrus, a multi-million dollar industry in Florida. The observed recent increase in citrus infested with A. suspensa in Florida has raised questions regarding host-specificity of certain populations and genetic diversity of the pest throughout its geographical distribution. Cytochrome oxidase I (COI) DNA sequence data was used to characterize the genetic diversity of A. suspensa from Florida and Caribbean populations reared from different host plants. Maximum likelihood and Bayesian phylogenetic methods were used to analyse COI data. Sequence variation among mitochondrial COI genes from 107 A. suspensa samples collected throughout Florida and the Caribbean ranged between 0 and 10% and placed all A. suspensa as a monophyletic group that united all A. suspensa in a clade sister to a Central American group of the A. fraterculus paraphyletic species complex. The most likely tree of the COI locus indicated that COI sequence variation was too low to provide resolution at the subspecies level, therefore monophyletic groups based on host-plant use, geography (Florida, Jamaica, Cayman Islands, Puerto Rico or Dominican Republic) or population sampled are not supported. This result indicates that either no population segregation has occurred based on these biological or geographical distinctions and that this is a generalist, polyphagous invasive genotype. Alternatively, if populations are distinct, the segregation event was more recent than can be distinguished based on COI sequence variation.

The Complete Mitochondrial Genome of Galba pervia (Gastropoda: Mollusca), an Intermediate Host Snail of Fasciola spp

PubMed Central

Huang, Wei-Yi; Zhao, Guang-Hui; Wei, Shu-Jun; Song, Hui-Qun; Xu, Min-Jun; Lin, Rui-Qing; Zhou, Dong-Hui; Zhu, Xing-Quan

2012-01-01

Complete mitochondrial (mt) genomes and the gene rearrangements are increasingly used as molecular markers for investigating phylogenetic relationships. Contributing to the complete mt genomes of Gastropoda, especially Pulmonata, we determined the mt genome of the freshwater snail Galba pervia, which is an important intermediate host for Fasciola spp. in China. The complete mt genome of G. pervia is 13,768 bp in length. Its genome is circular, and consists of 37 genes, including 13 genes for proteins, 2 genes for rRNA, 22 genes for tRNA. The mt gene order of G. pervia showed novel arrangement (tRNA-His, tRNA-Gly and tRNA-Tyr change positions and directions) when compared with mt genomes of Pulmonata species sequenced to date, indicating divergence among different species within the Pulmonata. A total of 3655 amino acids were deduced to encode 13 protein genes. The most frequently used amino acid is Leu (15.05%), followed by Phe (11.24%), Ser (10.76%) and IIe (8.346%). Phylogenetic analyses using the concatenated amino acid sequences of the 13 protein-coding genes, with three different computational algorithms (maximum parsimony, maximum likelihood and Bayesian analysis), all revealed that the families Lymnaeidae and Planorbidae are closely related two snail families, consistent with previous classifications based on morphological and molecular studies. The complete mt genome sequence of G. pervia showed a novel gene arrangement and it represents the first sequenced high quality mt genome of the family Lymnaeidae. These novel mtDNA data provide additional genetic markers for studying the epidemiology, population genetics and phylogeographics of freshwater snails, as well as for understanding interplay between the intermediate snail hosts and the intra-mollusca stages of Fasciola spp.. PMID:22844544

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions☆

PubMed Central

Mailloux, Ryan J.; Jin, Xiaolei; Willmore, William G.

2013-01-01

Mitochondria have a myriad of essential functions including metabolism and apoptosis. These chief functions are reliant on electron transfer reactions and the production of ATP and reactive oxygen species (ROS). The production of ATP and ROS are intimately linked to the electron transport chain (ETC). Electrons from nutrients are passed through the ETC via a series of acceptor and donor molecules to the terminal electron acceptor molecular oxygen (O2) which ultimately drives the synthesis of ATP. Electron transfer through the respiratory chain and nutrient oxidation also produces ROS. At high enough concentrations ROS can activate mitochondrial apoptotic machinery which ultimately leads to cell death. However, if maintained at low enough concentrations ROS can serve as important signaling molecules. Various regulatory mechanisms converge upon mitochondria to modulate ATP synthesis and ROS production. Given that mitochondrial function depends on redox reactions, it is important to consider how redox signals modulate mitochondrial processes. Here, we provide the first comprehensive review on how redox signals mediated through cysteine oxidation, namely S-oxidation (sulfenylation, sulfinylation), S-glutathionylation, and S-nitrosylation, regulate key mitochondrial functions including nutrient oxidation, oxidative phosphorylation, ROS production, mitochondrial permeability transition (MPT), apoptosis, and mitochondrial fission and fusion. We also consider the chemistry behind these reactions and how they are modulated in mitochondria. In addition, we also discuss emerging knowledge on disorders and disease states that are associated with deregulated redox signaling in mitochondria and how mitochondria-targeted medicines can be utilized to restore mitochondrial redox signaling. PMID:24455476

Live imaging of mitochondrial dynamics in CNS dopaminergic neurons in vivo demonstrates early reversal of mitochondrial transport following MPP+ exposure

PubMed Central

Dukes, April A.; Bai, Qing; Van Laar, Victor S.; Zhou, Yangzhong; Ilin, Vladimir; David, Christopher N.; Agim, Zeynep S.; Bonkowsky, Joshua L.; Cannon, Jason R.; Watkins, Simon C.; St. Croix, Claudette M.; Burton, Edward A.; Berman, Sarah B.

2016-01-01

Extensive convergent evidence collectively suggests that mitochondrial dysfunction is central to the pathogenesis of Parkinson’s disease (PD). Recently, changes in the dynamic properties of mitochondria have been increasingly implicated as a key proximate mechanism underlying neurodegeneration. However, studies have been limited by the lack of a model in which mitochondria can be imaged directly and dynamically in dopaminergic neurons of the intact vertebrate CNS. We generated transgenic zebrafish in which mitochondria of dopaminergic neurons are labeled with a fluorescent reporter, and optimized methods allowing direct intravital imaging of CNS dopaminergic axons and measurement of mitochondrial transport in vivo. The proportion of mitochondria undergoing axonal transport in dopaminergic neurons decreased overall during development between 2 days post-fertilization (dpf) and 5dpf, at which point the major period of growth and synaptogenesis of the relevant axonal projections is complete. Exposure to 0.5 – 1.0mM MPP+ between 4 – 5 dpf did not compromise zebrafish viability or cause detectable changes in the number or morphology of dopaminergic neurons, motor function or monoaminergic neurochemistry. However, 0.5mM MPP+ caused a 300% increase in retrograde mitochondrial transport and a 30% decrease in anterograde transport. In contrast, exposure to higher concentrations of MPP+ caused an overall reduction in mitochondrial transport. This is the first time mitochondrial transport has been observed directly in CNS dopaminergic neurons of a living vertebrate and quantified in a PD model in vivo. Our findings are compatible with a model in which damage at presynaptic dopaminergic terminals causes an early compensatory increase in retrograde transport of compromised mitochondria for degradation in the cell body. These data are important because manipulation of early pathogenic mechanisms might be a valid therapeutic approach to PD. The novel transgenic lines and

Live imaging of mitochondrial dynamics in CNS dopaminergic neurons in vivo demonstrates early reversal of mitochondrial transport following MPP(+) exposure.

PubMed

Dukes, April A; Bai, Qing; Van Laar, Victor S; Zhou, Yangzhong; Ilin, Vladimir; David, Christopher N; Agim, Zeynep S; Bonkowsky, Joshua L; Cannon, Jason R; Watkins, Simon C; Croix, Claudette M St; Burton, Edward A; Berman, Sarah B

2016-11-01

Extensive convergent evidence collectively suggests that mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD). Recently, changes in the dynamic properties of mitochondria have been increasingly implicated as a key proximate mechanism underlying neurodegeneration. However, studies have been limited by the lack of a model in which mitochondria can be imaged directly and dynamically in dopaminergic neurons of the intact vertebrate CNS. We generated transgenic zebrafish in which mitochondria of dopaminergic neurons are labeled with a fluorescent reporter, and optimized methods allowing direct intravital imaging of CNS dopaminergic axons and measurement of mitochondrial transport in vivo. The proportion of mitochondria undergoing axonal transport in dopaminergic neurons decreased overall during development between 2days post-fertilization (dpf) and 5dpf, at which point the major period of growth and synaptogenesis of the relevant axonal projections is complete. Exposure to 0.5-1.0mM MPP(+) between 4 and 5dpf did not compromise zebrafish viability or cause detectable changes in the number or morphology of dopaminergic neurons, motor function or monoaminergic neurochemistry. However, 0.5mM MPP(+) caused a 300% increase in retrograde mitochondrial transport and a 30% decrease in anterograde transport. In contrast, exposure to higher concentrations of MPP(+) caused an overall reduction in mitochondrial transport. This is the first time mitochondrial transport has been observed directly in CNS dopaminergic neurons of a living vertebrate and quantified in a PD model in vivo. Our findings are compatible with a model in which damage at presynaptic dopaminergic terminals causes an early compensatory increase in retrograde transport of compromised mitochondria for degradation in the cell body. These data are important because manipulation of early pathogenic mechanisms might be a valid therapeutic approach to PD. The novel transgenic lines and

Acquired Downregulation of Donor-Specific Antibody Production After ABO-Incompatible Kidney Transplantation.

PubMed

Tasaki, M; Saito, K; Nakagawa, Y; Imai, N; Ito, Y; Aoki, T; Kamimura, M; Narita, I; Tomita, Y; Takahashi, K

2017-01-01

The mechanism of long-term B cell immunity against donor blood group antigens in recipients who undergo ABO-incompatible (ABOi) living-donor kidney transplantation (LKTx) is unknown. To address this question, we evaluated serial anti-A and anti-B antibody titers in 50 adult recipients. Donor-specific antibody titers remained low (≤1:4) in 42 recipients (84%). However, antibodies against nondonor blood group antigens were continuously produced in recipients with blood type O. We stimulated recipients' peripheral blood mononuclear cells in vitro to investigate whether B cells produced antibodies against donor blood group antigens in the absence of graft adsorption in vivo. Antibodies in cell culture supernatant were measured using specific enzyme-linked immunosorbent assays (ELISAs). Thirty-five healthy volunteers and 57 recipients who underwent ABO-compatible LKTx served as controls. Antibody production in vitro against donor blood group antigens by cells from ABOi LKTx patients was lower than in the control groups. Immunoglobulin deposits were undetectable in biopsies of grafts of eight recipients with low antibody titers (≤1:4) after ABOi LKTx. One patient with blood type A1 who received a second ABOi LKTx from a type B donor did not produce B-specific antibodies. These findings suggest diminished donor-specific antibody production function in the setting of adult ABOi LKTx. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Benefits of fidelity: does host specialization impact nematode parasite life history and fecundity?

PubMed

Koprivnikar, J; Randhawa, H S

2013-04-01

The range of hosts used by a parasite is influenced by macro-evolutionary processes (host switching, host-parasite co-evolution), as well as 'encounter filters' and 'compatibility filters' at the micro-evolutionary level driven by host/parasite ecology and physiology. Host specialization is hypothesized to result in trade-offs with aspects of parasite life history (e.g. reproductive output), but these have not been well studied. We used previously published data to create models examining general relationships among host specificity and important aspects of life history and reproduction for nematodes parasitizing animals. Our results indicate no general trade-off between host specificity and the average pre-patent period (time to first reproduction), female size, egg size, or fecundity of these nematodes. However, female size was positively related to egg size, fecundity, and pre-patent period. Host compatibility may thus not be the primary determinant of specificity in these parasitic nematodes if there are few apparent trade-offs with reproduction, but rather, the encounter opportunities for new host species at the micro-evolutionary level, and other processes at the macro-evolutionary level (i.e. phylogeny). Because host specificity is recognized as a key factor determining the spread of parasitic diseases understanding factors limiting host use are essential to predict future changes in parasite range and occurrence.

Rapid Functional Decline of Activated and Memory Graft-vs-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation

PubMed Central

Li, Hao Wei; Andreola, Giovanna; Carlson, Alicia; Shao, Steven; Lin, Charles; Zhao, Guiling; Sykes, Megan

2015-01-01

Inflammation in the priming host environment has critical effects on the graft-vs-host (GVH) responses mediated by naïve donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show here that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared to naïve T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared to freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-γ-dependent. Toll-like receptor (TLR) stimulation following transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for GVHD and T cell-mediated immunotherapies. PMID:26085679

Mitochondrial phylogeography of a Beringian relict: the endemic freshwater genus of blackfish Dallia (Esociformes).

PubMed

Campbell, M A; Lopéz, J A

2014-02-01

Mitochondrial genetic variability among populations of the blackfish genus Dallia (Esociformes) across Beringia was examined. Levels of divergence and patterns of geographic distribution of mitochondrial DNA lineages were characterized using phylogenetic inference, median-joining haplotype networks, Bayesian skyline plots, mismatch analysis and spatial analysis of molecular variance (SAMOVA) to infer genealogical relationships and to assess patterns of phylogeography among extant mitochondrial lineages in populations of species of Dallia. The observed variation includes extensive standing mitochondrial genetic diversity and patterns of distinct spatial segregation corresponding to historical and contemporary barriers with minimal or no mixing of mitochondrial haplotypes between geographic areas. Mitochondrial diversity is highest in the common delta formed by the Yukon and Kuskokwim Rivers where they meet the Bering Sea. Other regions sampled in this study host comparatively low levels of mitochondrial diversity. The observed levels of mitochondrial diversity and the spatial distribution of that diversity are consistent with persistence of mitochondrial lineages in multiple refugia through the last glacial maximum. © 2014 The Fisheries Society of the British Isles.

Genetic evidence from mitochondrial, nuclear, and endosymbiont markers for the evolution of host plant associated species in the aphid genus Hyalopterus (Hemiptera: Aphididae).

PubMed

Lozier, Jeffrey D; Roderick, George K; Mills, Nicholas J

2007-06-01

Over the past several decades biologists' fascination with plant-herbivore interactions has generated intensive research into the implications of these interactions for insect diversification. The study of closely related phytophagous insect species or populations from an evolutionary perspective can help illuminate ecological and selective forces that drive these interactions. Here we present such an analysis for aphids in the genus Hyalopterus (Hemiptera: Aphididae), a cosmopolitan group that feeds on plants in the genus Prunus (Rosaceae). Hyalopterus currently contains two recognized species associated with different Prunus species, although the taxonomy and evolutionary history of the group is poorly understood. Using mitochondrial COI sequences, 16S rDNA sequences from the aphid endosymbiont Buchnera aphidicola, and nine microsatellite loci we investigated population structure in Hyalopterus from the most commonly used Prunus host species throughout the Mediterranean as well as in California, where the species H. pruni is an invasive pest. We found three deeply divergent lineages structured in large part by specific associations with plum, almond, and peach trees. There was no evidence that geographic or temporal barriers could explain the overall diversity in the genus. Levels of genetic differentiation are consistent with that typically attributed to aphid species and indicate divergence times older than the domestication of Prunus for agriculture. Interestingly, in addition to their typical hosts, aphids from each of the three lineages were frequently found on apricot trees. Apricot also appears to act as a resource mediated hybrid zone for plum and almond associated lineages. Together, results suggest that host plants have played a role in maintaining host-associated differentiation in Hyalopterus for as long as several million years, despite worldwide movement of host plants and the potential for ongoing hybridization.

All-electric control of donor nuclear spin qubits in silicon

NASA Astrophysics Data System (ADS)

Sigillito, Anthony J.; Tyryshkin, Alexei M.; Schenkel, Thomas; Houck, Andrew A.; Lyon, Stephen A.

2017-10-01

The electronic and nuclear spin degrees of freedom of donor impurities in silicon form ultra-coherent two-level systems that are potentially useful for applications in quantum information and are intrinsically compatible with industrial semiconductor processing. However, because of their smaller gyromagnetic ratios, nuclear spins are more difficult to manipulate than electron spins and are often considered too slow for quantum information processing. Moreover, although alternating current magnetic fields are the most natural choice to drive spin transitions and implement quantum gates, they are difficult to confine spatially to the level of a single donor, thus requiring alternative approaches. In recent years, schemes for all-electrical control of donor spin qubits have been proposed but no experimental demonstrations have been reported yet. Here, we demonstrate a scalable all-electric method for controlling neutral 31P and 75As donor nuclear spins in silicon. Using coplanar photonic bandgap resonators, we drive Rabi oscillations on nuclear spins exclusively using electric fields by employing the donor-bound electron as a quantum transducer, much in the spirit of recent works with single-molecule magnets. The electric field confinement leads to major advantages such as low power requirements, higher qubit densities and faster gate times. Additionally, this approach makes it possible to drive nuclear spin qubits either at their resonance frequency or at its first subharmonic, thus reducing device bandwidth requirements. Double quantum transitions can be driven as well, providing easy access to the full computational manifold of our system and making it convenient to implement nuclear spin-based qudits using 75As donors.

Assembly of β-barrel proteins in the mitochondrial outer membrane.

PubMed

Höhr, Alexandra I C; Straub, Sebastian P; Warscheid, Bettina; Becker, Thomas; Wiedemann, Nils

2015-01-01

Mitochondria evolved through endosymbiosis of a Gram-negative progenitor with a host cell to generate eukaryotes. Therefore, the outer membrane of mitochondria and Gram-negative bacteria contain pore proteins with β-barrel topology. After synthesis in the cytosol, β-barrel precursor proteins are first transported into the mitochondrial intermembrane space. Folding and membrane integration of β-barrel proteins depend on the mitochondrial sorting and assembly machinery (SAM) located in the outer membrane, which is related to the β-barrel assembly machinery (BAM) in bacteria. The SAM complex recognizes β-barrel proteins by a β-signal in the C-terminal β-strand that is required to initiate β-barrel protein insertion into the outer membrane. In addition, the SAM complex is crucial to form membrane contacts with the inner mitochondrial membrane by interacting with the mitochondrial contact site and cristae organizing system (MICOS) and shares a subunit with the endoplasmic reticulum-mitochondria encounter structure (ERMES) that links the outer mitochondrial membrane to the endoplasmic reticulum (ER). Copyright © 2014 Elsevier B.V. All rights reserved.

Haploidentical and Matched Sibling Donor Hematopoietic Cell Transplantation for Patients with HLA-Homozygous Haplotypes.

PubMed

Kanda, Junya; Ikegame, Kazuhiro; Fuji, Shigeo; Kurokawa, Mineo; Kanamori, Heiwa; Fukuda, Takahiro; Ohashi, Kazuteru; Ishikawa, Jun; Ogawa, Hiroyasu; Inoue, Masami; Ichinohe, Tatsuo; Atsuta, Yoshiko; Kanda, Yoshinobu

2016-11-01

More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in the graft-versus-host direction are readily available donor candidates for hematopoietic cell transplantation (HCT). In this study, the outcomes of patients with homozygous HLA-A, -B, and -DRB1 antigens who received HCT without T cell depletion from a haploidentical related donor with mismatches in the host-versus-graft direction only (hetero-to-homo, n = 78) or from an HLA-matched sibling donor (MSD) (MSD-homo, n = 153) were compared with those in patients with heterozygous haplotypes who received HCT from an MSD (MSD-hetero, n = 7242). Transplant outcomes in the hetero-to-homo group were similar to those in the MSD-hetero group regarding neutrophil engraftment, grades III to IV acute graft-versus-host disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival. On the other hand, the incidences of severe aGVHD and NRM in the MSD-homo group were significantly lower than those in the MSD-hetero group (grades III to IV aGVHD: aHR .50, P = .034; NRM: aHR .48, P = .004). In conclusion, patients with HLA-homozygous haplotypes achieved lower GVHD and NRM rates for MSD transplantation than those with HLA-heterozygous haplotypes. When an MSD or an appropriate alternative donor is not available for patients with HLA-homozygous haplotypes who need immediate transplantation, transplantation from a haploidentical donor without T cell depletion is a viable option, given the comparable transplant outcomes for hetero-to-homo HCT and MSD-hetero HCT. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

[Study on the attenuation of graft versus host disease by methoxy polyethylene glycol modification of donor lymphocytes].

PubMed

Zhang, Quan; Yuan, Yi; Li, Su-Bo; Dou, Na; Ma, Fu-Ling; Ji, Shou-Ping

2004-05-01

To find out why mPEG modification of donor's lymphocytes can attenuate the occurrence of graft versus host disease(GVHD), but not affect the hemopoietic reconstitution of stem/progenitor cells after transplanting the mPEG-modified mononuclear cells from human cord blood into the SCID mice. The followings were observed: (1) Changes of CD4(+) and CD8(+) T cells and the ratio of CD4(+)/CD8(+) T cells were examined by flow cytometry before and after mononuclear cells from human cord blood were modified with mPEG. (2) The difference in forming the CFU-GM in-vitro between the mPEG modified-stem/progenitor cell group and non-modified cell group was observed. (3) The time of appearance of GVHD and the survival of the SCID mice were observed after the pre- and post-modification mononuclear cells were transplanted. (4) The number of humanized CD45(+) cells in the mouse's bone marrow was detected about 7 weeks after transplantation. (1) mPEG nearly completely covered up the CD4 and CD8 antigens on T cells, while the number of CFU-GM did not show any obvious change between the modified and non-modified cell groups. (2) GVHD appeared later in the modified mononuclear cell group than in the non-modified group, and the survival rate was elevated in the modified group than in the non-modified group. (3) Humanized CD45 cells were found in mouse's bone marrow at the 47th day after transplantation of both mPEG-modified and non-modified mononuclear cells. After CD4 and CD8 antigens were covered up with mPEG, the graft's immune response against host was weakened, but the proliferation and differentiation of transplanted hemopoietic stem/progenitor cells were not affected.

Manipulating the Mitochondrial Genome To Enhance Cattle Embryo Development

PubMed Central

Srirattana, Kanokwan; St. John, Justin C.

2017-01-01

The mixing of mitochondrial DNA (mtDNA) from the donor cell and the recipient oocyte in embryos and offspring derived from somatic cell nuclear transfer (SCNT) compromises genetic integrity and affects embryo development. We set out to generate SCNT embryos that inherited their mtDNA from the recipient oocyte only, as is the case following natural conception. While SCNT blastocysts produced from Holstein (Bos taurus) fibroblasts were depleted of their mtDNA, and oocytes derived from Angus (Bos taurus) cattle possessed oocyte mtDNA only, the coexistence of donor cell and oocyte mtDNA resulted in blastocysts derived from nondepleted cells. Moreover, the use of the reprogramming agent, Trichostatin A (TSA), further improved the development of embryos derived from depleted cells. RNA-seq analysis highlighted 35 differentially expressed genes from the comparison between blastocysts generated from nondepleted cells and blastocysts from depleted cells, both in the presence of TSA. The only differences between these two sets of embryos were the presence of donor cell mtDNA, and a significantly higher mtDNA copy number for embryos derived from nondepleted cells. Furthermore, the use of TSA on embryos derived from depleted cells positively modulated the expression of CLDN8, TMEM38A, and FREM1, which affect embryonic development. In conclusion, SCNT embryos produced by mtDNA depleted donor cells have the same potential to develop to the blastocyst stage without the presumed damaging effect resulting from the mixture of donor and recipient mtDNA. PMID:28500053

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells.

PubMed

Dong, Lan-Feng; Kovarova, Jaromira; Bajzikova, Martina; Bezawork-Geleta, Ayenachew; Svec, David; Endaya, Berwini; Sachaphibulkij, Karishma; Coelho, Ana R; Sebkova, Natasa; Ruzickova, Anna; Tan, An S; Kluckova, Katarina; Judasova, Kristyna; Zamecnikova, Katerina; Rychtarcikova, Zuzana; Gopalan, Vinod; Andera, Ladislav; Sobol, Margarita; Yan, Bing; Pattnaik, Bijay; Bhatraju, Naveen; Truksa, Jaroslav; Stopka, Pavel; Hozak, Pavel; Lam, Alfred K; Sedlacek, Radislav; Oliveira, Paulo J; Kubista, Mikael; Agrawal, Anurag; Dvorakova-Hortova, Katerina; Rohlena, Jakub; Berridge, Michael V; Neuzil, Jiri

2017-02-15

Recently, we showed that generation of tumours in syngeneic mice by cells devoid of mitochondrial (mt) DNA (ρ 0 cells) is linked to the acquisition of the host mtDNA. However, the mechanism of mtDNA movement between cells remains unresolved. To determine whether the transfer of mtDNA involves whole mitochondria, we injected B16ρ 0 mouse melanoma cells into syngeneic C57BL/6N su9-DsRed2 mice that express red fluorescent protein in their mitochondria. We document that mtDNA is acquired by transfer of whole mitochondria from the host animal, leading to normalisation of mitochondrial respiration. Additionally, knockdown of key mitochondrial complex I (NDUFV1) and complex II (SDHC) subunits by shRNA in B16ρ 0 cells abolished or significantly retarded their ability to form tumours. Collectively, these results show that intact mitochondria with their mtDNA payload are transferred in the developing tumour, and provide functional evidence for an essential role of oxidative phosphorylation in cancer.

From mammals back to birds: Host-switch of the acanthocephalan Corynosoma australe from pinnipeds to the Magellanic penguin Spheniscus magellanicus.

PubMed

Hernández-Orts, Jesús Servando; Brandão, Martha; Georgieva, Simona; Raga, Juan Antonio; Crespo, Enrique Alberto; Luque, José Luis; Aznar, Francisco Javier

2017-01-01

Trophically-transmitted parasites are regularly exposed to potential new hosts through food web interactions. Successful colonization, or switching, to novel hosts, occur readily when 'donor' and 'target' hosts are phylogenetically related, whereas switching between distantly related hosts is rare and may result from stochastic factors (i.e. rare favourable mutations). This study investigates a host-switching event between a marine acanthocephalan specific to pinnipeds that is apparently able to reproduce in Magellanic penguins Spheniscus magellanicus from Brazil. Detailed analysis of morphological and morphometrical data from acanthocephalans from penguins indicates that they belong to Corynosoma australe Johnston, 1937. Partial fragments of the 28S rRNA and mitochondrial cox1 genes were amplified from isolates from penguins and two pinniped species (i.e. South American sea lion Otaria flavescens and South American fur seal Arctocephalus australis) to confirm this identification. Infection parameters clearly differ between penguins and the two pinniped species, which were significantly lower in S. magellanicus. The sex ratio of C. australe also differed between penguins and pinnipeds; in S. magellanicus was strongly biased against males, while in pinnipeds it was close to 1:1. Females of C. australe from O. flavescens were smaller than those from S. magellanicus and A. australis. However, fecundity (i.e. the proportion of fully developed eggs) was lower and more variable in females collected from S. magellanicus. At first glance, the occurrence of reproductive individuals of C. australe in Magellanic penguins could be interpreted as an adaptive colonization of a novel avian host through favourable mutations. However, it could also be considered, perhaps more likely, as an example of ecological fitting through the use of a plesimorphic (host) resource, since the ancestors of Corynosoma infected aquatic birds.

Genetic variability among Trichuris ovis isolates from different hosts in Guangdong Province, China revealed by sequences of three mitochondrial genes.

PubMed

Wang, Yan; Liu, Guo-Hua; Li, Jia-Yuan; Xu, Min-Jun; Ye, Yong-Gang; Zhou, Dong-Hui; Song, Hui-Qun; Lin, Rui-Qing; Zhu, Xing-Quan

2013-02-01

This study examined sequence variation in three mitochondrial DNA (mtDNA) regions, namely cytochrome c oxidase subunit 1 (cox1), NADH dehydrogenase subunit 5 (nad5) and cytochrome b (cytb), among Trichuris ovis isolates from different hosts in Guangdong Province, China. A portion of the cox1 (pcox1), nad5 (pnad5) and cytb (pcytb) genes was amplified separately from individual whipworms by PCR, and was subjected to sequencing from both directions. The size of the sequences of pcox1, pnad5 and pcytb was 618, 240 and 464 bp, respectively. Although the intra-specific sequence variations within T. ovis were 0-0.8% for pcox1, 0-0.8% for pnad5 and 0-1.9% for pcytb, the inter-specific sequence differences among members of the genus Trichuris were significantly higher, being 24.3-26.5% for pcox1, 33.7-56.4% for pnad5 and 24.8-26.1% for pcytb, respectively. Phylogenetic analyses using combined sequences of pcox1, pnad5 and pcytb, with three different computational algorithms (maximum likelihood, maximum parsimony and Bayesian inference), indicated that all of the T. ovis isolates grouped together with high statistical support. These findings demonstrated the existence of intra-specific variation in mtDNA sequences among T. ovis isolates from different hosts, and have implications for studying molecular epidemiology and population genetics of T. ovis.

Effects of Wolbachia on mitochondrial DNA variation in populations of Athetis lepigone (Lepidoptera: Noctuidae) in China

USDA-ARS?s Scientific Manuscript database

Wolbachia are endosymbiotic bacteria that infect arthropods and incompatibility among strains can affect gene flow within host insect populations, that can result in significant host mitochondrial DNA (MtD) variation. The effects of Wolbachia infection on mtDNA variation was studied in Athetis lepi...

Impairment of Host Liver Repopulation by Transplanted Hepatocytes in Aged Rats and the Release by Short-Term Growth Hormone Treatment.

PubMed

Stock, Peggy; Bielohuby, Maximilian; Staege, Martin S; Hsu, Mei-Ju; Bidlingmaier, Martin; Christ, Bruno

2017-03-01

Hepatocyte transplantation is an alternative to whole liver transplantation. Yet, efficient liver repopulation by transplanted hepatocytes is low in livers of old animals. This restraint might be because of the poor proliferative capacity of aged donor hepatocytes or the regenerative impairment of the recipient livers. The age-dependent liver repopulation by transplanted wild-type hepatocytes was investigated in juvenile and senescent rats deficient in dipeptidyl-peptidase IV. Repopulation was quantified by flow cytometry and histochemical estimation of dipeptidyl-peptidase IV enzyme activity of donor cells in the negative host liver. As a potential pathway involved, expression of cell cycle proteins was assessed. Irrespective of the age of the donor hepatocytes, large cell clusters appeared in juvenile, but only small clusters in senescent host livers. Because juvenile and senescent donor hepatocytes were likewise functional, host-derived factor(s) impaired senescent host liver repopulation. Growth hormone levels were significantly higher in juvenile than in senescent rats, suggesting that growth hormone might promote host liver repopulation. Indeed, short-term treatment with growth hormone augmented senescent host liver repopulation involving the growth hormone-mediated release of the transcriptional blockade of genes associated with cell cycle progression. Short-term growth hormone substitution might improve liver repopulation by transplanted hepatocytes, thus augmenting the therapeutic benefit of clinical hepatocyte transplantation in older patients. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PROTECTION OF MICE AGAINST IRRADIATION AND TETANUS BY HOMOLOGOUS BONE MARROW CELLS FROM HYPERIMMUNIZED DONORS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoloff, I.L.; Weiss, A.J.

1963-07-01

Female mice of inbred strains (101 x C3H, BDF, C57B1, Balb/C, C3H, CBA, and LAF) were immunized with 0.2 ml of alum-precipitated tetanus toxoid subcutaneously, followed in 3 weeks by 0.2 ml of fluid toxoid intravenously. Four days after the last injection the marrow was mechanically dispersed and 10- 20 million marrow cells were inoculated intravenously into mice that had received on the previous day a lethal dose of whole-body x irradiation. The LD/sub 96/ for 30 days of each host strain was: BDF, 950 r; LAF, 950 r; 101 x C3H, 900 r; Balb/C, 800 r; C3H, 800 r;more » C57B1, 800 r; and CBA, 700 r. Mice in which isologous bone marrow cells from hyperimmunized donors were transferred to irradiated hosts showed a high degree of protection against irradiation in all strains studied. The percentage of 30-day irradiation survivors follows: C3H, 100%; 101 x C3H, 100%; CBA, 90%; BDF, 90%; Balb/C, 60%; and C57B1, 70%. There were no survivors among groups irradiated but not protected with bone marrow. The percentage of 7- day survivors after toxin challenge for each of 4 different strains receiving isologous cells from hyperimmunized donors ranged between 87 and 100%. Normal mice, similar in weight to the experimental groups (called toxin controls) all died of tetanus within 48 hr of challenge with toxin. Other results showed that homologous disease does not interfere significantly with the in vivo neutralization of tetanus toxin by antitoxin. It was concluded that homologous disease is a clinical entity which, in some donor-host combinations, is associated with a host-vs-graft reaction and, in one strain combination so far tested, is associated with a graft-vshost reaction. The experiments showed that the genetic relation between donor and host is a factor in determining which type of immunologic reaction may occur. (TCO)« less

Donor impurity incorporation during layer growth of Zn II-VI semiconductors

NASA Astrophysics Data System (ADS)

Barlow, D. A.

2017-12-01

The maximum halogen donor concentration in Zn II-VI semiconductors during layer growth is studied using a standard model from statistical mechanics. Here the driving force for incorporation is an increase in entropy upon mixing of the donor impurity into the available anion lattice sites in the host binary. A formation energy opposes this increase and thus equilibrium is attained at some maximum concentration. Considering the halogen donor impurities within the Zn II-VI binary semiconductors ZnO, ZnS, ZnSe and ZnTe, a heat of reaction obtained from reported diatomic bond strengths is shown to be directly proportional to the log of maximum donor concentration. The formation energy can then be estimated and an expression for maximum donor concentration derived. Values for the maximum donor concentration with each of the halogen impurities, within the Zn II-VI compounds, are computed. This model predicts that the halogens will serve as electron donors in these compounds in order of increasing effectiveness as: F, Br, I, Cl. Finally, this result is taken to be equivalent to an alternative model where donor concentration depends upon impurity diffusion and the conduction band energy shift due to a depletion region at the growing crystal's surface. From this, we are able to estimate the diffusion activation energy for each of the impurities mentioned above. Comparisons are made with reported values and relevant conclusions presented.

Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells.

PubMed

Iyer, Shilpa; Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R; Bennett, James P

2012-06-01

Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ∼1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future.

CRISPR/Cas9 and mitochondrial gene replacement therapy: promising techniques and ethical considerations

PubMed Central

Fogleman, Sarah; Santana, Casey; Bishop, Casey; Miller, Alyssa; Capco, David G

2016-01-01

Thousands of mothers are at risk of transmitting mitochondrial diseases to their offspring each year, with the most severe form of these diseases being fatal [1]. With no cure, transmission prevention is the only current hope for decreasing the disease incidence. Current methods of prevention rely on low mutant maternal mitochondrial DNA levels, while those with levels close to or above threshold (>60%) are still at a very high risk of transmission [2]. Two novel approaches may offer hope for preventing and treating mitochondrial disease: mitochondrial replacement therapy, and CRISPR/Cas9. Mitochondrial replacement therapy has emerged as a promising tool that has the potential to prevent transmission in patients with higher mutant mitochondrial loads. This method is the subject of many ethical concerns due its use of a donor embryo to transplant the patient’s nuclear DNA; however, it has ultimately been approved for use in the United Kingdom and was recently declared ethically permissible by the FDA. The leading-edge CRISPR/Cas9 technology exploits the principles of bacterial immune function to target and remove specific sequences of mutated DNA. This may have potential in treating individuals with disease caused by mutant mitochondrial DNA. As the technology progresses, it is important that the ethical considerations herein emerge and become more established. The purpose of this review is to discuss current research surrounding the procedure and efficacy of the techniques, compare the ethical concerns of each approach, and look into the future of mitochondrial gene replacement therapy. PMID:27725916

Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors.

PubMed

Bosch-Vizcaya, Anna; Pérez-García, Arianne; Brunet, Salut; Solano, Carlos; Buño, Ismael; Guillem, Vicent; Martínez-Laperche, Carolina; Sanz, Guillermo; Barrenetxea, Cristina; Martínez, Carmen; Tuset, Esperanza; Lloveras, Natàlia; Coll, Rosa; Guardia, Ramon; González, Yolanda; Roncero, Josep M; Bustins, Anna; Gardella, Santiago; Fernández, Cristalina; Buch, Joan; Gallardo, David

2012-01-01

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Tumor cell death induced by the inhibition of mitochondrial electron transport: The effect of 3-hydroxybakuchiol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jaña, Fabián; Faini, Francesca; Lapier, Michel

Changes in mitochondrial ATP synthesis can affect the function of tumor cells due to the dependence of the first step of glycolysis on mitochondrial ATP. The oxidative phosphorylation (OXPHOS) system is responsible for the synthesis of approximately 90% of the ATP in normal cells and up to 50% in most glycolytic cancers; therefore, inhibition of the electron transport chain (ETC) emerges as an attractive therapeutic target. We studied the effect of a lipophilic isoprenylated catechol, 3-hydroxybakuchiol (3-OHbk), a putative ETC inhibitor isolated from Psoralea glandulosa. 3-OHbk exerted cytotoxic and anti-proliferative effects on the TA3/Ha mouse mammary adenocarcinoma cell line andmore » induced a decrease in the mitochondrial transmembrane potential, the activation of caspase-3, the opening of the mitochondrial permeability transport pore (MPTP) and nuclear DNA fragmentation. Additionally, 3-OHbk inhibited oxygen consumption, an effect that was completely reversed by succinate (an electron donor for Complex II) and duroquinol (electron donor for Complex III), suggesting that 3-OHbk disrupted the electron flow at the level of Complex I. The inhibition of OXPHOS did not increase the level of reactive oxygen species (ROS) but caused a large decrease in the intracellular ATP level. ETC inhibitors have been shown to induce cell death through necrosis and apoptosis by increasing ROS generation. Nevertheless, we demonstrated that 3-OHbk inhibited the ETC and induced apoptosis through an interaction with Complex I. By delivering electrons directly to Complex III with duroquinol, cell death was almost completely abrogated. These results suggest that 3-OHbk has antitumor activity resulting from interactions with the ETC, a system that is already deficient in cancer cells. - Highlights: • We studied the anticancer activity of a natural compound, 3-OHbk, on TA3/Ha cells. • 3-OHbk inhibited mitochondrial electron flow by interacting with Complex I. • Complex I

Living Liver Donor Selection and Resection at the University of Tokyo Hospital.

PubMed

Akamatsu, N; Kokudo, N

2016-05-01

Donor selection and operative procedures for adult-to-adult living donor liver transplantation at the University of Tokyo are presented. Donor selection criteria are as follows: age between 20 and 65 years, within 3 degrees of consanguinity, without coercion, free from any major comorbidities, body mass index (BMI) < 30, and ABO blood type identical or compatible. Liver biopsy is indicated for BMI > 25 kg/m(2) or any liver function abnormality, and those with macroscopic steatosis >10% are rejected. Thereafter, an indocyanine green retention test and dynamic computed tomography are evaluated. Graft type is determined based on computed tomography volumetry. An estimated graft volume of 40% to recipient standard liver volume ratio is the lower limit. For donor safety, the left liver is the first choice, provided that it satisfies the lower limit. Otherwise, right liver harvesting is indicated, providing that the estimated remnant liver volume is >30% of the donor's total liver volume. A posterior sector graft is a possible option. Between 1996 and 2014, 462 donor hepatectomies were performed, with 257 right livers, 179 left livers, and 26 posterior sectors. There was no mortality, and the incidence of morbidity grades I, II, IIIa, and IIIb was 16%, 5%, 5%, and 3%, respectively, without a difference between right and left liver grafts. The left liver was used without impairing recipient outcome. Two aborted hepatectomies (0.4%) and 3 near-miss events (0.6%) were encountered. Maximal effort should be applied to donor selection and operation for donor safety. Copyright © 2016 Elsevier Inc. All rights reserved.

Support of Unrelated Stem Cell Donor Searches by Donor Center-Initiated HLA Typing of Potentially Matching Donors

PubMed Central

Schmidt, Alexander H.; Solloch, Ute V.; Baier, Daniel; Grathwohl, Alois; Hofmann, Jan; Pingel, Julia; Stahr, Andrea; Ehninger, Gerhard

2011-01-01

Large registries of potential unrelated stem cell donors have been established in order to enable stem cell transplantation for patients without HLA-identical related donors. Donor search is complicated by the fact that the stored HLA information of many registered donors is incomplete. We carried out a project that was aimed to improve chances of patients with ongoing donor searches to find an HLA-matched unrelated donor. For that purpose, we carried out additional donor center-initiated HLA-DRB1 typing of donors who were only typed for the HLA loci A and B so far and were potential matches for patients in need of a stem cell transplant. In total, 8,861 donors were contacted for donor center-initiated HLA-DRB1 typing within 1,089 donor searches. 12 of these donors have donated stem cells so far, 8 thereof for their respective target patients. We conclude that chances of patients with ongoing donor searches to find an HLA-matched unrelated donor can indeed be improved by donor-center initiated typing that is carried out in addition to the standard donor search process. Our results also raise questions regarding the appropriate use of incompletely typed donors within unrelated donor searches. PMID:21625451

Hematopoietic stem cell transplantation in children with leukemia: a single institution experience with respect to donors.

PubMed

Baek, Hee Jo; Kook, Hoon; Han, Dong Kyun; Hwang, Tai Ju

2011-12-01

Aim of this study was to compare the outcomes of transplantation by donor source and to help select the best alternative donor in children with leukemia. Donor sources included matched related donor (MRD, n = 35), allele-matched unrelated donor (M-UD, n = 10) or -mismatched (MM)-UD (n = 13) or unrelated umbilical cord blood (UCB, n = 11). UCB group had a significantly higher incidence of grade II-IV acute graft versus host disease (MRD, 11.8%; M-UD, 30.0%; MM-UD, 15.4%, UCB, 54.4%, P = 0.004) but there was no difference in incidence of chronic graft versus host disease between 4 groups. The 5-yr leukemia-free survival (LFS) was 76.7%, 60.0%, 69.2%, and 45.5%, respectively (P = 0.128). MRD group showed higher LFS rate than UCB group (P = 0.022). However, LFS of M-UD and MM-UD together (65.2%) was not different from that of MRD group (76.7%, P = 0.325), or from that of UCB (45.5%, P = 0.190). The relapse incidence at 5 yr was 17.1%, 20.0%, 15.4%, and 0%, respectively (P = 0.460). The 100-day treatment-related mortality was 2.9%, 20.0%, 7.7%, and 36.4%, respectively (P = 0.011). Despite the limitations of small number of patients, unrelated donor transplants including even allele-mismatched ones, seem to be as effective in children with leukemia lacking suitable relative donors. Also, UCB transplant may serve as another possible option in urgent transplants.

Effect of Donor and Recipient Factors on Corneal Graft Rejection

PubMed Central

Stulting, R. Doyle; Sugar, Alan; Beck, Roy; Belin, Michael; Dontchev, Mariya; Feder, Robert S.; Gal, Robin L.; Holland, Edward J.; Kollman, Craig; Mannis, Mark J.; Price, Francis; Stark, Walter; Verdier, David D.

2014-01-01

Purpose To assess the relationship between donor and recipient factors and corneal allograft rejection in eyes that underwent penetrating keratoplasty (PK) in the Cornea Donor Study. Methods 1090 subjects undergoing corneal transplantation for a moderate risk condition (principally Fuchs’ dystrophy or pseudophakic corneal edema) were followed for up to 5 years. Associations of baseline recipient and donor factors with the occurrence of a probable or definite rejection event were assessed in univariate and multivariate proportional hazards models. Results Eyes with pseudophakic or aphakic corneal edema (N=369) were more likely to experience a rejection event than eyes with Fuchs’ dystrophy (N=676) (34% ± 6% versus 22% ± 4%; hazard ratio = 1.56; 95% confidence interval 1.21 to 2.03). Among eyes with Fuchs’dystrophy, a higher probability of a rejection event was observed in phakic post-transplant eyes compared with eyes that underwent cataract extraction with or without intraocular lens implantation during PK (29% vs. 19%; hazard ratio = 0.54; 95% confidence interval 0.36 to 0.82). Female recipients had a higher probability of a rejection event than males (29% vs. 21%; hazard ratio=1.42; 95% confidence interval 1.08 to 1.87), after controlling for the effect of preoperative diagnosis and lens status. Donor age and donor recipient ABO compatibility were not associated with rejection. Conclusions There was a substantially higher graft rejection rate in eyes with pseudophakic or aphakic corneal edema compared with eyes with Fuchs’ dystrophy. Female recipients were more likely to have a rejection event than males. Graft rejection was not associated with donor age. PMID:22488114

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors.

PubMed

Williams, Robert C; Opelz, Gerhard; McGarvey, Chelsea J; Weil, E Jennifer; Chakkera, Harini A

2016-05-01

Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor. Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival. Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted for recipient and donor characteristics demonstrated a 13% higher risk (hazard ratio, 1.13; 95% confidence interval, 1.06-1.21) with 1 mismatch and a 64% higher risk (hazard ratio, 1.64, 95% confidence interval, 1.56-1.73) with 6 mismatches. Dividing the mismatch categories into 27 ordered permutations, and testing their 57 within mismatch category differences, demonstrated that all but 1 were equal, independent of locus. A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.

Mitochondrial Regulation of Cell Cycle and Proliferation

PubMed Central

Antico Arciuch, Valeria Gabriela; Elguero, María Eugenia; Poderoso, Juan José

2012-01-01

Abstract Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O2, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O2 utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis. Antioxid. Redox Signal. 16, 1150–1180. PMID:21967640

Voluntary whole-blood donors, and compensated platelet donors and plasma donors: motivation to donate, altruism and aggression.

PubMed

Trimmel, Michael; Lattacher, Helene; Janda, Monika

2005-10-01

To establish if voluntary whole-blood donors and compensated platelet donors and plasma donors may differ in their motivation to donate, altruism, aggression and autoaggression. Whole-blood (n=51), platelet (n=52) and plasma donors (n=48) completed a battery of validated questionnaires while waiting to donate. Bivariate and multivariate analyses of variance and t-tests were performed to detect differences between groups as noted. Altruism (mean=40.2) was slightly higher in whole-blood donors than in platelet (mean=38.3) and plasma donors (mean=39.1) (p=0.07). Blood donors (mean=2.8) scored lower in the spontaneous aggression measure than platelet (mean=4.1) and plasma donors (mean=4.4) (p=0.01). Plasma donors (mean=4.9) had higher auto-aggression than whole-blood donors and platelet donors (mean for both groups=3.4) (p=0.01). Differences between the three groups were mediated by sociodemographic variables (MANCOVA). Whole-blood donors donated to help others, platelet and plasma donors mostly to receive the compensation. However, those platelet and plasma donors, who would continue to donate without compensation were similar in altruism and aggression to whole-blood donors. While most platelet donors and plasma donors were motivated by the compensation, those who stated that they would continue to donate without compensation had altruism and aggression scores similar to voluntary whole-blood donors.

Pathogenesis of graft-versus-host disease: innate immunity amplifying acute alloimmune responses.

PubMed

Maeda, Yoshinobu

2013-09-01

In addition to reduced-intensity conditioning, which has expanded the eligibility for hematopoietic cell transplantation (HCT) to older patients, increased availability of alternative donors, including HLA-mismatched unrelated donors, has increased access to allogeneic HCT for more patients. However, acute graft-versus-host disease (GVHD) remains a lethal complication, even in HLA-matched donor-recipient pairs. The pathophysiology of GVHD depends on aspects of adaptive immunity and interactions between donor T-cells and host dendritic cells (DCs). Recent work has revealed that the role of other immune cells and endothelial cells and components of the innate immune response are also important. Tissue damage caused by the conditioning regimen leads to the release of exogenous and endogenous "danger signals". Exogenous danger signals called pathogen-associated molecular patterns and endogenous noninfectious molecules known as damage-associated molecular patterns (DAMPs) are responsible for initiating or amplifying acute GVHD by enhancing DC maturation and alloreactive T-cell responses. A significant association of innate immune receptor polymorphisms with outcomes, including GVHD severity, was observed in patients receiving allogeneic HCT. Understanding of the role of innate immunity in acute GVHD might offer new therapeutic approaches.

Mitochondrial genome data confirm that yaks can serve as the intermediate host of Echinococcus canadensis (G10) on the Tibetan Plateau.

PubMed

Wu, Yantao; Li, Li; Zhu, Guoqiang; Li, Wenhui; Zhang, Nianzhang; Li, Shuangnan; Yao, Gang; Tian, Wenjun; Fu, Baoquan; Yin, Hong; Zhu, Xingquan; Yan, Hongbin; Jia, Wanzhong

2018-03-09

Cervids used to be considered the only animal intermediate hosts of the G10 genotype of Echinococcus canadensis. Yaks are often herded in the Qinghai-Tibet Plateau, China, where echinococcosis remains prevalent. However, no E. canadensis G10 cases have been recorded in yaks until now. The aim of our study was to identify causative agents of echinococcosis in yaks in this region. Total genomic DNA was extracted from the germinal layer of one hydatid using a Blood and Tissue Kit. Full-length mitochondrial (mt) cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes were amplified by PCR. All purified PCR products were directly sequenced in both directions. Then seven pairs of overlap primers were designed to amplify the entire mt genome sequence of a suspected E. canadensis G10 isolate. Phylogenetic analyses were performed based on concatenated nucleotides from the 12 protein-coding genes of mt genomes of Echinococcus species in a Bayesian framework using MrBayes v3.1 and implementing the GTR + I + G model. Hydatids were found in yaks (n = 129) when organs were inspected at the slaughterhouse in Maqu county, Gannan Tibetan Autonomous Prefecture, Gansu Province, China in October 2016. Of these, 33 (25.6%) harbored up to a dozen hydatid cysts. One cyst from each yak was characterized by sequencing its mitochondrial (mt) cox1 and nad1 genes. On the basis of these sequence data, 32 cysts were identified as Echinococcus granulosus (sensu stricto) (G1-G3) and the remaining one was identified as the G10 genotype of E. canadensis. Its mt genome was then fully sequenced and compared with that of the G10 genotype in GenBank (AB745463). Phylogenetic analysis using complete mt genomes confirmed the Chinese cyst as belonging to the G10 genotype. To our knowledge, this is the first report globally of E. canadensis (G10) from yaks in China, which suggests that the G10 genotype has a wider geographical distribution and broader host range than

Cardio-protective signalling by glyceryl trinitrate and cariporide in a model of donor heart preservation.

PubMed

Kwan, Jair C; Gao, Ling; Macdonald, Peter S; Hicks, Mark

2015-03-01

Storage of donor hearts in cardioplegic solutions supplemented with agents that mimic the ischaemic preconditioning response enhanced their post-reperfusion function. The present study examines the minimisation of cell death and activation of pro-survival signalling directed towards maintenance of mitochondrial homeostasis in hearts arrested and stored in two such agents, glyceryl-trinitrate, a nitric oxide donor and cariporide, (a sodium-hydrogen exchange inhibitor). After baseline functional measurement, isolated working rat hearts were arrested and stored for 6h at 4°C in either Celsior(®), Celsior(®) containing 0.1mg/ml glyceryl-trinitrate, 10μM cariporide or both agents. After reperfusion, function was remeasured. Hearts were then processed for immunoblotting or histology. Necrotic and apoptotic markers present in the Celsior(®) group post-reperfusion were abolished by glyceryl-trinitrate, cariporide or both. Increased phosphorylation of ERK and Bcl2, after reperfusion in groups stored in glyceryl-trinitrate, cariporide or both along with increased phospho-STAT3 levels in the glyceryl-trinitrate/cariporide group correlated with functional recovery. Inhibition of STAT3 phosphorylation blocked recovery. No phospho-Akt increase was seen in any treatment. Activation of signalling pathways that favour mitophagy activation (ERK and Bcl2 phosphorylation) and maintenance of mitochondrial transition pore closure after reperfusion (STAT3 and ERK phosphorylation) were crucial for functional recovery of the donor heart. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation.

PubMed

Shipounova, I N; Petinati, N A; Bigildeev, A E; Zezina, E A; Drize, N I; Kuzmina, L A; Parovichnikova, E N; Savchenko, V G

2014-12-01

Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the

Phytohemagglutinin facilitates the aggregation of blastomere pairs from Day 5 donor embryos with Day 4 host embryos for chimeric bovine embryo multiplication.

PubMed

Simmet, Kilian; Reichenbach, Myriam; Reichenbach, Horst-Dieter; Wolf, Eckhard

2015-12-01

Multiplication of bovine embryos by the production of aggregation chimeras is based on the concept that few blastomeres of a donor embryo form the inner cell mass (ICM) and thus the embryo proper, whereas cells of a host embryo preferentially contribute to the trophectoderm (TE), the progenitor cells of the embryonic part of the placenta. We aggregated two fluorescent blastomeres from enhanced green fluorescent protein (eGFP) transgenic Day 5 morulae with two Day 4 embryos that did not complete their first cleavage until 27 hours after IVF and tested the effect of phytohemagglutinin-L (PHA) on chimeric embryo formation. The resulting blastocysts were characterized by differential staining of cell lineages using the TE-specific factor CDX2 and confocal laser scanning microscopy to facilitate the precise localization of eGFP-positive cells. The proportions of blastocyst development of sandwich aggregates with (n = 99) and without PHA (n = 46) were 85.9% and 54.3% (P < 0.05), respectively. Epifluorescence microscopy showed that the proportion of blastocysts with eGFP-positive cells in the ICM was higher in the PHA group than in the no-PHA group (40% vs. 16%; P < 0.05). Confocal laser scanning microscopy revealed that the total cell numbers of blastocysts from the PHA group of aggregation chimeras (n = 17; 207.8 ± 67.3 [mean ± standard deviation]) were higher (P < 0.05) than those of embryos without ZP and exposed to PHA (n = 30; 159.6 ± 42.2) and of handling control embryos (n = 19; 176.9 ± 53.3). The same was true for ICM cell counts (56.5 ± 22.0 vs. 37.7 ± 14.2 and 38.7 ± 12.4) and TE cell counts (151.2 ± 58.0 vs. 121.9 ± 37.4 and 138.3 ± 53.0), whereas the ICM/total cell number ratio was not different between the groups. Of the 17 chimeric blastocysts analyzed by confocal laser scanning microscopy, nine had eGFP-positive cells (three of them in the ICM, three in the TE, and three in both lineages). When integration in

Oxygen, pH, and mitochondrial oxidative phosphorylation.

PubMed

Wilson, David F; Harrison, David K; Vinogradov, Sergei A

2012-12-15

The oxygen dependence of mitochondrial oxidative phosphorylation was measured in suspensions of isolated rat liver mitochondria using recently developed methods for measuring oxygen and cytochrome c reduction. Cytochrome-c oxidase (energy conservation site 3) activity of the mitochondrial respiratory chain was measured using an artificial electron donor (N,N,N',N'-tetramethyl-p-phenylenediamine) and ascorbate to directly reduce the cytochrome c, bypassing sites 1 and 2. For mitochondrial suspensions with added ATP, metabolic conditions approximating those in intact cells and decreasing oxygen pressure both increased reduction of cytochrome c and decreased respiratory rate. The kinetic parameters [K(M) and maximal rate (V(M))] for oxygen were determined from the respiratory rates calculated for 100% reduction of cytochrome c. At 22°C, the K(M) for oxygen is near 3 Torr (5 μM), 12 Torr (22 μM), and 18 Torr (32 μM) at pH 6.9, 7.4, and 7.9, respectively, and V(M) corresponds to a turnover number for cytochrome c at 100% reduction of near 80/s and is independent of pH. Uncoupling oxidative phosphorylation increased the respiratory rate at saturating oxygen pressures by twofold and decreased the K(M) for oxygen to <2 Torr at all tested pH values. Mitochondrial oxidative phosphorylation is an important oxygen sensor for regulation of metabolism, nutrient delivery to tissues, and cardiopulmonary function. The decrease in K(M) for oxygen with acidification of the cellular environment impacts many tissue functions and may give transformed cells a significant survival advantage over normal cells at low-pH, oxygen-limited environment in growing tumors.

Hepatocellular carcinoma developed in a living donor after left lobe donation: a case for caution.

PubMed

Ikegami, Toru; Yoshizumi, Tomoharu; Kawasaki, Junji; Shimagaki, Tomonari; Uchiyama, Hideaki; Soejima, Yuji; Maehara, Yoshihiko

2017-06-01

Although it has been recognized that those who are positive for anti-hepatitis B core antibody (anti-HBcAb) and negative for hepatitis B surface antigen (HBsAg) with normal liver function could be donors for living donor liver transplantation under appropriate prophylaxis, the negative impact of positive HBcAb on such donors themselves has not been reported. We present a case of a living donor with positive HBcAb, who donated his left lobe for his sister with unresectable giant hepatic hemangioma, and the donor himself developed a de novo hepatocellular carcinoma (HCC) 10 years after donation. He had been lost from the follow-up program since 1 year after donation. Imaging studies showed a heterogeneously enhanced mass compatible with HCC, which was 9 cm in size with portal invasion into the anterior portal vein of the remnant liver. Re-laparotomy for hepatectomy with the removal of the tumor thrombus in the anterior portal vein of the remnant liver was carried out, and he is free from recurrence 6 months after surgery on prophylactic sorafenib. At our institute, 58 (9.6%) donors among the 603 living donors were anti-HBcAb positive and anti-HBsAg negative, and we started regular HCC surveillance using sonogram every 6 months for these patients. © 2016 The Japan Society of Hepatology.

Mitochondrial Aging: Is There a Mitochondrial Clock?

PubMed

Zorov, Dmitry B; Popkov, Vasily A; Zorova, Ljubava D; Vorobjev, Ivan A; Pevzner, Irina B; Silachev, Denis N; Zorov, Savva D; Jankauskas, Stanislovas S; Babenko, Valentina A; Plotnikov, Egor Y

2017-09-01

Fragmentation (fission) of mitochondria, occurring in response to oxidative challenge, leads to heterogeneity in the mitochondrial population. It is assumed that fission provides a way to segregate mitochondrial content between the "young" and "old" phenotype, with the formation of mitochondrial "garbage," which later will be disposed. Fidelity of this process is the basis of mitochondrial homeostasis, which is disrupted in pathological conditions and aging. The asymmetry of the mitochondrial fission is similar to that of their evolutionary ancestors, bacteria, which also undergo an aging process. It is assumed that mitochondrial markers of aging are recognized by the mitochondrial quality control system, preventing the accumulation of dysfunctional mitochondria, which normally are subjected to disposal. Possibly, oncocytoma, with its abnormal proliferation of mitochondria occupying the entire cytoplasm, represents the case when segregation of damaged mitochondria is impaired during mitochondrial division. It is plausible that mitochondria contain a "clock" which counts the degree of mitochondrial senescence as the extent of flagging (by ubiquitination) of damaged mitochondria. Mitochondrial aging captures the essence of the systemic aging which must be analyzed. We assume that the mitochondrial aging mechanism is similar to the mechanism of aging of the immune system which we discuss in detail. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A Novel Methodology for Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-Regulated Metabolic Shift and Enables Mode of Action Analyses of Mitochondrial Inhibitors.

PubMed

Sakata-Kato, Tomoyo; Wirth, Dyann F

2016-12-09

Given that resistance to all drugs in clinical use has arisen, discovery of new antimalarial drug targets is eagerly anticipated. The Plasmodium mitochondrion has been considered a promising drug target largely based on its significant divergence from the host organelle as well as its involvement in ATP production and pyrimidine biosynthesis. However, the functions of Plasmodium mitochondrial protein complexes and associated metabolic pathways are not fully characterized. Here, we report the development of novel and robust bioenergetic assay protocols for Plasmodium falciparum asexual parasites utilizing a Seahorse Bioscience XFe24 Extracellular Flux Analyzer. These protocols allowed us to simultaneously assess the direct effects of metabolites and inhibitors on mitochondrial respiration and glycolytic activity in real-time with the readout of oxygen consumption rate and extracellular acidification rate. Using saponin-freed parasites at the schizont stage, we found that succinate, malate, glycerol-3-phosphate, and glutamate, but not pyruvate, were able to increase the oxygen consumption rate and that glycerol-3-phosphate dehydrogenase had the largest potential as an electron donor among tested mitochondrial dehydrogenases. Furthermore, we revealed the presence of a glucose-regulated metabolic shift between oxidative phosphorylation and glycolysis. We measured proton leak and reserve capacity and found bioenergetic evidence for oxidative phosphorylation in erythrocytic stage parasites but at a level much lower than that observed in mammalian cells. Lastly, we developed an assay platform for target identification and mode of action studies of mitochondria-targeting antimalarials. This study provides new insights into the bioenergetics and metabolomics of the Plasmodium mitochondria.

Expression of Fas and Fas-ligand in donor hematopoietic stem and progenitor cells is dissociated from the sensitivity to apoptosis.

PubMed

Pearl-Yafe, Michal; Yolcu, Esma S; Stein, Jerry; Kaplan, Ofer; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

2007-10-01

The interaction between the Fas receptor and its cognate ligand (FasL) has been implicated in the mutual suppression of donor and host hematopoietic cells after transplantation. Following the observation of deficient early engraftment of Fas and FasL-defective donor cells and recipients, we determined the role of the Fas-FasL interaction. Donor cells were recovered after syngeneic (CD45.1-->CD45.2) transplants from various organs and assessed for expression of Fas/FasL in reference to lineage markers, carboxyfluorescein succinimidyl ester dilution, Sca-1 and c-kit expression. Naïve and bone marrow-homed cells were challenged for apoptosis ex vivo. The Fas receptor and ligand were markedly upregulated to 40% to 60% (p < 0.001 vs 5-10% in naïve cells) within 2 days after syngeneic transplantation, while residual host cells displayed modest and delayed upregulation of these molecules ( approximately 10%). All lin(-)Sca(+)c-kit(+) cells were Fas(+)FasL(+), including 95% of Sca-1(+) and 30% of c-kit(+) cells. Fas and FasL expression varied in donor cells that homed to bone marrow, spleen, liver and lung, and was induced by interaction with the stroma, irradiation, cell cycling, and differentiation. Bone marrow-homed donor cells challenged with supralethal doses of FasL were insensitive to apoptosis (3.2% +/- 1% vs 38% +/- 5% in naïve bone marrow cells), and engraftment was not affected by pretransplantation exposure of donor cells to an apoptotic challenge with FasL. There was no evidence of Fas-mediated suppression of donor and host cell activity after transplantation. Resistance to Fas-mediated apoptosis evolves as a functional characteristic of hematopoietic reconstituting stem and progenitor cells, providing them competitive engraftment advantage over committed progenitors.

Incentive compatibility in kidney exchange problems.

PubMed

Villa, Silvia; Patrone, Fioravante

2009-12-01

The problem of kidney exchanges shares common features with the classical problem of exchange of indivisible goods studied in the mechanism design literature, while presenting additional constraints on the size of feasible exchanges. The solution of a kidney exchange problem can be summarized in a mapping from the relevant underlying characteristics of the players (patients and their donors) to the set of matchings. The goal is to select only matchings maximizing a chosen welfare function. Since the final outcome heavily depends on the private information in possess of the players, a basic requirement in order to reach efficiency is the truthful revelation of this information. We show that for the kidney exchange problem, a class of (in principle) efficient mechanisms does not enjoy the incentive compatibility property and therefore is subject to possible manipulations made by the players in order to profit of the misrepresentation of their private information.

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells

PubMed Central

Dong, Lan-Feng; Kovarova, Jaromira; Bajzikova, Martina; Bezawork-Geleta, Ayenachew; Svec, David; Endaya, Berwini; Sachaphibulkij, Karishma; Coelho, Ana R; Sebkova, Natasa; Ruzickova, Anna; Tan, An S; Kluckova, Katarina; Judasova, Kristyna; Zamecnikova, Katerina; Rychtarcikova, Zuzana; Gopalan, Vinod; Andera, Ladislav; Sobol, Margarita; Yan, Bing; Pattnaik, Bijay; Bhatraju, Naveen; Truksa, Jaroslav; Stopka, Pavel; Hozak, Pavel; Lam, Alfred K; Sedlacek, Radislav; Oliveira, Paulo J; Kubista, Mikael; Agrawal, Anurag; Dvorakova-Hortova, Katerina; Rohlena, Jakub; Berridge, Michael V; Neuzil, Jiri

2017-01-01

Recently, we showed that generation of tumours in syngeneic mice by cells devoid of mitochondrial (mt) DNA (ρ0 cells) is linked to the acquisition of the host mtDNA. However, the mechanism of mtDNA movement between cells remains unresolved. To determine whether the transfer of mtDNA involves whole mitochondria, we injected B16ρ0 mouse melanoma cells into syngeneic C57BL/6Nsu9-DsRed2 mice that express red fluorescent protein in their mitochondria. We document that mtDNA is acquired by transfer of whole mitochondria from the host animal, leading to normalisation of mitochondrial respiration. Additionally, knockdown of key mitochondrial complex I (NDUFV1) and complex II (SDHC) subunits by shRNA in B16ρ0 cells abolished or significantly retarded their ability to form tumours. Collectively, these results show that intact mitochondria with their mtDNA payload are transferred in the developing tumour, and provide functional evidence for an essential role of oxidative phosphorylation in cancer. DOI: http://dx.doi.org/10.7554/eLife.22187.001 PMID:28195532

Additional mitochondrial DNA influences the interactions between the nuclear and mitochondrial genomes in a bovine embryo model of nuclear transfer.

PubMed

Srirattana, Kanokwan; St John, Justin C

2018-05-08

We generated cattle embryos using mitochondrial supplementation and somatic cell nuclear transfer (SCNT), named miNT, to determine how additional mitochondrial DNA (mtDNA) modulates the nuclear genome. To eliminate any confounding effects from somatic cell mtDNA in intraspecies SCNT, donor cell mtDNA was depleted prior to embryo production. Additional oocyte mtDNA did not affect embryo development rates but increased mtDNA copy number in blastocyst stage embryos. Moreover, miNT-derived blastocysts had different gene expression profiles when compared with SCNT-derived blastocysts. Additional mtDNA increased expression levels of genes involved in oxidative phosphorylation, cell cycle and DNA repair. Supplementing the embryo culture media with a histone deacetylase inhibitor, Trichostatin A (TSA), had no beneficial effects on the development of miNT-derived embryos, unlike SCNT-derived embryos. When compared with SCNT-derived blastocysts cultured in the presence of TSA, additional mtDNA alone had beneficial effects as the activity of glycolysis may increase and embryonic cell death may decrease. However, these beneficial effects were not found with additional mtDNA and TSA together, suggesting that additional mtDNA alone enhances reprogramming. In conclusion, additional mtDNA increased mtDNA copy number and expression levels of genes involved in energy production and embryo development in blastocyst stage embryos emphasising the importance of nuclear-mitochondrial interactions.

Donor Outcomes in Living Donor Liver Transplantation-Analysis of 275 Donors From a Single Centre in India.

PubMed

Narasimhan, Gomathy; Safwan, Mohamed; Kota, Venugopal; Reddy, Mettu S; Bharathan, Anand; Dabora, Abderrhaim; Kaliamoorthy, Ilankumaran; Kanagavelu, Rathnavel G; Srinivasan, Vijaya; Rela, Mohamed

2016-06-01

Live donor liver transplantation is the predominant form of liver transplantation in India and in most Asian countries. Donor outcome reports are an important source of information to be shared with prospective donors at the time of informed consent. This is the first donor outcome series from India. Analysis of donor characteristics and morbidity of 275 live donors from a single large volume center is documented. Two hundred seventy-five patients donated from November 2009 to October 2014, 144 were women and 131 were men, 180 donated to adults and 95 donated to children. Right lobe donors were majority at 62.2% followed by left lateral segment 28%. Two thirds of the live donors did not have any morbidity; 114 complications were encountered in 85 patients. The complications were graded as per Clavien 5 tier grading and major morbidity (grade III b, grade IV grade V) was 4.36%. Postoperative biliary complication was seen in 3 donors. This large single-center study is the first donor outcome report from India, and the results are comparable to other published donor series. Documentation and regular audit of donor outcomes is important to help improve the safety of donor hepatectomy and to provide a database for informed consent of prospective donors.

Analysis of the Results of ABO-Incompatible Kidney Transplantation: In Comparison with ABO-Compatible Kidney Transplantation

PubMed Central

Jeon, Byung Joo; Seong, Youl Keun; Han, Bo Hyun

2010-01-01

Purpose The number of patients waiting for kidney transplantation is incessantly increasing, but the number of cadaveric kidney transplantations or ABO-compatible donors is so insufficient that ABO-incompatible kidney transplantation is being performed as an alternative. There are overseas studies and research showing that the 5-year survival rate and 5-year graft survival rate of ABO-incompatible kidney transplantation are not much different from those of ABO-compatible kidney transplantation. However, domestic research on the subject is rare. Therefore, we report the results of 22 ABO-incompatible kidney transplantation cases performed in our hospital. Materials and Methods This research was from 22 patients in our hospital who underwent ABO-incompatible kidney transplantation from 15 February 2007 to 20 May 2010. Results As yet, there have been no donor graft losses and no deaths after transplantation. The results of the two groups were analyzed by analysis of covariance of the creatinine value of the recipients at 6 months after the operation, corrected for the preoperative value in order to statistically identify whether there were differences in renal function after the operation between ABO-compatible and ABO-incompatible kidney transplantation. The results of the analysis of covariance showed no statistical difference in renal function after the operation between the two groups. Conclusions Even though there were not many cases, our initial results for ABO-incompatible kidney transplantation were positive. Considering the increasing number of patients waiting for kidney transplantation, longer-term domestic research studies of ABO-incompatible kidney transplantation are necessary. PMID:21221208

HLA matching in unrelated donor bone marrow transplantation.

PubMed

Charron, D J

1996-11-01

The availability of an HLA-matched sibling donor in only 30% to 35% of patients requiring allogeneic bone marrow transplantation (BMT) has led to the proposal of unrelated donors as an alternative source of bone marrow. The greater HLA incompatibility, which, although present, was undetected until recently in many unrelated donor BMT cases, has resulted in a higher rate of posttransplant complications and impaired acturial survival when compared with HLA-matched sibling BMT. Molecular HLA typing enables us to evaluate the impact of incompatibility at each locus in the outcome of unrelated donor BMT. The overall retrospective data would recommend that HLA-A, -B and -C allelic molecular matching should be implemented in addition to HLA-DR allelic matching. Further retrospective analysis is needed in order to assess which incompatibility or combinations are better tolerated than others. Only the definitive knowledge at the sequence level of the donor and the recipient HLA allelic diversity involved in controlling the allogeneic immune response will allow us to understand the precise biologic rationale of the graft-versus-host disease. Knowledge and control of the HLA incompatibilities should allow us to offset the detrimental effects of histoincompatibility while developing strategies to take advantage of the beneficial graft-versus-leukemia effect. Also the role of minor histocompatibility antigens remains largely unknown and will require careful evaluation before minor antigens can be used as a selection criterion in BMT. Carefully designed prospective studies will enable us to test the impact of each HLA locus. HLA typing and BMT represent a successful example of productive cooperation between basic and clinical sciences that should be pursued for the improvement of the clinical outcome of unrelated donor BMT.

Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease.

PubMed

Tobin, L M; Healy, M E; English, K; Mahon, B P

2013-05-01

Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchymal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on delivery of human peripheral blood mononuclear cells (PBMC) to non-obese diabetic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rγ(null) (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-γ-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimerism, as CD45(+) and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3(+) T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4(+) T cell proliferation and reduction of human tumour necrosis factor-α in serum. © 2012 British Society for Immunology.

Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.

PubMed

Rice, Ann C; Keeney, Paula M; Algarzae, Norah K; Ladd, Amy C; Thomas, Ravindar R; Bennett, James P

2014-01-01

Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD.

Global genetic differentiation in a cosmopolitan pest of stored beans: effects of geography, host-plant usage and anthropogenic factors.

PubMed

Tuda, Midori; Kagoshima, Kumiko; Toquenaga, Yukihiko; Arnqvist, Göran

2014-01-01

Genetic differentiation can be promoted allopatrically by geographic isolation of populations due to limited dispersal ability and diversification over time or sympatrically through, for example, host-race formation. In crop pests, the trading of crops across the world can lead to intermixing of genetically distinct pest populations. However, our understanding of the importance of allopatric and sympatric genetic differentiation in the face of anthropogenic genetic intermixing is limited. Here, we examined global sequence variation in two mitochondrial and one nuclear genes in the seed beetle Callosobruchus maculatus that uses different legumes as hosts. We analyzed 180 samples from 42 populations of this stored bean pest from tropical and subtropical continents and archipelagos: Africa, the Middle East, South and Southeast Asia, Oceania and South America. For the mitochondrial genes, there was weak but significant genetic differentiation across continents/archipelagos. Further, we found pronounced differentiation among subregions within continents/archipelagos both globally and within Africa but not within Asia. We suggest that multiple introductions into Asia and subsequent intermixing within Asia have generated this pattern. The isolation by distance hypothesis was supported globally (with or without continents controlled) but not when host species was restricted to cowpeas Vigna unguiculata, the ancestral host of C. maculatus. We also document significant among-host differentiation both globally and within Asia, but not within Africa. We failed to reject a scenario of a constant population size in the recent past combined with selective neutrality for the mitochondrial genes. We conclude that mitochondrial DNA differentiation is primarily due to geographic isolation within Africa and to multiple invasions by different alleles, followed by host shifts, within Asia. The weak inter-continental differentiation is most likely due to frequent inter-continental gene

Deceased donor renal transplantation from older donors to increase the donor pool.

PubMed

Kute, Vivek B; Trivedi, Hargovind L; Vanikar, Aruna V; Shah, Pankaj R; Gumber, Manoj R; Patel, Himanshu V; Modi, Pranjal R; Shah, Veena R

2012-09-01

Use of kidneys from donors aged 70 years and older is controversial. Organ shortage has led many transplant centers to accept kidneys from old, suboptimal deceased donors and make increasing use of old-for-old allocation systems. We describe our institutional experience with outcomes from transplanting deceased-donor kidneys from older donors (=70 years). 20 deceased donor renal transplants (DDRTx) were performed at our center using grafts from deceased donors 70 years and older between June 2004 and September 2011. Kidneys were allocated to dual or single grafting according to pre-transplant biopsy. Mean age of recipients was 47.60 ± 11.38 years, 13 of whom were males. Mean donor age was 76.49 ± 4.9 years; 10 of whom were males. The most common cause of donor death was cerebrovascular/road traffic accidents. Mean dialysis duration pre-transplantation was 19.5 ± 6.5 months. Mean HLA (Human Leukocyte Antigens) match was 1 ± 0.8. Most common recipient diseases leading to ESRD were chronic glomerulonephritis (25%), diabetes (20%), and hypertension (20%). Post-transplant immunosuppression consisted of a calcineurin inhibitor-based regimen. Over a mean follow-up of 2.8 ± 1.7 years, patient and graft survival rates were 75% (n = 15) and 80% ( n = 16), respectively, with a mean serum creatinine of 1.78 ± 0.56 mg/dl; 20% of the patients had biopsy-proven acute rejection episodes. A total of 25% (n = 5) patients died, mainly due to infections. DDRTx from older donors achieves acceptable graft function with patient/graft survival, provided that organs are allocated to dual or single grafting according to pre-transplant biopsy. These findings encourage the use of this approach even in low-income countries.

Alternative donor hematopoietic stem cell transplantation for sickle cell disease

PubMed Central

Eckrich, Michael J.; Epstein, Stacy; Barnhart, Carrie; Cannon, Mark; Fukes, Tracy; Hyland, Michelle; Shah, Krishna; Grochowski, Darci; Champion, Elizabeth; Ivanova, Anastasia

2017-01-01

Most patients who could be cured of sickle cell disease (SCD) with stem cell transplantation do not have a matched sibling donor. Successful use of alternative donors, including mismatched family members, could provide a donor for almost all patients with SCD. The use of a reduced-intensity conditioning regimen may decrease late adverse effects. Ten patients with symptomatic SCD underwent CD34+ cell-selected, T-cell–depleted peripheral blood stem cell transplantation from a mismatched family member or unrelated donor. A reduced-intensity conditioning regimen including melphalan, thiotepa, fludarabine, and rabbit anti-thymocyte globulin was used. Patients were screened for a companion study for immune reconstitution that included a donor lymphocyte infusion given 30-42 days after transplant with intravenous methotrexate as graft-versus-host disease (GVHD) prophylaxis. Seven eligible patients were treated on the companion study. Nine of 10 patients are alive with a median follow-up of 49 months (range, 14-60 months). Surviving patients have stable donor hematopoietic engraftment (mean donor chimerism, 99.1% ± 0.7%). There were no sickle cell complications after transplant. Two patients had grade II-IV acute GVHD. One patient had chronic GVHD. Epstein-Barr virus–related posttransplant lymphoproliferative disorder (PTLD) occurred in 3 patients, and 1 patient died as a consequence of treatment of PTLD. Two-year overall survival was 90%, and event-free survival was 80%. A reduced-intensity conditioning regimen followed by CD34+ cell-selected, T-cell–depleted alternative donor peripheral blood stem cell transplantation achieved primary engraftment in all patients with a low incidence of GVHD, although PTLD was problematic. This trial was registered at clinicaltrials.gov as #NCT00968864. PMID:29296761

Host-Induced gene silencing in barley powdery mildew reveals a class of ribonuclease-like effectors

USDA-ARS?s Scientific Manuscript database

Obligate biotrophic pathogens of plants require the ability to circumvent host defenses to enable colonization. To establish compatibility, pathogens secrete a variety of effectors, which regulate host immunity, and thus, facilitate the establishment of haustorial feeding structures. These structur...

Comparison of brain mitochondrial cytochrome c oxidase activity with cyanide LD(50) yields insight into the efficacy of prophylactics.

PubMed

Marziaz, Mandy L; Frazier, Kathryn; Guidry, Paul B; Ruiz, Robyn A; Petrikovics, Ilona; Haines, Donovan C

2013-01-01

Cyanide inhibits cytochrome c oxidase, the terminal oxidase of the mitochondrial respiratory pathway, therefore inhibiting the cell oxygen utilization and resulting in the condition of histotoxic anoxia. The enzyme rhodanese detoxifies cyanide by utilizing sulfur donors to convert cyanide to thiocyanate, and new and improved sulfur donors are actively sought as researchers seek to improve cyanide prophylactics. We have determined brain cytochrome c oxidase activity as a marker for cyanide exposure for mice pre-treated with various cyanide poisoning prophylactics, including sulfur donors thiosulfate (TS) and thiotaurine (TT3). Brain mitochondria were isolated by differential centrifugation, the outer mitochondrial membrane was disrupted by a maltoside detergent, and the decrease in absorbance at 550 nm as horse heart ferrocytochrome c (generated by the dithiothreitol reduction of ferricytochrome c) was oxidized was monitored. Overall, the TS control prophylactic treatment provided significant protection of the cytochrome c oxidase activity. The TT3-treated mice showed reduced cytochrome c oxidase activity even in the absence of cyanide. In both treatment series, addition of exogenous Rh did not significantly enhance the prevention of cytochrome c oxidase inhibition, but the addition of sodium nitrite did. These findings can lead to a better understanding of the protection mechanism by various cyanide antidotal systems. Copyright © 2011 John Wiley & Sons, Ltd.

Regional assessment of energy-producing metabolic activity in the endothelium of donor corneas.

PubMed

Greiner, Mark A; Burckart, Kimberlee A; Wagoner, Michael D; Schmidt, Gregory A; Reed, Cynthia R; Liaboe, Chase A; Flamme-Wiese, Miles J; Zimmerman, M Bridget; Mullins, Robert F; Kardon, Randy H; Goins, Kenneth M; Aldrich, Benjamin T

2015-05-01

We characterized mitochondrial respiration and glycolysis activity of human corneal endothelium, and compared metabolic activity between central and peripheral regions. Endothelial keratoplasty-suitable corneas were obtained from donors aged 50 to 75 years. The endothelium-Descemet membrane complex (EDM) was isolated, and 3-mm punches were obtained from central and peripheral regions. Endothelium-Descemet membrane punches were assayed for mitochondrial respiration (oxygen consumption) and glycolysis (extracellular acidification) using an extracellular flux analyzer. Enzymatic (citrate synthase, glucose hexokinase) and mitochondrial density (MitoTracker) assays also were performed. Ten corneas were analyzed per assay. Metabolic activity for mitochondrial respiration and glycolysis showed expected changes to assay compounds (P < 0.01, all pairwise comparisons). Basal mitochondrial respiration and glycolysis activity did not differ between regions (P > 0.99). Similarly, central versus peripheral activity after assay compound treatment showed no significant differences (P > 0.99, all time points). The intracorneal coefficient of variation for basal readings between two and four peripheral punches was 18.5% of the mean. Although peripheral samples displayed greater enzymatic activity than central samples (P < 0.05), similar to extracellular flux results, mitochondrial density did not differ between regions (P = 0.78). Extracellular flux analysis of oxygen and pH is a valid technique for characterizing metabolic activity of human corneal endothelium. This technique demonstrates high reproducibility, allows quantification of metabolic parameters using small quantities of live cells, and permits estimation of overall metabolic output. Neither oxygen consumption nor extracellular acidification differed between central and peripheral regions of transplant suitable corneas in this series. Our results show that endothelial cell health can be quantified biochemically in

Progression of Prostate Carcinogenesis and Dietary Methyl Donors: Temporal Dependence

PubMed Central

Shabbeer, Shabana; Williams, Simon A.; Simons, Brian W.; Herman, James G.; Carducci, Michael A.

2011-01-01

Insufficient dose of dietary methyl groups are associated with a host of conditions ranging from neural tube defects to cancer. On the other hand, it is not certain what effect excess dietary methyl groups could have on cancer. This is especially true for prostate cancer (PCa), a disease that is characterized by increasing DNA methylation changes with increasing grade of the cancer. In this three-part study in animals, we look at (i) the effect of excess methyl donors on the growth rate of PCa in vivo, (ii) the ability of 5-aza-2'-deoxycytidine, a demethylating agent, to demethylate in the presence of excess dietary methyl donors and (iii) the effect of in utero feeding of excess methyl donors to the later onset of PCa. The results show that when mice are fed a dietary excess of methyl donors, we do not see (i) an increase in the growth rate of DU-145 and PC-3 xenografts in vivo, or (ii) interference in the ability of 5-aza-2'-deoxycytidine to demethylate the promoters of Androgen Receptor or Reprimo of PCa xenografts but (iii) a protective effect on the development of higher grades of PCa in the “Hi-myc” mouse model of PCa which were fed the increased methyl donors in utero. We conclude that the impact of dietary methyl donors on PCa progression depends upon the timing of exposure to the dietary agents. When fed before the onset of cancer, i.e. in utero, excess methyl donors can have a protective effect on the progression of cancer. PMID:22139053

Fatty Acid Composition of Novel Host Jack Pine Do Not Prevent Host Acceptance and Colonization by the Invasive Mountain Pine Beetle and Its Symbiotic Fungus

PubMed Central

Ishangulyyeva, Guncha; Najar, Ahmed; Curtis, Jonathan M.

2016-01-01

Fatty acids are major components of plant lipids and can affect growth and development of insect herbivores. Despite a large literature examining the roles of fatty acids in conifers, relatively few studies have tested the effects of fatty acids on insect herbivores and their microbial symbionts. Particularly, whether fatty acids can affect the suitability of conifers for insect herbivores has never been studied before. Thus, we evaluated if composition of fatty acids impede or facilitate colonization of jack pine (Pinus banksiana) by the invasive mountain pine beetle (Dendroctonus ponderosae) and its symbiotic fungus (Grosmannia clavigera). This is the first study to examine the effects of tree fatty acids on any bark beetle species and its symbiotic fungus. In a novel bioassay, we found that plant tissues (hosts and non-host) amended with synthetic fatty acids at concentrations representative of jack pine were compatible with beetle larvae. Likewise, G. clavigera grew in media amended with lipid fractions or synthetic fatty acids at concentrations present in jack pine. In contrast, fatty acids and lipid composition of a non-host were not suitable for the beetle larvae or the fungus. Apparently, concentrations of individual, rather than total, fatty acids determined the suitability of jack pine. Furthermore, sampling of host and non-host tree species across Canada demonstrated that the composition of jack pine fatty acids was similar to the different populations of beetle’s historical hosts. These results demonstrate that fatty acids composition compatible with insect herbivores and their microbial symbionts can be important factor defining host suitability to invasive insects. PMID:27583820

Hosts and parasites as aliens.

PubMed

Taraschewski, H

2006-06-01

Over the past decades, various free-living animals (hosts) and their parasites have invaded recipient areas in which they had not previously occurred, thus gaining the status of aliens or exotics. In general this happened to a low extent for hundreds of years. With variable frequency, invasions have been followed by the dispersal and establishment of non-indigenous species, whether host or parasite. In the literature thus far, colonizations by both hosts and parasites have not been treated and reviewed together, although both are usually interwoven in various ways. As to those factors permitting invasive success and colonization strength, various hypotheses have been put forward depending on the scientific background of respective authors and on the conspicuousness of certain invasions. Researchers who have tried to analyse characteristic developmental patterns, the speed of dispersal or the degree of genetic divergence in populations of alien species have come to different conclusions. Among parasitologists, the applied aspects of parasite invasions, such as the negative effects on economically important hosts, have long been at the centre of interest. In this contribution, invasions by hosts as well as parasites are considered comparatively, revealing many similarities and a few differences. Two helminths, the liver fluke, Fasciola hepatica, of cattle and sheep and the swimbladder nematode, Anguillicola crassus, of eels are shown to be useful as model parasites for the study of animal invasions and environmental global change. Introductions of F. hepatica have been associated with imports of cattle or other grazing animals. In various target areas, susceptible lymnaeid snails serving as intermediate hosts were either naturally present and/or were introduced from the donor continent of the parasite (Europe) and/or from other regions which were not within the original range of the parasite, partly reflecting progressive stages of a global biota change. In several

The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment.

PubMed

Spitzer, Austin L; Lao, Oliver B; Dick, André A S; Bakthavatsalam, Ramasamy; Halldorson, Jeffrey B; Yeh, Matthew M; Upton, Melissa P; Reyes, Jorge D; Perkins, James D

2010-07-01

To expand the donor liver pool, ways are sought to better define the limits of marginally transplantable organs. The Donor Risk Index (DRI) lists 7 donor characteristics, together with cold ischemia time and location of the donor, as risk factors for graft failure. We hypothesized that donor hepatic steatosis is an additional independent risk factor. We analyzed the Scientific Registry of Transplant Recipients for all adult liver transplants performed from October 1, 2003, through February 6, 2008, with grafts from deceased donors to identify donor characteristics and procurement logistics parameters predictive of decreased graft survival. A proportional hazard model of donor variables, including percent steatosis from higher-risk donors, was created with graft survival as the primary outcome. Of 21,777 transplants, 5051 donors had percent macrovesicular steatosis recorded on donor liver biopsy. Compared to the 16,726 donors with no recorded liver biopsy, the donors with biopsied livers had a higher DRI, were older and more obese, and a higher percentage died from anoxia or stroke than from head trauma. The donors whose livers were biopsied became our study group. Factors most strongly associated with graft failure at 1 year after transplantation with livers from this high-risk donor group were donor age, donor liver macrovesicular steatosis, cold ischemia time, and donation after cardiac death status. In conclusion, in a high-risk donor group, macrovesicular steatosis is an independent risk factor for graft survival, along with other factors of the DRI including donor age, donor race, donation after cardiac death status, and cold ischemia time.

Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia.

PubMed

Gadalla, Shahinaz M; Wang, Tao; Haagenson, Michael; Spellman, Stephen R; Lee, Stephanie J; Williams, Kirsten M; Wong, Jason Y; De Vivo, Immaculata; Savage, Sharon A

2015-02-10

Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity. To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia. The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013. Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution. Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up. Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P = .009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence

Transfer and detection of freshly isolated or cultured chicken (Gallus gallus) and exotic species' embryonic gonadal germ stem cells in host embryos.

PubMed

Imus, Nastassja; Roe, Mandi; Charter, Suellen; Durrant, Barbara; Jensen, Thomas

2014-06-01

The management of captive avian breeding programs increasingly utilizes various artificial reproductive technologies, including in ovo sexing of embryos to adjust population sex ratios. Currently, however, no attention has been given to the loss of genetic diversity following sex-selective incubation, even with respect to individuals from critically endangered species. This project evaluated the possibility of using xenotransfer of embryonic gonadal germline stem cells (GGCs) for future reintroduction of their germplasm into the gene pool. We examined and compared the host gonad colonization of freshly isolated and 3 day (3d) cultured donor GGCs from chicken and 13 species of exotic embryos. Following 3d-culture of GGCs, there was a significant increase in the percentage of stem cell marker (SSEA-1, -3, -4) positive cells. However, the percentage of positive host gonads with chicken donor-derived cells decreased from 68% (fresh) to 22% (3d), while the percentage of exotic species donor-cells positive host gonads decreased from 61% (fresh) to 49% (3d-cultured). Donor GGCs from both chicken and exotic species were localized within the caudal endoderm, including the region encompassing the gonadal ridge by 16 hours post-injection. Furthermore, donor-derived cells isolated from stage 36 host embryos were antigenic for anti SSEA-1, VASA/DDX4 and EMA-1 antibodies, presumably indicating maintenance of stem cell identity. This study demonstrates that GGCs from multiple species can migrate to the gonadal region and maintain presumed stemness following xenotransfer into a chicken host embryo, suggesting that germline stem cell migration is highly conserved in birds.

Evaluation of Potential Donors in Living Donor Liver Transplantation.

PubMed

Dirican, A; Baskiran, A; Dogan, M; Ates, M; Soyer, V; Sarici, B; Ozdemir, F; Polat, Y; Yilmaz, S

2015-06-01

Correct donor selection in living donor liver transplantation (LDLT) is essential not only to decrease the risks of complications for the donors but also to increase the survival of both the graft and the recipient. Knowing their most frequent reasons of donor elimination is so important for transplantation centers to gain time. In this study we evaluated the effectiveness of potential donors in LDLT and studied the reasons for nonmaturation of potential liver donors at our transplantation center. We studied the outcomes of 342 potential living donor candidates for 161 recipient candidates for liver transplantation between January 2013 and June 2014. Donor candidates' gender, age, body mass index (BMI), relationship with recipient, and causes of exclusion were recorded. Among 161 recipients, 96 had a LDLT and 7 had cadaveric liver transplantation. Twelve of the 342 potential donors did not complete their evaluation; 106 of the remaining 330 donor candidates were accepted as suitable for donation (32%) but 10 of these were excluded preoperatively. The main reasons for unsuitability for liver donation were small remnant liver size (43%) and fatty changes of the liver (38.4%). Other reasons were arterial anatomic variations, ABO incompatibility, and Gilbert syndrome. Only 96 of the candidates (29% of the 330 candidates who completed the evaluation) underwent donation. Effective donors were 29% of potential and 90.5% of suitable donors. In our center, 106 of 330 (32%) donor candidates were suitable for donation and the main reasons for unsuitability for liver donation were small remnant liver size and fatty changes of the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of mitochondrial permeability transition pores in mitochondrial autophagy.

PubMed

Rodriguez-Enriquez, Sara; He, Lihua; Lemasters, John J

2004-12-01

During autophagy, cells rid themselves of damaged and superfluous mitochondria, as well as other organelles. This activation of mitochondrial turnover could be the result of changes in the physiological state of mitochondria. Confocal microscopy and fluorescence techniques indicate that onset of mitochondrial permeability transition is one such change. The mitochondrial permeability transition is a reversible phenomenon whereby the mitochondrial inner membrane becomes freely permeable to solutes of less than 1500 Da. At onset of the mitochondrial permeability transition, mitochondria depolarize, uncouple, and undergo large amplitude swelling due to opening of permeability transition pores, which may form by aggregation of damaged, misfolded membrane proteins. When injurious cellular stresses occur, cells may protect themselves using autophagy to remove damaged mitochondria and mutated mitochondrial DNA. Ca(2+) overloading, reactive oxygen and nitrogen species, decreased mitochondrial membrane potential, and oxidation of pyridine nucleotides and glutathione all promote mitochondrial damage and onset of the mitochondrial permeability transition. The mitochondrial permeability transition is also associated with necrosis and apoptosis after a variety of stimuli. This review emphasizes the role of the mitochondrial permeability transition as a key event in mitochondrial autophagy.

Graft-versus-leukemia effects of transplantation and donor lymphocytes.

PubMed

Kolb, Hans-Jochem

2008-12-01

Allogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graft-versus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versus-host disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treatment. Immunosuppressive therapy before donor lymphocyte transfusions may augment the effect as well as concomitant cytokine treatment. Possible target antigens are histocompatibility antigens and tumor-associated antigens. Immune escape of tumor cells and changes in the reactivity of T cells are to be considered. Durable responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies.

Gamete donors' expectations and experiences of contact with their donor offspring

PubMed Central

Kirkman, Maggie; Bourne, Kate; Fisher, Jane; Johnson, Louise; Hammarberg, Karin

2014-01-01

STUDY QUESTION What are the expectations and experiences of anonymous gamete donors about contact with their donor offspring? SUMMARY ANSWER Rather than consistently wanting to remain distant from their donor offspring, donors' expectations and experiences of contact with donor offspring ranged from none to a close personal relationship. WHAT IS KNOWN ALREADY Donor conception is part of assisted reproduction in many countries, but little is known about its continuing influence on gamete donors' lives. STUDY DESIGN, SIZE, DURATION A qualitative research model appropriate for understanding participants' views was employed; semi-structured interviews were conducted during January–March 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS Before 1998, gamete donors in Victoria, Australia, were subject to evolving legislation that allowed them to remain anonymous or (from 1988) to consent to the release of identifying information. An opportunity to increase knowledge of donors' expectations and experiences of contact with their donor offspring recently arose in Victoria when a recommendation was made to introduce mandatory identification of donors on request from their donor offspring, with retrospective effect. Pre-1998 donors were invited through an advertising campaign to be interviewed about their views, experiences and expectations; 36 sperm donors and 6 egg donors participated. MAIN RESULTS AND THE ROLE OF CHANCE This research is unusual in achieving participation by donors who would not normally identify themselves to researchers or government inquiries. Qualitative thematic analysis revealed that most donors did not characterize themselves as parents of their donor offspring. Donors' expectations and experiences of contact with donor offspring ranged from none to a close personal relationship. LIMITATIONS, REASONS FOR CAUTION It is not possible to establish whether participants were representative of all pre-1998 donors. WIDER IMPLICATIONS OF THE FINDINGS Anonymous

Molecular cloning, organellar targeting and developmental expression of mitochondrial chaperone HSP60 in Toxoplasma gondii.

PubMed

Toursel, C; Dzierszinski, F; Bernigaud, A; Mortuaire, M; Tomavo, S

2000-12-01

The obligate intracellular protozoan parasite Toxoplasma gondii has a single tubular mitochondrion. During infection, it recruits the host cell's mitochondria abutting to the intracellular vacuole, that contains the parasites. The respective contribution of host and parasitic mitochondria in the intracellular growth of T. gondii remains unknown. Heat shock protein, HSP60 has been reported in all eukaryotes examined, as an essential chaperone required for the folding and multimeric complex assembly of mitochondrial proteins. Here, we report the isolation and molecular characterization of two cDNAs corresponding to a single T. gondii gene coding for HSP60. Using a model fusion protein, preHSP60-chloramphenicol acetyl transferase (CAT), we demonstrate that the classical 22 amino acid mitochondrial presequence and the adjacent 32 amino acids of the mature protein are both required for the in vivo import into T. gondii mitochondria. The T. gondii HSP60 gene composed of five introns and six exons is transcribed into two related but differently spliced transcripts. Whereas the two transcripts can be detected in both developmental stages within the intermediate host, their levels are significantly increased in bradyzoites when compared to tachyzoites. By immunoblot analysis, the predicted 60-kDa protien corresponding to HSP60 was detected in both tachyzoite and bradyzoite forms. Using immunofluorescence assays. the polyclonal antibodies specific to T. gondii HSP60 recognized the mitochondrion in tachyzoites, as expected. In contrast, these antibodies reacted against two unknown vesicular bodies which are distinct from the classical mitochondrial pattern in bradyzoites. Taken together. these expression patterns of mitochondrial chaperone HSP60 suggests stage-specific induction of the respiratory pathway in the protozoan parasite T. gondii.

Mitochondrial Dynamics: Coupling Mitochondrial Fitness with Healthy Aging.

PubMed

Sebastián, David; Palacín, Manuel; Zorzano, Antonio

2017-03-01

Aging is associated with a decline in mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these mitochondrial alterations and the role of the latter in aging are still not fully understood. Mitochondrial dynamics is a key process regulating mitochondrial function and quality. Altered expression of some mitochondrial dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans, mice, and humans. Here, we review the link between alterations in mitochondrial dynamics, aging, and age-related impairment. We propose that the dysregulation of mitochondrial dynamics leads to age-induced accumulation of unhealthy mitochondria and contributes to alterations linked to aging, such as diabetes and neurodegeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Retention of "safe" blood donors. The Retrovirus Epidemiology Donor Study.

PubMed

Thomson, R A; Bethel, J; Lo, A Y; Ownby, H E; Nass, C C; Williams, A E

1998-04-01

There are obvious advantages to increasing donor retention. However, for reasons of blood safety, certain donors may, in fact, be more desirable to retain than others. "Safe" donors are defined as those who provided a blood donation that was negative on all laboratory screening tests and who subsequently reported no behavioral risks in response to an anonymous survey. This study identifies the most important factors affecting the intention of "safe" donors to provide another donation. An anonymous survey asking about donation history, sexual history, injecting drug use, and recent donation experience was mailed to 50,162 randomly selected allogeneic donors (including directed donors) who gave blood from April through July or from October through December 1993 at one of the five United States blood centers participating in the Retrovirus Epidemiology Donor Study. Before mailing, questionnaires were coded to designate donors with nonreactive laboratory screening tests at their most recent donation. A total of 34,726 donors (69%) responded, with substantially higher response among repeat donors. According to reported intentions only, the vast majority of "safe" donors indicated a high likelihood of donating again within the next 12 months. Only 3.4 percent reported a low likelihood of donating again. A comparison of those likely to return and those unlikely to return reveals significant differences in demographics and in ratings of the donation experience. A higher proportion of those unlikely to return were first-time donors, minority-group donors, and donors with less education. The highest projected loss among "safe" donors was seen for those who gave a fair to poor assessment of their treatment by blood center staff or of their physical well-being during or after donating. These data suggest that efforts to improve donors' perceptions of their donation experience, as well as attention to the physical effects of blood donation, may aid in the retention of both

The Compatibility Between Biomphalaria glabrata Snails and Schistosoma mansoni: An Increasingly Complex Puzzle.

PubMed

Mitta, G; Gourbal, B; Grunau, C; Knight, M; Bridger, J M; Théron, A

2017-01-01

This review reexamines the results obtained in recent decades regarding the compatibility polymorphism between the snail, Biomphalaria glabrata, and the pathogen, Schistosoma mansoni, which is one of the agents responsible for human schistosomiasis. Some results point to the snail's resistance as explaining the incompatibility, while others support a "matching hypothesis" between the snail's immune receptors and the schistosome's antigens. We propose here that the two hypotheses are not exclusive, and that the compatible/incompatible status of a particular host/parasite couple probably reflects the balance of multiple molecular determinants that support one hypothesis or the other. Because these genes are involved in a coevolutionary arms race, we also propose that the underlying mechanisms can vary. Finally, some recent results show that environmental factors could influence compatibility. Together, these results make the compatibility between B. glabrata and S. mansoni an increasingly complex puzzle. We need to develop more integrative approaches in order to find targets that could potentially be manipulated to control the transmission of schistosomiasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Motivations for Giving of Alumni Donors, Lapsed Donors and Non-Donors: Implications for Christian Higher Education

ERIC Educational Resources Information Center

Rugano, Emilio Kariuki

2011-01-01

This descriptive and causal comparative study sought to identify motivations for alumni donor acquisition and retention in Christian institutions of higher learning. To meet this objective, motivations for alumni donors, lapsed donors, and non-donors were analyzed and compared. Data was collected through an electronic survey of a stratified sample…

Mitochondrial vasculopathy

PubMed Central

Finsterer, Josef; Zarrouk-Mahjoub, Sinda

2016-01-01

Mitochondrial disorders (MIDs) are usually multisystem disorders (mitochondrial multiorgan disorder syndrome) either on from onset or starting at a point during the disease course. Most frequently affected tissues are those with a high oxygen demand such as the central nervous system, the muscle, endocrine glands, or the myocardium. Recently, it has been shown that rarely also the arteries may be affected (mitochondrial arteriopathy). This review focuses on the type, diagnosis, and treatment of mitochondrial vasculopathy in MID patients. A literature search using appropriate search terms was carried out. Mitochondrial vasculopathy manifests as either microangiopathy or macroangiopathy. Clinical manifestations of mitochondrial microangiopathy include leukoencephalopathy, migraine-like headache, stroke-like episodes, or peripheral retinopathy. Mitochondrial macroangiopathy manifests as atherosclerosis, ectasia of arteries, aneurysm formation, dissection, or spontaneous rupture of arteries. The diagnosis relies on the documentation and confirmation of the mitochondrial metabolic defect or the genetic cause after exclusion of non-MID causes. Treatment is not at variance compared to treatment of vasculopathy due to non-MID causes. Mitochondrial vasculopathy exists and manifests as micro- or macroangiopathy. Diagnosing mitochondrial vasculopathy is crucial since appropriate treatment may prevent from severe complications. PMID:27231520

Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease

PubMed Central

Toubai, Tomomi; Sun, Yaping; Tawara, Isao; Friedman, Ann; Liu, Chen; Evers, Rebecca; Nieves, Evelyn; Malter, Chelsea; Chockley, Peter; Maillard, Ivan; Winandy, Susan

2011-01-01

Host hematopoietically derived APCs play a vital role in the initiation of GVH responses. However, the APC autonomous molecular mechanisms that are critical for the induction of GVHD are not known. We report here that the Ikaros-Notch axis in host hematopoietically derived APCs regulates the severity of acute GVHD across multiple clinically relevant murine models of experimental bone marrow transplantation. In the present study, Ikaros deficiency (Ik−/−) limited to host hematopoietically derived APCs enhanced donor T-cell expansion and intensified acute GVHD, as determined by survival and other GVHD-specific parameters. The Ik−/− conventional CD8+ and CD8−CD11c+ dendritic cells (DCs), the most potent APCs, showed no increase in the expression of activation markers or in response to TLR stimulation compared with wild-type controls. However, Ik−/− DCs demonstrated an enhanced stimulation of allogeneic T cells. Deficiency of Ikaros in the conventional CD8+ and CD8−CD11c+ DCs was associated with an increase in Notch signaling, the blockade of which mitigated the enhanced in vitro and in vivo allostimulatory capacity. Therefore, the Ikaros-Notch axis is a novel pathway that modulates DC biology in general, and targeting this pathway in host hematopoietically derived APCs may reduce GVHD. PMID:21471527

Substrate-dependent changes in mitochondrial function, intracellular free calcium concentration and membrane channels in pancreatic beta-cells.

PubMed

Duchen, M R; Smith, P A; Ashcroft, F M

1993-08-15

Microfluorimetric and patch-clamp techniques have been combined to determine the relationship between changes in mitochondrial metabolism, the activity of KATP channels and changes in intracellular free calcium concentration ([Ca2+]i) in isolated pancreatic beta-cells in response to glucose, ketoisocaproic acid (KIC) and the electron donor couple tetramethyl p-phenylenediamine (TMPD) and ascorbate. Exposure of cells to 20 mM glucose raised NAD(P)H autofluorescence after a delay of 28 +/- 1 s (mean +/- S.E.M., n = 30). The mitochondrial inner membrane potential, delta psi m (monitored using rhodamine 123 fluorescence), hyperpolarized with a latency of 49 +/- 6 s (n = 17), and the [Ca2+]i rose after 129 +/- 13 s (n = 5). The amplitudes of the metabolic changes were graded appropriately with glucose concentration over the range 2.5-20 mM. All variables responded to KIC with shorter latencies: NAD(P)H autofluorescence rose after a delay of 20 +/- 3 s (n = 5) and rhodamine 123 changed after 21 +/- 3 s (n = 6). The electron donor couple, TMPD with ascorbate, rapidly hyperpolarized delta psi m and raised [Ca2+]i. When [Ca2+]i was raised by sustained exposure to 20 mM glucose, TMPD had no further effect. TMPD also decreased whole-cell KATP currents and depolarized the cell membrane, measured with the perforated patch configuration. These data are consistent with a central role for mitochondrial oxidative phosphorylation in coupling changes in glucose concentration with the secretion of insulin.

Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy.

PubMed

Sleigh, Alison; Lupson, Victoria; Thankamony, Ajay; Dunger, David B; Savage, David B; Carpenter, T Adrian; Kemp, Graham J

2016-01-11

The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable. The device exploits an MR-compatible high-density material (BaSO4) to form a weight which is attached directly to the ankle, and a one-minute dynamic knee extension protocol produced highly reproducible measurements of post-exercise PCr recovery kinetics in both healthy subjects and patients. As sophisticated exercise equipment is unnecessary for this measurement, our extremely simple design provides an effective and easy-to-implement apparatus that is readily translatable across sites. Its design, being tailored to the needs of the patient, makes it particularly well suited to clinical applications, and we argue the potential of this method for investigating in vivo mitochondrial function in new cohorts of growing clinical interest.

Compatible intracellular ion composition of the host improves carbon assimilation by zooxanthellae in mutualistic symbioses.

PubMed

Seibt, C; Schlichter, D

2001-09-01

Cytosymbiotic algae within the host's plasma are exposed to completely different ionic conditions than microalgae living in the sea. The altered ionic gradients, in particular, could be the reason for higher in hospite carbon assimilation levels. To study the effect of varying extracellular ionic conditions on isolated zooxanthellae, their photosynthetic capacity in pure seawater was compared to that in a test medium in which the concentrations of the major inorganic ions, the pH and the osmolality were adjusted to the conditions measured in the host cytoplasm. In this test medium the ratio between oxygen evolution and carbon fixation was 1.2:1.0; in contrast, zooxanthellae in the hyperionic seawater medium showed a comparatively higher oxygen production (2.6:1.0). These results are attributed to a higher energy demand for ion regulation of the isolated algae in the hyperionic medium. Isolated cytosymbionts in seawater need more energy both for the readjustment to the original intracellular ion concentration within the host cell and also for the maintenance of a much steeper gradient during incubation under hyperionic conditions outside the host. The particular intracellular ion concentration of the host cells could have been a decisive evolutionary factor for the very successful establishment of the mutualistic symbioses between anthozoans and dinoflagellates more than 200 million years ago.

An in silico argument for mitochondrial microRNA as a determinant of primary non function in liver transplantation.

PubMed

Khorsandi, Shirin Elizabeth; Salehi, Siamak; Cortes, Miriam; Vilca-Melendez, Hector; Menon, Krishna; Srinivasan, Parthi; Prachalias, Andreas; Jassem, Wayel; Heaton, Nigel

2018-02-15

Mitochondria have their own genomic, transcriptomic and proteomic machinery but are unable to be autonomous, needing both nuclear and mitochondrial genomes. The aim of this work was to use computational biology to explore the involvement of Mitochondrial microRNAs (MitomiRs) and their interactions with the mitochondrial proteome in a clinical model of primary non function (PNF) of the donor after cardiac death (DCD) liver. Archival array data on the differential expression of miRNA in DCD PNF was re-analyzed using a number of publically available computational algorithms. 10 MitomiRs were identified of importance in DCD PNF, 7 with predicted interaction of their seed sequence with the mitochondrial transcriptome that included both coding, and non coding areas of the hypervariability region 1 (HVR1) and control region. Considering miRNA regulation of the nuclear encoded mitochondrial proteome, 7 hypothetical small proteins were identified with homolog function that ranged from co-factor for formation of ATP Synthase, REDOX balance and an importin/exportin protein. In silico, unconventional seed interactions, both non canonical and alternative seed sites, appear to be of greater importance in MitomiR regulation of the mitochondrial genome. Additionally, a number of novel small proteins of relevance in transplantation have been identified which need further characterization.

Mitochondrial genome rearrangements in glomus species triggered by homologous recombination between distinct mtDNA haplotypes.

PubMed

Beaudet, Denis; Terrat, Yves; Halary, Sébastien; de la Providencia, Ivan Enrique; Hijri, Mohamed

2013-01-01

Comparative mitochondrial genomics of arbuscular mycorrhizal fungi (AMF) provide new avenues to overcome long-lasting obstacles that have hampered studies aimed at understanding the community structure, diversity, and evolution of these multinucleated and genetically polymorphic organisms.AMF mitochondrial (mt) genomes are homogeneous within isolates, and their intergenic regions harbor numerous mobile elements that have rapidly diverged, including homing endonuclease genes, small inverted repeats, and plasmid-related DNA polymerase genes (dpo), making them suitable targets for the development of reliable strain-specific markers. However, these elements may also lead to genome rearrangements through homologous recombination, although this has never previously been reported in this group of obligate symbiotic fungi. To investigate whether such rearrangements are present and caused by mobile elements in AMF, the mitochondrial genomes from two Glomeraceae members (i.e., Glomus cerebriforme and Glomus sp.) with substantial mtDNA synteny divergence,were sequenced and compared with available glomeromycotan mitochondrial genomes. We used an extensive nucleotide/protein similarity network-based approach to investigated podiversity in AMF as well as in other organisms for which sequences are publicly available. We provide strong evidence of dpo-induced inter-haplotype recombination, leading to a reshuffled mitochondrial genome in Glomus sp. These findings raise questions as to whether AMF single spore cultivations artificially underestimate mtDNA genetic diversity.We assessed potential dpo dispersal mechanisms in AMF and inferred a robust phylogenetic relationship with plant mitochondrial plasmids. Along with other indirect evidence, our analyses indicate that members of the Glomeromycota phylum are potential donors of mitochondrial plasmids to plants.

Mitochondrial Genome Rearrangements in Glomus Species Triggered by Homologous Recombination between Distinct mtDNA Haplotypes

PubMed Central

Beaudet, Denis; Terrat, Yves; Halary, Sébastien; de la Providencia, Ivan Enrique; Hijri, Mohamed

2013-01-01

Comparative mitochondrial genomics of arbuscular mycorrhizal fungi (AMF) provide new avenues to overcome long-lasting obstacles that have hampered studies aimed at understanding the community structure, diversity, and evolution of these multinucleated and genetically polymorphic organisms. AMF mitochondrial (mt) genomes are homogeneous within isolates, and their intergenic regions harbor numerous mobile elements that have rapidly diverged, including homing endonuclease genes, small inverted repeats, and plasmid-related DNA polymerase genes (dpo), making them suitable targets for the development of reliable strain-specific markers. However, these elements may also lead to genome rearrangements through homologous recombination, although this has never previously been reported in this group of obligate symbiotic fungi. To investigate whether such rearrangements are present and caused by mobile elements in AMF, the mitochondrial genomes from two Glomeraceae members (i.e., Glomus cerebriforme and Glomus sp.) with substantial mtDNA synteny divergence, were sequenced and compared with available glomeromycotan mitochondrial genomes. We used an extensive nucleotide/protein similarity network-based approach to investigate dpo diversity in AMF as well as in other organisms for which sequences are publicly available. We provide strong evidence of dpo-induced inter-haplotype recombination, leading to a reshuffled mitochondrial genome in Glomus sp. These findings raise questions as to whether AMF single spore cultivations artificially underestimate mtDNA genetic diversity. We assessed potential dpo dispersal mechanisms in AMF and inferred a robust phylogenetic relationship with plant mitochondrial plasmids. Along with other indirect evidence, our analyses indicate that members of the Glomeromycota phylum are potential donors of mitochondrial plasmids to plants. PMID:23925788

Electrical Manipulation of Donor Spin Qubits in Silicon and Germanium

NASA Astrophysics Data System (ADS)

Sigillito, Anthony James

Many proposals for quantum information devices rely on electronic or nuclear spins in semiconductors because of their long coherence times and compatibility with industrial fabrication processes. One of the most notable qubits is the electron spin bound to phosphorus donors in silicon, which offers coherence times exceeding seconds at low temperatures. These donors are naturally isolated from their environments to the extent that silicon has been coined a "semiconductor vacuum". While this makes for ultra-coherent qubits, it is difficult to couple two remote donors so quantum information proposals rely on high density arrays of qubits. Here, single qubit addressability becomes an issue. Ideally one would address individual qubits using electric fields which can be easily confined. Typically these schemes rely on tuning a donor spin qubit onto and off of resonance with a magnetic driving field. In this thesis, we measure the electrical tunability of phosphorus donors in silicon and use the extracted parameters to estimate the effects of electric-field noise on qubit coherence times. Our measurements show that donor ionization may set in before electron spins can be sufficiently tuned. We therefore explore two alternative options for qubit addressability. First, we demonstrate that nuclear spin qubits can be directly driven using electric fields instead of magnetic fields and show that this approach offers several advantages over magnetically driven spin resonance. In particular, spin transitions can occur at half the spin resonance frequency and double quantum transitions (magnetic-dipole forbidden) can occur. In a second approach to realizing tunable qubits in semiconductors, we explore the option of replacing silicon with germanium. We first measure the coherence and relaxation times for shallow donor spin qubits in natural and isotopically enriched germanium. We find that in isotopically enriched material, coherence times can exceed 1 ms and are limited by a

MitoQ blunts mitochondrial and renal damage during cold preservation of porcine kidneys.

PubMed

Parajuli, Nirmala; Campbell, Lia H; Marine, Akira; Brockbank, Kelvin G M; Macmillan-Crow, Lee Ann

2012-01-01

Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a key target for injury. Our laboratory has demonstrated that cold storage of renal cells and rat kidneys leads to increased mitochondrial superoxide levels and mitochondrial electron transport chain damage, and that addition of Mitoquinone (MitoQ) to the preservation solutions blunted this injury. In order to better translate animal studies, the inclusion of large animal models is necessary to develop safe preclinical protocols. Therefore, we tested the hypothesis that addition of MitoQ to cold storage solution preserves mitochondrial function by decreasing oxidative stress, leading to less renal tubular damage during cold preservation of porcine kidneys employing a standard criteria donor model. Results showed that cold storage significantly induced oxidative stress (nitrotyrosine), renal tubular damage, and cell death. Using High Resolution Respirometry and fresh porcine kidney biopsies to assess mitochondrial function we showed that MitoQ significantly improved complex II/III respiration of the electron transport chain following 24 hours of cold storage. In addition, MitoQ blunted oxidative stress, renal tubular damage, and cell death after 48 hours. These results suggested that MitoQ decreased oxidative stress, tubular damage and cell death by improving mitochondrial function during cold storage. Therefore this compound should be considered as an integral part of organ preservation solution prior to transplantation.

MitoQ Blunts Mitochondrial and Renal Damage during Cold Preservation of Porcine Kidneys

PubMed Central

Parajuli, Nirmala; Campbell, Lia H.; Marine, Akira; Brockbank, Kelvin G. M.; MacMillan-Crow, Lee Ann

2012-01-01

Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a key target for injury. Our laboratory has demonstrated that cold storage of renal cells and rat kidneys leads to increased mitochondrial superoxide levels and mitochondrial electron transport chain damage, and that addition of Mitoquinone (MitoQ) to the preservation solutions blunted this injury. In order to better translate animal studies, the inclusion of large animal models is necessary to develop safe preclinical protocols. Therefore, we tested the hypothesis that addition of MitoQ to cold storage solution preserves mitochondrial function by decreasing oxidative stress, leading to less renal tubular damage during cold preservation of porcine kidneys employing a standard criteria donor model. Results showed that cold storage significantly induced oxidative stress (nitrotyrosine), renal tubular damage, and cell death. Using High Resolution Respirometry and fresh porcine kidney biopsies to assess mitochondrial function we showed that MitoQ significantly improved complex II/III respiration of the electron transport chain following 24 hours of cold storage. In addition, MitoQ blunted oxidative stress, renal tubular damage, and cell death after 48 hours. These results suggested that MitoQ decreased oxidative stress, tubular damage and cell death by improving mitochondrial function during cold storage. Therefore this compound should be considered as an integral part of organ preservation solution prior to transplantation. PMID:23139796

Donor profiles: demographic factors and their influence on the donor career.

PubMed

Veldhuizen, I J T; Doggen, C J M; Atsma, F; De Kort, W L A M

2009-08-01

Studying the contribution of demographic factors to the donor career provides important knowledge to be used for donor management. The aim of this study is to gain insight into donor characteristics, more specifically into the demographic profile of active vs. resigned donors, and multi-gallon vs. occasional donors. The study population consisted of all registered Dutch whole-blood donors between 1 January 2004 and 1 January 2005 (N = 370 470). The effect of several blood donor characteristics and demographic variables on (i) resigning donating and (ii) being a multi-gallon donor were assessed. Blood donor characteristics were extracted from the blood bank information system and included age, sex, blood group, number of donations and invitations. Demographic characteristics were constituted by population data on urbanization level, socio-economic status (income, housing value), and ethnicity. Men clearly resigned less often than women (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.72-0.75). Being older than 24 years, having a high income, a high-priced house, living in less urbanized areas or areas with relatively few ethnically diverse people also reduced the stopping risk. With respect to multi-gallon donorship, men were five times more often multi-gallon donor than women (OR 5.27, 95% CI 5.15-5.39) irrespective of the number of donation invitations. Furthermore, multi-gallon donors appeared to live in urbanized areas and have a higher income than occasional donors. Our results show that different donor profiles can be distinguished. Differences between active and resigned donors include age, the number of donations, sex, socio-economic-status, ethnicity, and urbanization level. The factors highly associated with being a multi-gallon donor are sex, age, socio-economic status, and to a lesser extent urbanization level. Donor profiles do provide the blood bank with knowledge on their donor population, which may be used as valuable information for donor

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

PubMed Central

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD. PMID:27148267

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation.

PubMed

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD.

Renal Allograft Survival in Nonhuman Primates Infused with Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells

PubMed Central

Ezzelarab, M.B.; Raich-Regue, D.; Lu, L.; Zahorchak, A.F.; Perez-Gutierrez, A.; Humar, A.; Wijkstrom, M.; Minervini, M.; Wiseman, R.W.; Cooper, D.K.C.; Morelli, A.E.; Thomson, A.W.

2017-01-01

Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg pre-loaded with cell membrane vesicles from allogeneic PBMC, induce T cell hyporesponsiveness to donor alloAg in vitro. These donor alloAg-pulsed autologous DCreg (1.4–3.6 x 106/kg) were administered intravenously, one day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n=6 historical controls) and 29 days with control unpulsed DCreg (n=2), to 56 days with donor Ag-pulsed DCreg (n=5), was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days post-transplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen. PMID:28009481

Are drowned donors marginal donors? A single pediatric center experience.

PubMed

Kumm, Kayla R; Galván, N Thao N; Koohmaraie, Sarah; Rana, Abbas; Kueht, Michael; Baugh, Katherine; Hao, Liu; Yoeli, Dor; Cotton, Ronald; O'Mahony, Christine A; Goss, John A

2017-09-01

Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single-center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Integrative Identification of Arabidopsis Mitochondrial Proteome and Its Function Exploitation through Protein Interaction Network

PubMed Central

Cui, Jian; Liu, Jinghua; Li, Yuhua; Shi, Tieliu

2011-01-01

Mitochondria are major players on the production of energy, and host several key reactions involved in basic metabolism and biosynthesis of essential molecules. Currently, the majority of nucleus-encoded mitochondrial proteins are unknown even for model plant Arabidopsis. We reported a computational framework for predicting Arabidopsis mitochondrial proteins based on a probabilistic model, called Naive Bayesian Network, which integrates disparate genomic data generated from eight bioinformatics tools, multiple orthologous mappings, protein domain properties and co-expression patterns using 1,027 microarray profiles. Through this approach, we predicted 2,311 candidate mitochondrial proteins with 84.67% accuracy and 2.53% FPR performances. Together with those experimental confirmed proteins, 2,585 mitochondria proteins (named CoreMitoP) were identified, we explored those proteins with unknown functions based on protein-protein interaction network (PIN) and annotated novel functions for 26.65% CoreMitoP proteins. Moreover, we found newly predicted mitochondrial proteins embedded in particular subnetworks of the PIN, mainly functioning in response to diverse environmental stresses, like salt, draught, cold, and wound etc. Candidate mitochondrial proteins involved in those physiological acitivites provide useful targets for further investigation. Assigned functions also provide comprehensive information for Arabidopsis mitochondrial proteome. PMID:21297957

The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy

PubMed Central

Vincent, Amy E.; Ng, Yi Shiau; White, Kathryn; Davey, Tracey; Mannella, Carmen; Falkous, Gavin; Feeney, Catherine; Schaefer, Andrew M.; McFarland, Robert; Gorman, Grainne S.; Taylor, Robert W.; Turnbull, Doug M.; Picard, Martin

2016-01-01

Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID:27506553

Fingerprinting of HLA class I genes for improved selection of unrelated bone marrow donors.

PubMed

Martinelli, G; Farabegoli, P; Buzzi, M; Panzica, G; Zaccaria, A; Bandini, G; Calori, E; Testoni, N; Rosti, G; Conte, R; Remiddi, C; Salvucci, M; De Vivo, A; Tura, S

1996-02-01

The degree of matching of HLA genes between the selected donor and recipient is an important aspect of the selection of unrelated donors for allogeneic bone marrow transplantation (UBMT). The most sensitive methods currently used are serological typing of HLA class I genes, mixed lymphocyte culture (MLC), IEF and molecular genotyping of HLA class II genes by direct sequencing of PCR products. Serological typing of class I antigenes (A, B and C) fails to detect minor differences demonstrated by direct sequencing of DNA polymorphic regions. Molecular genotyping of HLA class I genes by DNA analysis is costly and work-intensive. To improve compatibility between donor and recipient, we have set up a new rapid and non-radioisotopic application of the 'fingerprinting PCR' technique for the analysis of the polymorphic second exon of the HLA class I A, B and C genes. This technique is based on the formation of specific patterns (PCR fingerprints) of homoduplexes and heteroduplexes between heterologous amplified DNA sequences. After an electrophoretic run on non-denaturing polyacrylamide gel, different HLA class I types give allele-specific banding patterns. HLA class I matching is performed, after the gel has been soaked in ethidium bromide or silver-stained, by visual comparison of patients' fingerprints with those of donors. Identity can be confirmed by mixing donor and recipient DNAs in an amplification cross-match. To assess the technique, 10 normal samples, 22 related allogeneic bone marrow transplanted pairs and 10 unrelated HLA-A and HLA-B serologically matched patient-donor pairs were analysed for HLA class I polymorphic regions. In all the related pairs and in 1/10 unrelated pairs, matched donor-recipient patterns were identified. This new application of PCR fingerprinting may confirm the HLA class I serological selection of unrelated marrow donors.

A re-evaluation of the role of mitochondrial pyruvate transport in the hormonal control of rat liver mitochondrial pyruvate metabolism.

PubMed Central

Halestrap, A P; Armston, A E

1984-01-01

The inhibitor of mitochondrial pyruvate transport alpha-cyano-beta-(1-phenylindol-3-yl)-acrylate was used to inhibit progressively pyruvate carboxylation by liver mitochondria from control and glucagon-treated rats. The data showed that, contrary to our previous conclusions [Halestrap (1978) Biochem. J. 172, 389-398], pyruvate transport could not regulate metabolism under these conditions. This was confirmed by measuring the intramitochondrial pyruvate concentration, which almost equilibrated with the extramitochondrial pyruvate concentration in control mitochondria, but was significantly decreased in mitochondria from glucagon-treated rats, where rates of pyruvate metabolism were elevated. Computer-simulation studies explain how this is compatible with linear Dixon plots of the inhibition of pyruvate metabolism by alpha-cyano-4-hydroxycinnamate. Parallel measurements of the mitochondrial membrane potential by using [3H]triphenylmethylphosphonium ions showed that it was elevated by about 3 mV after pretreatment of rats with both glucagon and phenylephrine. There was no significant change in the transmembrane pH gradient. It is shown that the increase in pyruvate metabolism can be explained by a stimulation of the respiratory chain, producing an elevation in the protonmotive force and a consequent rise in the intramitochondrial ATP/ADP ratio, which in turn increases pyruvate carboxylase activity. Mild inhibition of the respiratory chain with Amytal reversed the effects of hormone treatment on mitochondrial pyruvate metabolism and ATP concentrations, but not on citrulline synthesis. The significance of these observations for the hormonal regulation of gluconeogenesis from L-lactate in vivo is discussed. PMID:6095807

Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.

PubMed

Béhin, A; Jardel, C; Claeys, K G; Fagart, J; Louha, M; Romero, N B; Laforêt, P; Eymard, B; Lombès, A

2012-02-28

In this study we aim to demonstrate the occurrence of adult forms of TK2 mutations causing progressive mitochondrial myopathy with significant muscle mitochondrial DNA (mtDNA) depletion. Patients' investigations included serum creatine kinase, blood lactate, electromyographic, echocardiographic, and functional respiratory analyses as well as TK2 gene sequencing and TK2 activity measurement. Mitochondrial activities and mtDNA were analyzed in the patients' muscle biopsy. The 3 adult patients with TK2 mutations presented with slowly progressive myopathy compatible with a fairly normal life during decades. Apart from its much slower progression, these patients' phenotype closely resembled that of pediatric cases including early onset, absence of CNS symptoms, generalized muscle weakness predominating on axial and proximal muscles but affecting facial, ocular, and respiratory muscles, typical mitochondrial myopathy with a mosaic pattern of COX-negative and ragged-red fibers, combined mtDNA-dependent respiratory complexes deficiency and mtDNA depletion. In accordance with the disease's relatively slow progression, the residual mtDNA content was higher than that observed in pediatric cases. That difference was not explained by the type of the TK2 mutations or by the residual TK2 activity. TK2 mutations can cause mitochondrial myopathy with a slow progression. Comparison of patients with similar mutations but different disease progression might address potential mechanisms of mtDNA maintenance modulation.

Mitochondrial myopathies.

PubMed

DiMauro, Salvatore

2006-11-01

Our understanding of mitochondrial diseases (defined restrictively as defects of the mitochondrial respiratory chain) is expanding rapidly. In this review, I will give the latest information on disorders affecting predominantly or exclusively skeletal muscle. The most recently described mitochondrial myopathies are due to defects in nuclear DNA, including coenzyme Q10 deficiency and mutations in genes controlling mitochondrial DNA abundance and structure, such as POLG, TK2, and MPV17. Barth syndrome, an X-linked recessive mitochondrial myopathy/cardiopathy, is associated with decreased amount and altered structure of cardiolipin, the main phospholipid of the inner mitochondrial membrane, but a secondary impairment of respiratory chain function is plausible. The role of mutations in protein-coding genes of mitochondrial DNA in causing isolated myopathies has been confirmed. Mutations in tRNA genes of mitochondrial DNA can also cause predominantly myopathic syndromes and--contrary to conventional wisdom--these mutations can be homoplasmic. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle, causing exercise intolerance, cramps, recurrent myoglobinuria, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis) and progressive external ophthalmoplegia.

Gamete donation: parents' experiences of searching for their child's donor siblings and donor.

PubMed

Freeman, T; Jadva, V; Kramer, W; Golombok, S

2009-03-01

This study investigates the new phenomenon of parents of donor offspring searching for and contacting their child's 'donor siblings' (i.e. donor offspring conceived by the same donor) and donor. Online questionnaires were completed by 791 parents (39% lone-mother, 35% lesbian-couple, 21% heterosexual-couple, 5% non-specified) recruited via the Donor Sibling Registry; a US-based international registry that facilitates contact between donor conception families who share the same donor. Data were collected on parents' reasons for searching for their child's donor siblings and/or donor, the outcome of these searches and parents' and their child's experiences of any resulting contact. Parents' principal motivation for searching for their child's donor siblings was curiosity and for their donor, enhancing their child's sense of identity. Some parents had discovered large numbers of donor siblings (maximum = 55). Most parents reported positive experiences of contacting and meeting their child's donor siblings and donor. This study highlights that having access to information about a child's donor origins is important for some parents and has potentially positive consequences. These findings have wider implications because the removal of donor anonymity in the UK and elsewhere means that increasing numbers of donor offspring are likely to seek contact with their donor relations in the future.

[Personality and donor-recipient relationships of potential donors before living donor liver transplantation--diagnostics with the repertory-grid technique].

PubMed

Walter, Marc; Walter, Otto B; Fliege, Herbert; Klapp, Burghard F; Danzer, Gerhard

2003-06-01

Living-donor liver transplantation (LDLT) is developing into an established therapy for terminal liver diseases in adults. Potential donors are faced with the risk of postoperative complications and are subject to a high level of psychological pressure and ambivalent feelings. Our assumption is that ambivalent feelings before donation are crucially influenced by the personality and the quality of the donor-recipient relationship. In highly motivated donors we expected a positive description of the recipient and a similarity in the characterisation of the donor and recipient. 58 potential living donors were evaluated between March 2000 and June 2001. On the basis of the clinical interview 10 were rated as unsuited for donation. Among those potential donors assessed as unsuited, we found a high level of ambivalent feelings. For 50 potential donors we gained a set of completed psychometric diagnostic questionnaires. A Repertory-grid investigation was conducted with a total of 28 potential donors. Seven of them were not recommended as living donors. The relationship between donors and recipients was analysed concerning constructs that were most important to the characterisation of the donor or recipient. By means of inter-element distances self-concept of donors and donor-recipient relation were analysed. Ambivalent candidates who were not recommended as living donors tended to describe the recipient negatively (selfish, carping, and unable to take criticism) and did not show a similarity in the characterisations of self and ideal-self. Whereas the highly motivated candidates were marked by a closeness of self and ideal-self concepts. Both groups saw the recipient as indifferent. Closeness between self and ideal-self-indicating satisfaction with the decision to donate seems to be one suitable criterion to distinguish between highly motivated potential donors on the one hand and ambivalent candidates on the other hand. Another criterion appears to be a description of

Resveratrol Improves the Mitochondrial Function and Fertilization Outcome of Bovine Oocytes

PubMed Central

TAKEO, Shun; SATO, Daichi; KIMURA, Koji; MONJI, Yasunori; KUWAYAMA, Takehito; KAWAHARA-MIKI, Ryoka; IWATA, Hisataka

2013-01-01

The aim of the present study was to address the effect of resveratrol-mediated upregulation of sirtuin 1 (SIRT1) during oocyte maturation on mitochondrial function, the developmental ability of oocytes and on mechanisms responsible for blockage of polyspermic fertilization. Oocytes collected from slaughterhouse-derived ovaries were cultured in TCM-199 medium supplemented with 10% FCS and 0 or 20 µM resveratrol (Res). We examined the effect of Res on SIRT1 expression in in vitro-matured oocytes (Exp 1); fertilization and developmental ability (Exp 2); mitochondrial DNA copy number (Mt number), ATP content and mitochondrial membrane potential in matured oocytes (Exp 3); and the time required for proteinase to dissolve the zona pellucida following in vitro fertilization (as a marker of zona pellucida hardening), as well as on the distribution of cortical granules before and after fertilization (Exp 4). In Exp 1, the 20 µM Res treatment upregulated protein expression of SIRT1 in oocytes. In Exp 2, Res treatment improved the ratio of normal fertilization and the total cell number of blastocysts. In Exp 3, Res treatment significantly increased the ATP content in matured oocytes. Additionally, Res increased the overall Mt number and mitochondrial membrane potential, but the effect was donor-dependent. In Exp 4, Res-induced zona hardening improved the distribution and exocytosis of cortical granules after in vitro fertilization. In conclusion, Res improved the quality of oocytes by improving mitochondrial quantity and quality. In addition, Res added to the maturation medium enhanced SIRT1 protein expression in oocytes and improved fertilization via reinforcement of the mechanisms responsible for blockage of polyspermic fertilization. PMID:24390595

Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.

PubMed

He, J; Cooper, H M; Reyes, A; Di Re, M; Sembongi, H; Litwin, T R; Gao, J; Neuman, K C; Fearnley, I M; Spinazzola, A; Walker, J E; Holt, I J

2012-07-01

Mitochondrial ribosomes and translation factors co-purify with mitochondrial nucleoids of human cells, based on affinity protein purification of tagged mitochondrial DNA binding proteins. Among the most frequently identified proteins were ATAD3 and prohibitin, which have been identified previously as nucleoid components, using a variety of methods. Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. Altered ATAD3 expression also perturbs mtDNA maintenance and replication. These findings suggest an intimate association between nucleoids and the machinery of protein synthesis in mitochondria. ATAD3 and prohibitin are tightly associated with the mitochondrial membranes and so we propose that they support nucleic acid complexes at the inner membrane of the mitochondrion.

Oxygen sensitivity of mitochondrial function in rat arterial chemoreceptor cells

PubMed Central

Buckler, Keith J; Turner, Philip J

2013-01-01

The mechanism of oxygen sensing in arterial chemoreceptors is unknown but has often been linked to mitochondrial function. A common criticism of this hypothesis is that mitochondrial function is insensitive to physiological levels of hypoxia. Here we investigate the effects of hypoxia (down to 0.5% O2) on mitochondrial function in neonatal rat type-1 cells. The oxygen sensitivity of mitochondrial [NADH] was assessed by monitoring autofluorescence and increased in hypoxia with a P50 of 15 mm Hg (1 mm Hg = 133.3 Pa) in normal Tyrode or 46 mm Hg in Ca2+-free Tyrode. Hypoxia also depolarised mitochondrial membrane potential (ψm, measured using rhodamine 123) with a P50 of 3.1, 3.3 and 2.8 mm Hg in normal Tyrode, Ca2+-free Tyrode and Tyrode containing the Ca2+ channel antagonist Ni2+, respectively. In the presence of oligomycin and low carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP; 75 nm) ψm is maintained by electron transport working against an artificial proton leak. Under these conditions hypoxia depolarised ψm/inhibited electron transport with a P50 of 5.4 mm Hg. The effects of hypoxia upon cytochrome oxidase activity were investigated using rotenone, myxothiazol, antimycin A, oligomycin, ascorbate and the electron donor tetramethyl-p-phenylenediamine. Under these conditions ψm is maintained by complex IV activity alone. Hypoxia inhibited cytochrome oxidase activity (depolarised ψm) with a P50 of 2.6 mm Hg. In contrast hypoxia had little or no effect upon NADH (P50= 0.3 mm Hg), electron transport or cytochrome oxidase activity in sympathetic neurons. In summary, type-1 cell mitochondria display extraordinary oxygen sensitivity commensurate with a role in oxygen sensing. The reasons for this highly unusual behaviour are as yet unexplained. PMID:23671162

Liver regeneration in donors and adult recipients after living donor liver transplantation.

PubMed

Haga, Junko; Shimazu, Motohide; Wakabayashi, Go; Tanabe, Minoru; Kawachi, Shigeyuki; Fuchimoto, Yasushi; Hoshino, Ken; Morikawa, Yasuhide; Kitajima, Masaki; Kitagawa, Yuko

2008-12-01

In living donor liver transplantation, the safety of the donor operation is the highest priority. The introduction of the right lobe graft was late because of concerns about donor safety. We investigated donor liver regeneration by the types of resected segments as well as recipients to assess that appropriate regeneration was occurring. Eighty-seven donors were classified into 3 groups: left lateral section donors, left lobe donors, and right lobe donors. Forty-seven adult recipients were classified as either left or right lobe grafted recipients. Volumetry was retrospectively performed at 1 week, 1, 2, 3, and 6 months, and 1 year after the operation. In the right lobe donor group, the remnant liver volume was 45.4%, and it rapidly increased to 68.9% at 1 month and 89.8% at 6 months. At 6 months, the regeneration ratios were almost the same in all donor groups. The recipient liver volume increased rapidly until 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume. Livers of the right lobe donor group regenerated fastest in the donor groups, and the recipient liver regenerated faster than the donor liver. Analyzing liver regeneration many times with a large number of donors enabled us to understand the normal liver regeneration pattern. Although the donor livers did not reach their initial volume, the donors showed normal liver function at 1 year. The donors have returned to their normal daily activities. Donor hepatectomy, even right hepatectomy, can be safely performed with accurate preoperative volumetry and careful decision-making concerning graft-type selection.

Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression.

PubMed

Mfarrej, Bechara; Tresoldi, Eleonora; Stabilini, Angela; Paganelli, Alessia; Caldara, Rossana; Secchi, Antonio; Battaglia, Manuela

2017-02-21

Operational tolerance is an alternative to lifelong immunosuppression after transplantation. One strategy to achieve tolerance is by T regulatory cells. Safety and feasibility of a T regulatory type 1 (Tr1)-cell-based therapy to prevent graft versus host disease in patients with hematological malignancies has been already proven. We are now planning to perform a Tr1-cell-based therapy after kidney transplantation. Upon tailoring the lab-grade protocol to patients on dialysis, aims of the current work were to develop a clinical-grade compatible protocol to generate a donor-specific Tr1-cell-enriched medicinal product (named T 10 cells) and to test the Tr1-cell sensitivity to standard immunosuppression in vivo to define the best timing of cell infusion. We developed a medicinal product that was enriched in Tr1 cells, anergic to donor-cell stimulation, able to suppress proliferation upon donor- but not third-party stimulation in vitro, and stable upon cryopreservation. The protocol was reproducible upon up scaling to leukapheresis from patients on dialysis and was effective in yielding the expected number of T 10 cells necessary for the planned infusions. The tolerogenic gene signature of circulating Tr1 cells was minimally compromised in kidney transplant recipients under standard immunosuppression and it eventually started to recover 36 weeks post-transplantation, providing rationale for selecting the timings of the cell infusions. These data provide solid ground for proceeding with the trial and establish robust rationale for defining the correct timing of cell infusion during concomitant immunosuppressive treatment.

Host-Specific Phenotypic Plasticity of the Turtle Barnacle Chelonibia testudinaria: A Widespread Generalist Rather than a Specialist

PubMed Central

Chu, Ka Hou; Cheng, I-Jiunn; Chan, Benny K. K.

2013-01-01

Turtle barnacles are common epibionts on marine organisms. Chelonibia testudinaria is specific on marine turtles whereas C. patula is a host generalist, but rarely found on turtles. It has been questioned why C. patula, being abundant on a variety of live substrata, is almost absent from turtles. We evaluated the genetic (mitochondrial COI, 16S and 12S rRNA, and amplified fragment length polymorphism (AFLP)) and morphological differentiation of C. testudinaia and C. patula from different hosts, to determine the mode of adaptation exhibited by Chelonibia species on different hosts. The two taxa demonstrate clear differences in shell morphology and length of 4–6th cirri, but very similar in arthropodal characters. Moreover, we detected no genetic differentiation in mitochondrial DNA and AFLP analyses. Outlier detection infers insignificant selection across loci investigated. Based on combined morphological and molecular evidence, we proposed that C. testudinaria and C. patula are conspecific, and the two morphs with contrasting shell morphologies and cirral length found on different host are predominantly shaped by developmental plasticity in response to environmental setting on different hosts. Chelonibia testudinaria is, thus, a successful general epibiotic fouler and the phenotypic responses postulated can increase the fitness of the animals when they attach on hosts with contrasting life-styles. PMID:23469208

Hydrogen bonding assemblies in host guest complexes with 18-crown-6

NASA Astrophysics Data System (ADS)

Fonari, M. S.; Simonov, Yu. A.; Kravtsov, V. Ch.; Lipkowski, J.; Ganin, E. V.; Yavolovskii, A. A.

2003-02-01

Recent X-ray crystal structural data for two novel 1:2 host-guest complexes of 18-crown-6 with neutral organic molecules, thiaamide hydrazide of 2-aminobenzoic acid and thiaamide hydrazide of 4-amino-1,2,5-thiadiazole-3-carbonic acid are reported. The supramolecular structures of these two and five relative complexes are discussed from the point of view of participation of donor groups in coordination with the crown ether, and donor and acceptor groups in the self-assembly of the guest molecules. Guest molecules have incorporated amine and hydrazine moieties as proton donors and carbonyl oxygen and sulfur (in thiadiazole and in thiaamine moieties) as proton acceptors. The guest-guest interactions appeared to be crucial in the final architecture.

Improved Survival After Transplantation of More Donor Plasmacytoid Dendritic or Naïve T Cells From Unrelated-Donor Marrow Grafts: Results From BMTCTN 0201

PubMed Central

Waller, Edmund K.; Logan, Brent R.; Harris, Wayne A.C.; Devine, Steven M.; Porter, David L.; Mineishi, Shin; McCarty, John M.; Gonzalez, Corina E.; Spitzer, Thomas R.; Krijanovski, Oleg I.; Linenberger, Michael L.; Woolfrey, Ann; Howard, Alan; Wu, Juan; Confer, Dennis L.; Anasetti, Claudio

2014-01-01

Purpose To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor–mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. Patients and Methods Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). Results Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8+ T cells (CD8Tns), or naïve CD4+ T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. Conclusion Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation. PMID:24982459

Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.

PubMed

Waller, Edmund K; Logan, Brent R; Harris, Wayne A C; Devine, Steven M; Porter, David L; Mineishi, Shin; McCarty, John M; Gonzalez, Corina E; Spitzer, Thomas R; Krijanovski, Oleg I; Linenberger, Michael L; Woolfrey, Ann; Howard, Alan; Wu, Juan; Confer, Dennis L; Anasetti, Claudio

2014-08-01

To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8(+) T cells (CD8Tns), or naïve CD4(+) T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation. © 2014 by American Society of Clinical Oncology.

Fungal origin by horizontal transfer of a plant mitochondrial group I intron in the chimeric CoxI gene of Peperomia.

PubMed

Vaughn, J C; Mason, M T; Sper-Whitis, G L; Kuhlman, P; Palmer, J D

1995-11-01

We present phylogenetic evidence that a group I intron in an angiosperm mitochondrial gene arose recently by horizontal transfer from a fungal donor species. A 1,716-bp fragment of the mitochondrial coxI gene from the angiosperm Peperomia polybotrya was amplified via the polymerase chain reaction and sequenced. Comparison to other coxI genes revealed a 966-bp group I intron, which, based on homology with the related yeast coxI intron aI4, potentially encodes a 279-amino-acid site-specific DNA endonuclease. This intron, which is believed to function as a ribozyme during its own splicing, is not present in any of 19 coxI genes examined from other diverse vascular plant species. Phylogenetic analysis of intron origin was carried out using three different tree-generating algorithms, and on a variety of nucleotide and amino acid data sets from the intron and its flanking exon sequences. These analyses show that the Peperomia coxI gene intron and exon sequences are of fundamentally different evolutionary origin. The Peperomia intron is more closely related to several fungal mitochondrial introns, two of which are located at identical positions in coxI, than to identically located coxI introns from the land plant Marchantia and the green alga Prototheca. Conversely, the exon sequence of this gene is, as expected, most closely related to other angiosperm coxI genes. These results, together with evidence suggestive of co-conversion of exonic markers immediately flanking the intron insertion site, lead us to conclude that the Peperomia coxI intron probably arose by horizontal transfer from a fungal donor, using the double-strand-break repair pathway. The donor species may have been one of the symbiotic mycorrhizal fungi that live in close obligate association with most plants.

Population Structure of Phytophthora nicotianae Reveals Host-Specific Lineages on Brinjal, Ridge Gourd, and Tomato in South India.

PubMed

Chowdappa, P; Kumar, B J Nirmal; Kumar, S P Mohan; Madhura, S; Bhargavi, B Reddi; Lakshmi, M Jyothi

2016-12-01

Severe outbreaks of Phytophthora fruit rot on brinjal, ridge gourd, and tomato have been observed since 2011 in Andhra Pradesh, Karnataka, Telangana, and Tamil Nadu states of India. Therefore, 76 Phytophthora nicotianae isolates, recovered from brinjal (17), ridge gourd (40), and tomato (19) from different localities in these states during the June to December cropping season of 2012 and 2013, were characterized based on phenotypic and genotypic analyses and aggressiveness on brinjal, tomato, and ridge gourd. All brinjal and ridge gourd isolates were A2, while tomato isolates were both A1 (13) and A2 (6). All isolates were metalaxyl sensitive. In addition, isolates were genotyped for three mitochondrial (ribosomal protein L5-small subunit ribosomal RNA [rpl5-rns], small subunit ribosomal RNA-cytochrome c oxidase subunit 2 [rns-cox2], and cox2+spacer) and three nuclear loci (hypothetical protein [hyp], scp-like extracellular protein [scp], and beta-tubulin [β-tub]). All regions were polymorphic but nuclear regions were more variable than mitochondrial regions. The network analysis of genotypes using the combined dataset of three nuclear regions revealed a host-specific association. However, the network generated using mitochondrial regions limited such host-specific groupings only to brinjal isolates. P. nicotianae isolates were highly aggressive and produced significantly (P ≤ 0.01) larger lesions on their respective host of origin than on other hosts. The results indicate significant genetic variation in the population of P. nicotianae, leading to identification of host-specific lineages responsible for severe outbreaks on brinjal, ridge gourd, and tomato.

Knockdown of Both Mitochondrial Isocitrate Dehydrogenase Enzymes In Pancreatic Beta Cells Inhibits Insulin Secretion

PubMed Central

MacDonald, Michael J.; Brown, Laura J.; Longacre, Melissa J.; Stoker, Scott W.; Kendrick, Mindy A.; Hasan, Noaman M.

2013-01-01

Background There are three isocitrate dehydrogenases (IDHs) in the pancreatic insulin cell; IDH1 (cytosolic) and IDH2 (mitochondrial) use NADP(H). IDH3 is mitochondrial, uses NAD(H) and was believed to be the IDH that supports the citric acid cycle. Methods With shRNAs targeting mRNAs for these enzymes we generated cell lines from INS-1 832/13 cells with severe (80%–90%) knockdown of the mitochondrial IDHs separately and together in the same cell line. Results With knockdown of both mitochondrial IDH’s mRNA, enzyme activity and protein level, but not with knockdown of one mitochondrial IDH, glucose- and BCH (an allosteric activator of glutamate dehydrogenase)-plus-glutamine-stimulated insulin release were inhibited. Cellular levels of citrate, α-ketoglutarate, malate and ATP were altered in patterns consistent with blockage at the mitochondrial IDH reactions. We were able to generate only 50% knockdown of Idh1 mRNA in multiple cell lines (without inhibition of insulin release) possibly because greater knockdown of IDH1 was not compatible with cell line survival. Conclusions The mitochondrial IDHs are redundant for insulin secretion. When both enzymes are severely knocked down, their low activities (possibly assisted by transport of IDH products and other metabolic intermediates from the cytosol into mitochondria) are sufficient for cell growth, but inadequate for insulin secretion when the requirement for intermediates is certainly more rapid. The results also indicate that IDH2 can support the citric acid cycle. General Significance As almost all mammalian cells possess substantial amounts of all three IDH enzymes, the biological principles suggested by these results are probably extrapolatable to many tissues. PMID:23876293

Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity.

PubMed

Randriamboavonjy, Voahanginirina; Mann, W Alexander; Elgheznawy, Amro; Popp, Rüdiger; Rogowski, Paul; Dornauf, Imke; Dröse, Stefan; Fleming, Ingrid

2015-08-31

Polycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IR< 2. Moreover, treatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPKα1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.

Rhizobial peptidase HrrP cleaves host-encoded signaling peptides and mediates symbiotic compatibility

PubMed Central

Price, Paul A.; Tanner, Houston R.; Dillon, Brett A.; Shabab, Mohammed; Walker, Graham C.; Griffitts, Joel S.

2015-01-01

Legume–rhizobium pairs are often observed that produce symbiotic root nodules but fail to fix nitrogen. Using the Sinorhizobium meliloti and Medicago truncatula symbiotic system, we previously described several naturally occurring accessory plasmids capable of disrupting the late stages of nodule development while enhancing bacterial proliferation within the nodule. We report here that host range restriction peptidase (hrrP), a gene found on one of these plasmids, is capable of conferring both these properties. hrrP encodes an M16A family metallopeptidase whose catalytic activity is required for these symbiotic effects. The ability of hrrP to suppress nitrogen fixation is conditioned upon the genotypes of both the host plant and the hrrP-expressing rhizobial strain, suggesting its involvement in symbiotic communication. Purified HrrP protein is capable of degrading a range of nodule-specific cysteine-rich (NCR) peptides encoded by M. truncatula. NCR peptides are crucial signals used by M. truncatula for inducing and maintaining rhizobial differentiation within nodules, as demonstrated in the accompanying article [Horváth B, et al. (2015) Proc Natl Acad Sci USA, 10.1073/pnas.1500777112]. The expression pattern of hrrP and its effects on rhizobial morphology are consistent with the NCR peptide cleavage model. This work points to a symbiotic dialogue involving a complex ensemble of host-derived signaling peptides and bacterial modifier enzymes capable of adjusting signal strength, sometimes with exploitative outcomes. PMID:26401024

Rhizobial peptidase HrrP cleaves host-encoded signaling peptides and mediates symbiotic compatibility.

PubMed

Price, Paul A; Tanner, Houston R; Dillon, Brett A; Shabab, Mohammed; Walker, Graham C; Griffitts, Joel S

2015-12-08

Legume-rhizobium pairs are often observed that produce symbiotic root nodules but fail to fix nitrogen. Using the Sinorhizobium meliloti and Medicago truncatula symbiotic system, we previously described several naturally occurring accessory plasmids capable of disrupting the late stages of nodule development while enhancing bacterial proliferation within the nodule. We report here that host range restriction peptidase (hrrP), a gene found on one of these plasmids, is capable of conferring both these properties. hrrP encodes an M16A family metallopeptidase whose catalytic activity is required for these symbiotic effects. The ability of hrrP to suppress nitrogen fixation is conditioned upon the genotypes of both the host plant and the hrrP-expressing rhizobial strain, suggesting its involvement in symbiotic communication. Purified HrrP protein is capable of degrading a range of nodule-specific cysteine-rich (NCR) peptides encoded by M. truncatula. NCR peptides are crucial signals used by M. truncatula for inducing and maintaining rhizobial differentiation within nodules, as demonstrated in the accompanying article [Horváth B, et al. (2015) Proc Natl Acad Sci USA, 10.1073/pnas.1500777112]. The expression pattern of hrrP and its effects on rhizobial morphology are consistent with the NCR peptide cleavage model. This work points to a symbiotic dialogue involving a complex ensemble of host-derived signaling peptides and bacterial modifier enzymes capable of adjusting signal strength, sometimes with exploitative outcomes.

Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype

PubMed Central

Kharbanda, Sandhya; Koh, Winston; Martin, Lance R.; Khush, Kiran K.; Valantine, Hannah; Pritchard, Jonathan K.; De Vlaminck, Iwijn

2017-01-01

Quantification of cell-free DNA (cfDNA) in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD) quantifies donor-derived cfDNA (dd-cfDNA) by taking advantage of single-nucleotide polymorphisms (SNPs) distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM) of identity-by-descent (IBD) states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD). These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application. PMID:28771616

Duffy Blood Group Genotyping in Thai Blood Donors

PubMed Central

Intharanut, Kamphon; Siriphanthong, Kanokpol; Nathalang, Siriporn; Kupatawintu, Pawinee

2015-01-01

Background Duffy (FY) blood group genotyping is important in transfusion medicine because Duffy alloantibodies are associated with delayed hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. In this study, FY allele frequencies in Thai blood donors were determined by in-house PCR with sequence-specific primers (PCR-SSP), and the probability of obtaining compatible blood for alloimmunized patients was assessed. Methods Five hundred blood samples from Thai blood donors of the National Blood Centre, Thai Red Cross Society, were included. Only 200 samples were tested with anti-Fya and anti-Fyb using the gel technique. All 500 samples and four samples from a Guinea family with the Fy(a-b-) phenotype were genotyped by using PCR-SSP. Additionally, the probability of obtaining antigen-negative red blood cells (RBCs) for alloimmunized patients was calculated according to the estimated FY allele frequencies. Results The FY phenotyping and genotyping results were in 100% concordance. The allele frequencies of FY*A and FY*B in 500 central Thais were 0.962 (962/1,000) and 0.038 (38/1,000), respectively. Although the Fy(a-b-) phenotype was not observed in this study, FY*BES/FY*BES was identified by PCR-SSP in the Guinea family and was confirmed by DNA sequencing. Conclusions Our results confirm the high frequency of the FY*A allele in the Thai population, similar to that of Asian populations. At least 500 Thai blood donors are needed to obtain two units of antigen-negative RBCs for the Fy(a-b+) phenotype. PMID:26354350

Mitochondrial Bioenergetics and Dysfunction in Failing Heart.

PubMed

Sheeran, Freya L; Pepe, Salvatore

2017-01-01

Energy insufficiency has been recognized as a key feature of systolic heart failure. Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse. Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure. Diminished REDOX capacity with lower total glutathione and coenzyme Q 10 levels are also a feature of chronic left ventricular failure. Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications. In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins. Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure.

Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?

PubMed

Cashen, A F; Lazarus, H M; Devine, S M

2007-05-01

Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.

A Comparative Analysis of Mitochondrial ORFans: New Clues on Their Origin and Role in Species with Doubly Uniparental Inheritance of Mitochondria

PubMed Central

Milani, Liliana; Ghiselli, Fabrizio; Guerra, Davide; Breton, Sophie; Passamonti, Marco

2013-01-01

Despite numerous comparative mitochondrial genomics studies revealing that animal mitochondrial genomes are highly conserved in terms of gene content, supplementary genes are sometimes found, often arising from gene duplication. Mitochondrial ORFans (ORFs having no detectable homology and unknown function) were found in bivalve molluscs with Doubly Uniparental Inheritance (DUI) of mitochondria. In DUI animals, two mitochondrial lineages are present: one transmitted through females (F-type) and the other through males (M-type), each showing a specific and conserved ORF. The analysis of 34 mitochondrial major Unassigned Regions of Musculista senhousia F- and M-mtDNA allowed us to verify the presence of novel mitochondrial ORFs in this species and to compare them with ORFs from other species with ascertained DUI, with other bivalves and with animals showing new mitochondrial elements. Overall, 17 ORFans from nine species were analyzed for structure and function. Many clues suggest that the analyzed ORFans arose from endogenization of viral genes. The co-option of such novel genes by viral hosts may have determined some evolutionary aspects of host life cycle, possibly involving mitochondria. The structure similarity of DUI ORFans within evolutionary lineages may also indicate that they originated from independent events. If these novel ORFs are in some way linked to DUI establishment, a multiple origin of DUI has to be considered. These putative proteins may have a role in the maintenance of sperm mitochondria during embryo development, possibly masking them from the degradation processes that normally affect sperm mitochondria in species with strictly maternal inheritance. PMID:23824218

A comparative analysis of mitochondrial ORFans: new clues on their origin and role in species with doubly uniparental inheritance of mitochondria.

PubMed

Milani, Liliana; Ghiselli, Fabrizio; Guerra, Davide; Breton, Sophie; Passamonti, Marco

2013-01-01

Despite numerous comparative mitochondrial genomics studies revealing that animal mitochondrial genomes are highly conserved in terms of gene content, supplementary genes are sometimes found, often arising from gene duplication. Mitochondrial ORFans (ORFs having no detectable homology and unknown function) were found in bivalve molluscs with Doubly Uniparental Inheritance (DUI) of mitochondria. In DUI animals, two mitochondrial lineages are present: one transmitted through females (F-type) and the other through males (M-type), each showing a specific and conserved ORF. The analysis of 34 mitochondrial major Unassigned Regions of Musculista senhousia F- and M-mtDNA allowed us to verify the presence of novel mitochondrial ORFs in this species and to compare them with ORFs from other species with ascertained DUI, with other bivalves and with animals showing new mitochondrial elements. Overall, 17 ORFans from nine species were analyzed for structure and function. Many clues suggest that the analyzed ORFans arose from endogenization of viral genes. The co-option of such novel genes by viral hosts may have determined some evolutionary aspects of host life cycle, possibly involving mitochondria. The structure similarity of DUI ORFans within evolutionary lineages may also indicate that they originated from independent events. If these novel ORFs are in some way linked to DUI establishment, a multiple origin of DUI has to be considered. These putative proteins may have a role in the maintenance of sperm mitochondria during embryo development, possibly masking them from the degradation processes that normally affect sperm mitochondria in species with strictly maternal inheritance.

Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells.

PubMed

Ezzelarab, M B; Raich-Regue, D; Lu, L; Zahorchak, A F; Perez-Gutierrez, A; Humar, A; Wijkstrom, M; Minervini, M; Wiseman, R W; Cooper, D K C; Morelli, A E; Thomson, A W

2017-06-01

Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4-3.6 × 10 6 /kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4 + and CD8 + T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality.

PubMed

Mancusi, Antonella; Ruggeri, Loredana; Urbani, Elena; Pierini, Antonio; Massei, Maria Speranza; Carotti, Alessandra; Terenzi, Adelmo; Falzetti, Franca; Tosti, Antonella; Topini, Fabiana; Bozza, Silvia; Romani, Luigina; Tognellini, Rita; Stern, Martin; Aversa, Franco; Martelli, Massimo F; Velardi, Andrea

2015-05-14

Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donor-vs-recipient natural killer [NK]-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio [HR], 0.25; P = .01; KIR3DS1 present vs absent: HR, 0.18; P = .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P = .011; KIR3DS1 present vs absent: HR, 0.30; P = .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P = .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection. © 2015 by The American Society of Hematology.

Experiences of offspring searching for and contacting their donor siblings and donor.

PubMed

Jadva, Vasanti; Freeman, Tabitha; Kramer, Wendy; Golombok, Susan

2010-04-01

This study investigates a new phenomenon whereby individuals conceived by donor insemination are searching for and contacting their donor and/or 'donor siblings' (i.e. donor offspring conceived by the same donor who are their genetic half siblings). On-line questionnaires were completed by members of the Donor Sibling Registry (DSR), a US-based registry that facilitates contact between donor conception families who share the same donor. Of the 165 donor offspring who completed the survey, 15% were searching for their donor siblings, 13% were searching for their donor, and 64% were searching for both. Differences were found according to family type and age of disclosure. Fewer offspring from heterosexual couple families had told their father about their search when compared with offspring from lesbian couple families who had told their co-parent. Offspring who had found out about their conception after age 18 were more likely to be searching for medical reasons, whereas those who had found out before age 18 tended to be searching out of curiosity. Some offspring had discovered large numbers of half siblings (maximum=13). The majority of offspring who had found their donor relations reported positive experiences and remained in regular contact with them. Copyright (c) 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Complete mitochondrial genome sequences from five Eimeria species (Apicomplexa; Coccidia; Eimeriidae) infecting domestic turkeys.

PubMed

Ogedengbe, Mosun E; El-Sherry, Shiem; Whale, Julia; Barta, John R

2014-07-17

via host switching from another avian host. Phylogenetic analyses suggest E. necatrix and E. tenella are related distantly to other Eimeria of chickens. Mitochondrial genomes of Eimeria species sequenced to date are highly conserved with regard to gene content and structure. Nonetheless, complete mitochondrial genome sequences and, particularly the three CDS, possess sufficient sequence variability for differentiating Eimeria species of poultry. The mitochondrial genome sequences are highly suited for molecular diagnostics and phylogenetics of coccidia and, potentially, genetic markers for molecular epidemiology.

Analyses of the population structure in a global collection of Phytophthora nicotianae isolates inferred from mitochondrial and nuclear DNA sequences.

PubMed

Mammella, Marco A; Martin, Frank N; Cacciola, Santa O; Coffey, Michael D; Faedda, Roberto; Schena, Leonardo

2013-06-01

Genetic variation within the heterothallic cosmopolitan plant pathogen Phytophthora nicotianae was determined in 96 isolates from a wide range of hosts and geographic locations by characterizing four mitochondrial (10% of the genome) and three nuclear loci. In all, 52 single-nucleotide polymorphisms (SNPs) (an average of 1 every 58 bp) and 313 sites with gaps representing 5,450 bases enabled the identification of 50 different multilocus mitochondrial haplotypes. Similarly, 24 SNPs (an average of 1 every 69 bp), with heterozygosity observed at each locus, were observed in three nuclear regions (hyp, scp, and β-tub) differentiating 40 multilocus nuclear genotypes. Both mitochondrial and nuclear markers revealed a high level of dispersal of isolates and an inconsistent geographic structuring of populations. However, a specific association was observed for host of origin and genetic grouping with both nuclear and mitochondrial sequences. In particular, the majority of citrus isolates from Italy, California, Florida, Syria, Albania, and the Philippines clustered in the same mitochondrial group and shared at least one nuclear allele. A similar association was also observed for isolates recovered from Nicotiana and Solanum spp. The present study suggests an important role of nursery populations in increasing genetic recombination within the species and the existence of extensive phenomena of migration of isolates that have been likely spread worldwide with infected plant material.

Host specificity in parasitic plants-perspectives from mistletoes.

PubMed

Okubamichael, Desale Y; Griffiths, Megan E; Ward, David

2016-01-01

Host specificity has been investigated for centuries in mistletoes, viruses, insects, parasitoids, lice and flukes, yet it is poorly understood. Reviewing the numerous studies on mistletoe host specificity may contribute to our understanding of these plants and put into context the dynamics at work in root parasitic plants and animal parasites. The mechanisms that determine host specificity in mistletoes are not as well documented and understood as those in other groups of parasites. To rectify this, we synthesized the available literature and analyzed data compiled from herbaria, published monographs and our own field studies in South Africa. As for other groups of parasites, multiple factors influence mistletoe host specificity. Initially, pollination affects gene flow. Subsequently, seed dispersal vectors (birds and marsupials), host abundance and compatibility (genetic, morphological, physiological and chemical), history and environmental conditions affect the interaction of mistletoes and their hosts and determine host specificity. Mistletoe-host network analyses and a geographic mosaic approach combined with long-term monitoring of reciprocal transplant experiments, genetic analyses of confined mistletoe populations and comparative phylogenetic studies could provide further insights to our understanding of host specificity. Some of these approaches have been used to study animal-plant interactions and could be adopted to test and evaluate host specificity in mistletoes at local and larger geographic scales. © The Authors 2016. Published by Oxford University Press on behalf of the Annals of Botany Company.

Host specificity in parasitic plants—perspectives from mistletoes

PubMed Central

Okubamichael, Desale Y.; Griffiths, Megan E.; Ward, David

2016-01-01

Host specificity has been investigated for centuries in mistletoes, viruses, insects, parasitoids, lice and flukes, yet it is poorly understood. Reviewing the numerous studies on mistletoe host specificity may contribute to our understanding of these plants and put into context the dynamics at work in root parasitic plants and animal parasites. The mechanisms that determine host specificity in mistletoes are not as well documented and understood as those in other groups of parasites. To rectify this, we synthesized the available literature and analyzed data compiled from herbaria, published monographs and our own field studies in South Africa. As for other groups of parasites, multiple factors influence mistletoe host specificity. Initially, pollination affects gene flow. Subsequently, seed dispersal vectors (birds and marsupials), host abundance and compatibility (genetic, morphological, physiological and chemical), history and environmental conditions affect the interaction of mistletoes and their hosts and determine host specificity. Mistletoe–host network analyses and a geographic mosaic approach combined with long-term monitoring of reciprocal transplant experiments, genetic analyses of confined mistletoe populations and comparative phylogenetic studies could provide further insights to our understanding of host specificity. Some of these approaches have been used to study animal–plant interactions and could be adopted to test and evaluate host specificity in mistletoes at local and larger geographic scales. PMID:27658817

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

PubMed

Elgarten, Caitlin W; Arnold, Danielle E; Bunin, Nancy J; Seif, Alix E

2018-01-01

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure. Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population. © 2017 Wiley Periodicals, Inc.

Infected donors in renal transplantation: expanding the donor pool.

PubMed

Outerelo, C; Gouveia, R; Mateus, A; Cruz, P; Oliveira, C; Ramos, A

2013-04-01

The shortage of suitable organ donors is now the most important limiting factor in the field of transplantation and more expanded criteria have been accepted to overcome this problem. The objectives of this study were to evaluate the outcome of patients who received an organ from an infected donor and to compare them with patients who received organs from noninfected donors. Retrospective analysis of all patients who underwent transplantation in our unit between January 2008 and June 2011 was performed. The definition of infected donor included: (1) documented bacteremia at the time of transplantation; and (2) organ-related infection, either with or without isolation from biological products (urine, liquor, and bronchial secretions). Nineteen of 77 transplant recipients (24.7%) received organs from infected donors. There were 9 cases of pneumonia, 4 cases of meningitis with bacteremia, 5 cases of urinary tract infection, 1 case of bacteremia due to Staphylococcus aureus, and 1 case of ventriculo-peritoneal shunt infection. All these recipients were prescribed antibiotic prophylaxis for 10.9 ± 3.2 days, according to the antibiotic administered to the donor. Significant differences between both groups were not observed concerning demographics features, graft thrombosis, arterial disruption, delayed graft function, rejection episodes, and renal graft and patient survivals at 12 months. The recipients of infected donor kidneys were mostly treated with basiliximab for induction therapy. There was a trend toward fewer infectious complications among patients who received organs from infected donors (21.1% vs 44.8%; P = .065) and shorter hospital stay durations (median, 11 vs 17.5 days; P = .041). Kidney transplantation using organs from infected donors did not seem to be associated with a greater risk of complications. Antibiotic therapy initiated in the donor and continued in the recipient may explain these results, perhaps by reducing infectious complications that

Uncovering Wolbachia Diversity upon Artificial Host Transfer

PubMed Central

Schneider, Daniela I.; Riegler, Markus; Arthofer, Wolfgang; Merçot, Hervé; Stauffer, Christian; Miller, Wolfgang J.

2013-01-01

The common endosymbiotic Wolbachia bacteria influence arthropod hosts in multiple ways. They are mostly recognized for their manipulations of host reproduction, yet, more recent studies demonstrate that Wolbachia also impact host behavior, metabolic pathways and immunity. Besides their biological and evolutionary roles, Wolbachia are new potential biological control agents for pest and vector management. Importantly, Wolbachia-based control strategies require controlled symbiont transfer between host species and predictable outcomes of novel Wolbachia-host associations. Theoretically, this artificial horizontal transfer could inflict genetic changes within transferred Wolbachia populations. This could be facilitated through de novo mutations in the novel recipient host or changes of haplotype frequencies of polymorphic Wolbachia populations when transferred from donor to recipient hosts. Here we show that Wolbachia resident in the European cherry fruit fly, Rhagoletis cerasi, exhibit ancestral and cryptic sequence polymorphism in three symbiont genes, which are exposed upon microinjection into the new hosts Drosophila simulans and Ceratitis capitata. Our analyses of Wolbachia in microinjected D. simulans over 150 generations after microinjection uncovered infections with multiple Wolbachia strains in trans-infected lines that had previously been typed as single infections. This confirms the persistence of low-titer Wolbachia strains in microinjection experiments that had previously escaped standard detection techniques. Our study demonstrates that infections by multiple Wolbachia strains can shift in prevalence after artificial host transfer driven by either stochastic or selective processes. Trans-infection of Wolbachia can claim fitness costs in new hosts and we speculate that these costs may have driven the shifts of Wolbachia strains that we saw in our model system. PMID:24376534

Uncovering Wolbachia diversity upon artificial host transfer.

PubMed

Schneider, Daniela I; Riegler, Markus; Arthofer, Wolfgang; Merçot, Hervé; Stauffer, Christian; Miller, Wolfgang J

2013-01-01

The common endosymbiotic Wolbachia bacteria influence arthropod hosts in multiple ways. They are mostly recognized for their manipulations of host reproduction, yet, more recent studies demonstrate that Wolbachia also impact host behavior, metabolic pathways and immunity. Besides their biological and evolutionary roles, Wolbachia are new potential biological control agents for pest and vector management. Importantly, Wolbachia-based control strategies require controlled symbiont transfer between host species and predictable outcomes of novel Wolbachia-host associations. Theoretically, this artificial horizontal transfer could inflict genetic changes within transferred Wolbachia populations. This could be facilitated through de novo mutations in the novel recipient host or changes of haplotype frequencies of polymorphic Wolbachia populations when transferred from donor to recipient hosts. Here we show that Wolbachia resident in the European cherry fruit fly, Rhagoletis cerasi, exhibit ancestral and cryptic sequence polymorphism in three symbiont genes, which are exposed upon microinjection into the new hosts Drosophila simulans and Ceratitis capitata. Our analyses of Wolbachia in microinjected D. simulans over 150 generations after microinjection uncovered infections with multiple Wolbachia strains in trans-infected lines that had previously been typed as single infections. This confirms the persistence of low-titer Wolbachia strains in microinjection experiments that had previously escaped standard detection techniques. Our study demonstrates that infections by multiple Wolbachia strains can shift in prevalence after artificial host transfer driven by either stochastic or selective processes. Trans-infection of Wolbachia can claim fitness costs in new hosts and we speculate that these costs may have driven the shifts of Wolbachia strains that we saw in our model system.

Associations of health status with subsequent blood donor behavior-An alternative perspective on the Healthy Donor Effect from Donor InSight.

PubMed

van den Hurk, Katja; Zalpuri, Saurabh; Prinsze, Femmeke J; Merz, Eva-Maria; de Kort, Wim L A M

2017-01-01

In donor health research, the 'Healthy Donor Effect' (HDE) often biases study results and hampers their interpretation. This refers to the fact that donors are a selected 'healthier' subset of a population due to both donor selection procedures and self-selection. Donors with long versus short donor careers, or with high versus low donation intensities are often compared to avoid this HDE, but underlying health differences might also cause these differences in behaviour. Our aim was to estimate to what extent a donor´s perceived health status associates with donation cessation and intensity. All active whole blood donors participating in Donor InSight (2007-2009; 11,107 male; 12,616 female) were included in this prospective cohort study. We performed Cox survival and Poisson regression analyses to assess whether self-reported health status, medication use, disease diagnosed by a physician and recently having consulted a general practitioner (GP) or specialist were associated with (time to) donation cessation and donation intensity. At the end of 2013, 44% of the donors in this study had stopped donating. Donors in self-rated good health had a 15% lower risk to stop donating compared to donors in perceived poorer health. Medication use, disease diagnoses and consulting a GP were associated with a 20-40% increased risk to stop donating and a lower donation intensity, when adjusting for age, number of donations and new donor status. Both men and women reporting good health made on average 10% more donations. Donors with a "good" health status were less likely to stop donating blood and tended to donate blood more often than donors with perceived poorer health status. This implies that the HDE is an important source of selection bias in studies on donor health and this includes studies where comparisons within donors are made. This HDE should be adjusted for appropriately when assessing health effects of donation and donors' health status may provide estimates of

Abnormal mitochondrial respiration in failed human myocardium.

PubMed

Sharov, V G; Todor, A V; Silverman, N; Goldstein, S; Sabbah, H N

2000-12-01

Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced organelle size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance. Copyright 2000 Academic Press.

Feelings of living donors about adult-to-adult living donor liver transplantation.

PubMed

Kusakabe, Tomoko; Irie, Shinji; Ito, Naomi; Kazuma, Keiko

2008-01-01

This study investigated the feelings of living donors about adult-to-adult liver transplantation. We interviewed 18 donors about their feelings before and after transplantation using semistructured interviews and then conducted a content analysis of their responses. Before transplantation, many donors reported that they wanted recipients to live for the donor or his or her family, and there was no one else to donate. Many donors were not anxious, did not feel coerced, and did not consider donation dangerous. Some reported being excited at facing a new experience. Some said they would not mind whatever happens. Others were anxious or unsure about the operation. Diagnostic testing and preoperative blood banking were painful. Donors experienced increasing stress just before the operation. After transplantation, some donors verbalized feeling more grateful to others and that they gained maturity. Throughout the process, donors were concerned about their recipients. Our results suggest that donors might act for themselves or their family. It is important to recognize the varied responses of donors' feelings toward liver transplant recipients.

Transcriptome of Pneumocystis carinii during fulminate infection: carbohydrate metabolism and the concept of a compatible parasite.

PubMed

Cushion, Melanie T; Smulian, A George; Slaven, Bradley E; Sesterhenn, Tom; Arnold, Jonathan; Staben, Chuck; Porollo, Aleksey; Adamczak, Rafal; Meller, Jarek

2007-05-09

Members of the genus Pneumocystis are fungal pathogens that cause pneumonia in a wide variety of mammals with debilitated immune systems. Little is known about their basic biological functions, including life cycle, since no species can be cultured continuously outside the mammalian lung. To better understand the pathological process, about 4500 ESTS derived from sequencing of the poly(A) tail ends of P. carinii mRNAs during fulminate infection were annotated and functionally characterized as unassembled reads, and then clustered and reduced to a unigene set with 1042 members. Because of the presence of sequences from other microbial genomes and the rat host, the analysis and compression to a unigene set was necessarily an iterative process. BLASTx analysis of the unassembled reads (UR) vs. the Uni-Prot and TREMBL databases revealed 56% had similarities to existing polypeptides at E values ofmitochondrial function. Several gene homologs associated with mating, meiosis

Transcriptome of Pneumocystis carinii during Fulminate Infection: Carbohydrate Metabolism and the Concept of a Compatible Parasite

PubMed Central

Sesterhenn, Tom; Arnold, Jonathan; Staben, Chuck; Porollo, Aleksey; Adamczak, Rafal; Meller, Jarek

2007-01-01

Members of the genus Pneumocystis are fungal pathogens that cause pneumonia in a wide variety of mammals with debilitated immune systems. Little is known about their basic biological functions, including life cycle, since no species can be cultured continuously outside the mammalian lung. To better understand the pathological process, about 4500 ESTS derived from sequencing of the poly(A) tail ends of P. carinii mRNAs during fulminate infection were annotated and functionally characterized as unassembled reads, and then clustered and reduced to a unigene set with 1042 members. Because of the presence of sequences from other microbial genomes and the rat host, the analysis and compression to a unigene set was necessarily an iterative process. BLASTx analysis of the unassembled reads (UR) vs. the Uni-Prot and TREMBL databases revealed 56% had similarities to existing polypeptides at E values of≤10−6, with the remainder lacking any significant homology. The most abundant transcripts in the UR were associated with stress responses, energy production, transcription and translation. Most (70%) of the UR had similarities to proteins from filamentous fungi (e.g., Aspergillus, Neurospora) and existing P. carinii gene products. In contrast, similarities to proteins of the yeast-like fungi, Schizosaccharomyces pombe and Saccharomyces cerevisiae, predominated in the unigene set. Gene Ontology analysis using BLAST2GO revealed P. carinii dedicated most of its transcripts to cellular and physiological processes (∼80%), molecular binding and catalytic activities (∼70%), and were primarily derived from cell and organellar compartments (∼80%). KEGG Pathway mapping showed the putative P. carinii genes represented most standard metabolic pathways and cellular processes, including the tricarboxylic acid cycle, glycolysis, amino acid biosynthesis, cell cycle and mitochondrial function. Several gene homologs associated with mating, meiosis, and sterol biosynthesis in fungi were

Expanding the functional human mitochondrial DNA database by the establishment of primate xenomitochondrial cybrids

PubMed Central

Kenyon, Lesley; Moraes, Carlos T.

1997-01-01

The nuclear and mitochondrial genomes coevolve to optimize approximately 100 different interactions necessary for an efficient ATP-generating system. This coevolution led to a species-specific compatibility between these genomes. We introduced mitochondrial DNA (mtDNA) from different primates into mtDNA-less human cells and selected for growth of cells with a functional oxidative phosphorylation system. mtDNA from common chimpanzee, pigmy chimpanzee, and gorilla were able to restore oxidative phosphorylation in the context of a human nuclear background, whereas mtDNA from orangutan, and species representative of Old-World monkeys, New-World monkeys, and lemurs were not. Oxygen consumption, a sensitive index of respiratory function, showed that mtDNA from chimpanzee, pigmy chimpanzee, and gorilla replaced the human mtDNA and restored respiration to essentially normal levels. Mitochondrial protein synthesis was also unaltered in successful “xenomitochondrial cybrids.” The abrupt failure of mtDNA from primate species that diverged from humans as recently as 8–18 million years ago to functionally replace human mtDNA suggests the presence of one or a few mutations affecting critical nuclear–mitochondrial genome interactions between these species. These cellular systems provide a demonstration of intergenus mtDNA transfer, expand more than 20-fold the number of mtDNA polymorphisms that can be analyzed in a human nuclear background, and provide a novel model for the study of nuclear–mitochondrial interactions. PMID:9256447

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes.

PubMed

Hernandez-Valladares, Maria; Rihet, Pascal; Iraqi, Fuad A

2014-01-01

There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific host-pathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development.

Outcomes of strategic alternative donor selection or suspending donor search based on Japan Marrow Donor Program coordination status.

PubMed

Kawashima, Naomi; Nishiwaki, Satoshi; Shimizu, Naoko; Kamoshita, Sonoko; Watakabe, Kyoko; Yokohata, Emi; Kurahashi, Shingo; Ozawa, Yukiyasu; Miyamura, Koichi

2018-05-01

In allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors, delays in donor search are adversely associated with patient outcome. However, the optimal duration for either waiting for an unrelated donor or selecting alternative sources remains undetermined. Using data from the Japan Marrow Donor Program (JMDP) registry, we retrospectively analyzed 349 adult patients who had searched for unrelated donors. Two hundred and three patients received allo-HSCT from JMDP donors (Group A) with a median of 140 days required to identify a donor, 60 received allo-HSCT from alternative sources (Group B) after a median of 111.5 days at which point either all donor candidates had failed or the patient achieved a second or subsequent complete remission, and 77 suspended allo-HSCT (Group C) after a median of 310 days. The 5-year overall survival (OS) rate in Group A was superior to that of Group C (48.6 vs 38.5%, P = 0.001). Although Group B included more patients with high or very high disease risk index (DRI) at the time of allo-HSCT compared with Group A, the 5-year OS was not significantly different between Groups A and B (48.6 vs 40.9%, P = 0.07), indicating that switching to alternative donors may benefit patients with high DRI.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake.

PubMed

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-05-01

Mitochondrial calcium ([Ca 2+ ] m ) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca 2+ ] m uptake upon SK channel activation as detected by time lapse mitochondrial Ca 2+ measurements with the Ca 2+ -binding mitochondria-targeted aequorin and FRET-based [Ca 2+ ] m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca 2+ ] m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

PubMed Central

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-01-01

Mitochondrial calcium ([Ca2+]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca2+]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca2+ measurements with the Ca2+-binding mitochondria-targeted aequorin and FRET-based [Ca2+]m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca2+]m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death. PMID:28282037

Mind the gap! The mitochondrial control region and its power as a phylogenetic marker in echinoids.

PubMed

Bronstein, Omri; Kroh, Andreas; Haring, Elisabeth

2018-05-30

selection, and high compatibility across the entire class, outperforming conventional mitochondrial markers.

Mitochondrial peptides modulate mitochondrial function during cellular senescence.

PubMed

Kim, Su-Jeong; Mehta, Hemal H; Wan, Junxiang; Kuehnemann, Chisaka; Chen, Jingcheng; Hu, Ji-Fan; Hoffman, Andrew R; Cohen, Pinchas

2018-06-10

Cellular senescence is a complex cell fate response that is thought to underlie several age-related pathologies. Despite a loss of proliferative potential, senescent cells are metabolically active and produce energy-consuming effectors, including senescence-associated secretory phenotypes (SASPs). Mitochondria play crucial roles in energy production and cellular signaling, but the key features of mitochondrial physiology and particularly of mitochondria-derived peptides (MDPs), remain underexplored in senescence responses. Here, we used primary human fibroblasts made senescent by replicative exhaustion, doxorubicin or hydrogen peroxide treatment, and examined the number of mitochondria and the levels of mitochondrial respiration, mitochondrial DNA methylation and the mitochondria-encoded peptides humanin, MOTS-c, SHLP2 and SHLP6. Senescent cells showed increased numbers of mitochondria and higher levels of mitochondrial respiration, variable changes in mitochondrial DNA methylation, and elevated levels of humanin and MOTS-c. Humanin and MOTS-c administration modestly increased mitochondrial respiration and selected components of the SASP in doxorubicin-induced senescent cells partially via JAK pathway. Targeting metabolism in senescence cells is an important strategy to reduce SASP production for eliminating the deleterious effects of senescence. These results provide insight into the role of MDPs in mitochondrial energetics and the production of SASP components by senescent cells.

No evidence for host specialization or host-race formation in the European bitterling (Rhodeus amarus), a fish that parasitizes freshwater mussels.

PubMed

Reichard, M; Bryja, J; Polačik, M; Smith, C

2011-09-01

Coevolutionary relationships between parasites and hosts can elevate the rate of evolutionary changes owing to reciprocal adaptations between coevolving partners. Such relationships can result in the evolution of host specificity. Recent methodological advances have permitted the recognition of cryptic lineages, with important consequences for our understanding of biological diversity. We used the European bitterling (Rhodeus amarus), a freshwater fish that parasitizes unionid mussels, to investigate host specialization across regions of recent and ancient sympatry between coevolving partners. We combined genetic data (12 microsatellite and 2 mitochondrial markers) from five populations with experimental data for possible mechanisms of host species recognition (imprinting and conditioning). We found no strong evidence for the existence of cryptic lineages in R. amarus, though a small proportion of variation among individuals in an area of recent bitterling-mussel association was statistically significant in explaining host specificity. No other measures supported the existence of host-specific lineages. Behavioural data revealed a weak effect of conditioning that biased behavioural preferences towards specific host species. Host imprinting had no effect on oviposition behaviour. Overall, we established that populations of R. amarus show limited potential for specialization, manifested as weak effects of host conditioning and genetic within-population structure. Rhodeus amarus is the only species of mussel-parasitizing fish in Europe, which contrasts with the species-rich communities of bitterling in eastern Asia where several host-specific bitterling occur. We discuss costs and constraints on the evolution of host-specific lineages in our study system and more generally. © 2011 Blackwell Publishing Ltd.

Extended criteria donors in liver transplantation: adapting donor quality and recipient.

PubMed

Gastaca, M

2009-04-01

Despite the progressive increase in the number of liver transplantations, the mortality on the waiting list remains between 5% and 10%, and patients have to deal with longer waiting periods. Facing this situation, transplant centers have developed alternatives to increase the number of grafts by accepting donors who were previously considered to be inadequate, because they are at higher risk of initial poor function and graft failure or may cause disease transmission. Currently, some marginal donors are being routinely used: elderly donors, steatotic grafts, non-heart-beating donors, hepatitis C virus-positive (HCV+) or hepatitis B core antibody-positive donors. These so-called marginal or extended-criteria donors were initially used in high-risk or urgent recipients; however, the number of marginal grafts has significantly increased, forcing the transplant community toward their more rationale use to maintain excellent results of liver transplantation. In this new scenario, the adequacy between donor and recipient may be paramount. Advanced donor age seems to be related to a greater graft failure rate in HCV+ recipients. Early survival seems to be significantly reduced when steatotic grafts are used in recipients with high Model for End-stage Liver Disease (MELD) scores. Moreover, a decreased survival has been observed among high-risk patients receiving organs from marginal donors. No benefit seems to exist when high-donor risk index grafts are transplanted into recipients with low MELD Scores. The recognition of various donor groups according to their quality and the need for good donor and recipient selection must lead us to define new policies for organ allocation of marginal grafts that may come into conflict with current policies of organ allocation according to the risk of death among patients awaiting a liver transplantation.

Travel behavior and deferral of Dutch blood donors: consequences for donor availability.

PubMed

Lieshout-Krikke, Ryanne W; Oei, Welling; Habets, Karin; Pasker-de Jong, Pieternel C M

2015-01-01

Donors returning from areas with outbreaks of infectious diseases may donate infectious blood back home. Geographic donor deferral is an effective measure to ensure the blood safety, but donor deferral may pose a threat for the blood supply especially after holiday seasons. Insight into the travel behavior of blood donors is a first step to define appropriate deferral strategies. This study describes the travel behavior of Dutch donors, the actual deferral, and the consequences of deferral strategies on donor availability. A questionnaire designed to assess travel behavior (destination, frequency, and duration of travels) was sent to 2000 Dutch donors. The impact of travel deferral policies on donor availability was calculated, expressed as proportionate decrease in donor availability. The deferral policies considered were 1) deferral based on entire countries instead of affected regions where an infection is prevalent and 2) deferral after any travel outside Europe ("universal deferral"). Of the 1340 respondents, 790 (58.9%) donors traveled within Europe only, 61 (4.6%) outside Europe only, and 250 (18.7%) within and outside Europe. The deferral for entire countries and universal deferral would lead to 11.1 and 11.4% decrease in donor availability, respectively. Most Dutch donors traveled outside the Netherlands, while 23.2% traveled outside Europe. Universal deferral resulted in an additional decrease in donor availability of 0.3% compared with deferral for entire countries instead of affected regions where an infection is prevalent. Thus, the universal deferral could be considered as a simpler and safer measure. © 2014 AABB.

Utilization of elderly donors in living donor liver transplantation: when more is less?

PubMed

Dayangac, Murat; Taner, C Burcin; Yaprak, Onur; Demirbas, Tolga; Balci, Deniz; Duran, Cihan; Yuzer, Yildiray; Tokat, Yaman

2011-05-01

An accepted definition of donor exclusion criteria has not been established for living donor liver transplantation (LDLT). The use of elderly donors to expand the living donor pool raises ethical concerns about donor safety. The aims of this study were (1) the comparison of the postoperative outcomes of living liver donors by age (≥ 50 versus < 50 years) and (2) the evaluation of the impact of the extent of right hepatectomy on donor outcomes. The study group included 150 donors who underwent donor right hepatectomy between October 2004 and April 2009. Extended criteria surgery (ECS) was defined as right hepatectomy with middle hepatic vein (MHV) harvesting or right hepatectomy resulting in an estimated remnant liver volume (RLV) less than 35%. The primary endpoints were donor outcomes in terms of donor complications graded according to the Clavien classification. Group 1 consisted of donors who were 50 years old or older (n = 28), and group 2 consisted of donors who were less than 50 years old (n = 122). At least 1 ECS criterion was present in 74% of donors: 57% had 1 criterion, and 17% had 2 criteria. None of the donors had grade 4 complications or died. The overall and major complication rates were similar in the 2 donor age groups [28.6% and 14.3% in group 1 and 32% and 8.2% in group 2 for the overall complication rates (P = 0.8) and the major complication rates (P = 0.2), respectively]. However, there was a significant correlation between the rate of major complications and the type of surgery in donors who were 50 years old or older. In LDLT, extending the limits of surgery comes at the price of more complications in elderly donors. Right hepatectomy with MHV harvesting and any procedure causing an RLV less than 35% should be avoided in living liver donors who are 50 years old or older. Copyright © 2011 American Association for the Study of Liver Diseases.

Donor motivation in Xi'an, China: comparison with Canadian donors.

PubMed

O'Brien, S F; Shao, Z-J; Osmond, L; Yi, Q-L; Li, C-Y; An, Q-X

2013-04-01

In China, paid donation is prohibited by law. There is little literature assessing donor motivation in China, and comparison with western countries such as Canada is important in understanding the application of Western literature. We compared motivational factors in donors from the city of Xi'an, China, with Canadian donors matched for age, sex and donation status. A total of 218 donors in Xi'an completed an interview about motivation as did 218 Canadian donors matched for age, sex and donation status. Frequencies and percentages of responses to questions were tabulated and compared using the Chi-squared test. Donors in Xi'an and Canada felt a personal responsibility to donate blood (81·2% vs. 78·0%, P = 0·2057), but Xi'an donors were more likely to consider blood donation a social responsibility (81·7% vs. 45·2%, P < 0·0001). Xi'an donors more often believed that society views donation as a normal activity (98·6% vs. 48·4%, P < 0·0001) and that the social atmosphere promotes donation (90·3% vs. 53·5%, P < 0·0001) and saw greater health benefit (52·3% vs. 12·5%, P < 0·0001). Most Xi'an donors believed in balance between their life force (Qi) and blood (86·7% vs. 49·8%, P < 0·0001) but did not believe blood lost from donating would affect this (0·5% vs. 3·8%, P = 0·01). While traditional Chinese beliefs may not be seen as a barrier among people in Xi'an who donate blood, blood donation is seen differently than by Canadian donors. There is a need for more research specific to China to tailor recruitment strategies. © 2012 The Author(s). Vox Sanguinis © 2012 International Society of Blood Transfusion.

Layered host-guest long-afterglow ultrathin nanosheets: high-efficiency phosphorescence energy transfer at 2D confined interface.

PubMed

Gao, Rui; Yan, Dongpeng

2017-01-01

Tuning and optimizing the efficiency of light energy transfer play an important role in meeting modern challenges of minimizing energy loss and developing high-performance optoelectronic materials. However, attempts to fabricate systems giving highly efficient energy transfer between luminescent donor and acceptor have achieved limited success to date. Herein, we present a strategy towards phosphorescence energy transfer at a 2D orderly crystalline interface. We first show that new ultrathin nanosheet materials giving long-afterglow luminescence can be obtained by assembling aromatic guests into a layered double hydroxide host. Furthermore, we demonstrate that co-assembly of these long-lived energy donors with an energy acceptor in the same host generates an ordered arrangement of phosphorescent donor-acceptor pairs spatially confined within the 2D nanogallery, which affords energy transfer efficiency as high as 99.7%. Therefore, this work offers an alternative route to develop new types of long-afterglow nanohybrids and efficient light transfer systems with potential energy, illumination and sensor applications.

Donor milk volume and characteristics of donors and their children.

PubMed

Sierra-Colomina, Gemma; García-Lara, Nadia Raquel; Escuder-Vieco, Diana; Alonso-Díaz, Clara; Esteban, Eva María Andrés; Pallás-Alonso, Carmen Rosa

2014-05-01

Little is known regarding the effect of the characteristics of donors and their children on the volume of donor milk delivered to a human milk bank (HMB). Our study aimed to determine the relationship between different social and demographic variables of donors and their infants with the volume of human milk delivered. We included donors accepted at the Hospital Doce de Octubre HMB from January 1st, 2009 until April 31st, 2013, and who had finished their donation. Data of social and demographic characteristics of the donors and their children, and the total volume of DHM given were obtained from our HMB database. Included variables were previous donors, donor age, number of children, place of residence, gestational age of the infant at birth, child's age at the start of the donation, hospital admission, and death of the infant. A linear regression model was used to study the relationship between independent variables that were significant in bivariate analysis and the volume of donated milk. A total of 415 donations from 391 women were included. The median volume of milk delivered was 3.1l (IQR-interquartile range-1.3-8.3l). In the linear regression model, previous donors, smaller gestational age of children, and the start of donation at earlier stages of lactation were associated with a larger quantity of HMB donated (p≤0.001). Previous donors, smaller gestational age of children, and the start of donation at earlier stages of lactation are associated with a larger quantity of milk donated to the HMB. Copyright © 2014 Elsevier Ltd. All rights reserved.

Proteomic analysis of the compatible interaction of wheat and powdery mildew (Blumeria graminis f. sp. tritici).

PubMed

Li, Jie; Yang, Xiwen; Liu, Xinhao; Yu, Haibo; Du, Congyang; Li, Mengda; He, Dexian

2017-02-01

Proteome characteristics of wheat leaves with the powdery mildew pathogen Blumeria graminis f. sp. tritici (Bgt) infection were investigated by two-dimensional electrophoresis and tandem MALDI-TOF/TOF-MS. We identified 46 unique proteins which were differentially expressed at 24, 48, and 72 h post-inoculation. The functional classification of these proteins showed that most of them were involved in photosynthesis, carbohydrate and nitrogen metabolism, defense responses, and signal transduction. Upregulated proteins included primary metabolism pathways and defense responses, while proteins related to photosynthesis and signal transduction were mostly downregulated. As expected, more antioxidative proteins were activated at the later infection stage than the earlier stage, suggesting that the antioxidative system of host plays a role in maintaining the compatible interaction between wheat and powdery mildew. A high accumulation of 6-phosphogluconate dehydrogenase and isocitrate dehydrogenase in infected leaves indicated the regulation of the TCA cycle and pentose phosphate pathway in parallel to the activation of host defenses. The downregulation of MAPK5 could be facilitated for the compatible interaction of wheat plants and Bgt. qRT-PCR analysis supported the data of protein expression profiles. Our results reveal the relevance of primary plant metabolism and defense responses during compatible interaction, and provide new insights into the biology of susceptible wheat in response to Bgt infection. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Simulation shows that HLA-matched stem cell donors can remain unidentified in donor searches

PubMed Central

Sauter, Jürgen; Solloch, Ute V.; Giani, Anette S.; Hofmann, Jan A.; Schmidt, Alexander H.

2016-01-01

The heterogeneous nature of HLA information in real-life stem cell donor registries may hamper unrelated donor searches. It is even possible that fully HLA-matched donors with incomplete HLA information are not identified. In our simulation study, we estimated the probability of these unnecessarily failed donor searches. For that purpose, we carried out donor searches in several virtual donor registries. The registries differed by size, composition with respect to HLA typing levels, and genetic diversity. When up to three virtual HLA typing requests were allowed within donor searches, the share of unnecessarily failed donor searches ranged from 1.19% to 4.13%, thus indicating that non-identification of completely HLA-matched stem cell donors is a problem of practical relevance. The following donor registry characteristics were positively correlated with the share of unnecessarily failed donor searches: large registry size, high genetic diversity, and, most strongly correlated, large fraction of registered donors with incomplete HLA typing. Increasing the number of virtual HLA typing requests within donor searches up to ten had a smaller effect. It follows that the problem of donor non-identification can be substantially reduced by complete high-resolution HLA typing of potential donors. PMID:26876789

Simulation shows that HLA-matched stem cell donors can remain unidentified in donor searches

NASA Astrophysics Data System (ADS)

Sauter, Jürgen; Solloch, Ute V.; Giani, Anette S.; Hofmann, Jan A.; Schmidt, Alexander H.

2016-02-01

The heterogeneous nature of HLA information in real-life stem cell donor registries may hamper unrelated donor searches. It is even possible that fully HLA-matched donors with incomplete HLA information are not identified. In our simulation study, we estimated the probability of these unnecessarily failed donor searches. For that purpose, we carried out donor searches in several virtual donor registries. The registries differed by size, composition with respect to HLA typing levels, and genetic diversity. When up to three virtual HLA typing requests were allowed within donor searches, the share of unnecessarily failed donor searches ranged from 1.19% to 4.13%, thus indicating that non-identification of completely HLA-matched stem cell donors is a problem of practical relevance. The following donor registry characteristics were positively correlated with the share of unnecessarily failed donor searches: large registry size, high genetic diversity, and, most strongly correlated, large fraction of registered donors with incomplete HLA typing. Increasing the number of virtual HLA typing requests within donor searches up to ten had a smaller effect. It follows that the problem of donor non-identification can be substantially reduced by complete high-resolution HLA typing of potential donors.

Donor morbidity in right and left hemiliver living donor liver transplantation: the impact of graft selection and surgical innovation on donor safety.

PubMed

Iwasaki, Junji; Iida, Taku; Mizumoto, Masaki; Uemura, Tadahiro; Yagi, Shintaro; Hori, Tomohide; Ogawa, Kohei; Fujimoto, Yasuhiro; Mori, Akira; Kaido, Toshimi; Uemoto, Shinji

2014-11-01

This study investigated adequate liver graft selection for donor safety by comparing postoperative donor liver function and morbidity between the right and left hemilivers (RL and LL, respectively) of living donors. Between April 2006 and March 2012, RL (n = 168) and LL (n = 140) donor operations were performed for liver transplantation at Kyoto University Hospital. Postoperative hyperbilirubinemia and coagulopathy persisted in RL donors, whereas the liver function of LL donors normalized more rapidly. The overall complication rate of the RL donors was significantly higher than that of the LL donors (59.5% vs. 30.7%; P < 0.001). There were no significant differences in severe complications worse than Clavien grade IIIa or in biliary complication rates between the two donor groups. In April 2006, we introduced an innovative surgical procedure: hilar dissection preserving the blood supply to the bile duct during donor hepatectomy. Compared with our previous outcomes (1990-2006), the biliary complication rate of the RL donors decreased from 12.2% to 7.2%, and the severity of these complications was significantly lower. In conclusion, LL donors demonstrated good recovery in postoperative liver function and lower morbidity, and our surgical innovations reduced the severity of biliary complications in living donors. © 2014 Steunstichting ESOT.

Ancient host specificity within a single species of brood parasitic bird

PubMed Central

Spottiswoode, Claire N.; Stryjewski, Katherine Faust; Quader, Suhel; Colebrook-Robjent, John F. R.; Sorenson, Michael D.

2011-01-01

Parasites that exploit multiple hosts often experience diversifying selection for host-specific adaptations. This can result in multiple strains of host specialists coexisting within a single parasitic species. A long-standing conundrum is how such sympatric host races can be maintained within a single parasitic species in the face of interbreeding among conspecifics specializing on different hosts. Striking examples are seen in certain avian brood parasites such as cuckoos, many of which show host-specific differentiation in traits such as host egg mimicry. Exploiting a Zambian egg collection amassed over several decades and supplemented by recent fieldwork, we show that the brood parasitic Greater Honeyguide Indicator indicator exhibits host-specific differentiation in both egg size and egg shape. Genetic analysis of honeyguide eggs and chicks show that two highly divergent mitochondrial DNA lineages are associated with ground- and tree-nesting hosts, respectively, indicating perfect fidelity to two mutually exclusive sets of host species for millions of years. Despite their age and apparent adaptive diversification, however, these ancient lineages are not cryptic species; a complete lack of differentiation in nuclear genes shows that mating between individuals reared by different hosts is sufficiently frequent to prevent speciation. These results indicate that host specificity is maternally inherited, that host-specific adaptation among conspecifics can be maintained without reproductive isolation, and that host specificity can be remarkably ancient in evolutionary terms. PMID:21949391

Host shift and speciation in a coral-feeding nudibranch

PubMed Central

Faucci, Anuschka; Toonen, Robert J; Hadfield, Michael G

2006-01-01

While the role of host preference in ecological speciation has been investigated extensively in terrestrial systems, very little is known in marine environments. Host preference combined with mate choice on the preferred host can lead to population subdivision and adaptation leading to host shifts. We use a phylogenetic approach based on two mitochondrial genetic markers to disentangle the taxonomic status and to investigate the role of host specificity in the speciation of the nudibranch genus Phestilla (Gastropoda, Opisthobranchia) from Guam, Palau and Hawaii. Species of the genus Phestilla complete their life cycle almost entirely on their specific host coral (species of Porites, Goniopora and Tubastrea). They reproduce on their host coral and their planktonic larvae require a host-specific chemical cue to metamorphose and settle onto their host. The phylogenetic trees of the combined cytochrome oxidase I and ribosomal 16S gene sequences clarify the relationship among species of Phestilla identifying most of the nominal species as monophyletic clades. We found a possible case of host shift from Porites to Goniopora and Tubastrea in sympatric Phestilla spp. This represents one of the first documented cases of host shift as a mechanism underlying speciation in a marine invertebrate. Furthermore, we found highly divergent clades within Phestilla sp. 1 and Phestilla minor (8.1–11.1%), suggesting cryptic speciation. The presence of a strong phylogenetic signal for the coral host confirms that the tight link between species of Phestilla and their host coral probably played an important role in speciation within this genus. PMID:17134995

Heme modulates Trypanosoma cruzi bioenergetics inducing mitochondrial ROS production.

PubMed

Nogueira, Natália P; Saraiva, Francis M S; Oliveira, Matheus P; Mendonça, Ana Paula M; Inacio, Job D F; Almeida-Amaral, Elmo E; Menna-Barreto, Rubem F; Laranja, Gustavo A T; Torres, Eduardo J Lopes; Oliveira, Marcus F; Paes, Marcia C

2017-07-01

Trypanosoma cruzi is the causative agent of Chagas disease and has a single mitochondrion, an organelle responsible for ATP production and the main site for the formation of reactive oxygen species (ROS). T. cruzi is an obligate intracellular parasite with a complex life cycle that alternates between vertebrate and invertebrate hosts, therefore the development of survival strategies and morphogenetic adaptations to deal with the various environments is mandatory. Over the years our group has been studying the vector-parasite interactions using heme as a physiological oxidant molecule that triggered epimastigote proliferation however, the source of ROS induced by heme remained unknown. In the present study we demonstrate the involvement of heme in the parasite mitochondrial metabolism, decreasing oxygen consumption leading to increased mitochondrial ROS and membrane potential. First, we incubated epimastigotes with carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), an uncoupler of oxidative phosphorylation, which led to decreased ROS formation and parasite proliferation, even in the presence of heme, correlating mitochondrial ROS and T. cruzi survival. This hypothesis was confirmed after the mitochondria-targeted antioxidant ((2-(2,2,6,6 Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) decreased both heme-induced ROS and epimastigote proliferation. Furthermore, heme increased the percentage of tetramethylrhodamine methyl ester (TMRM) positive parasites tremendously-indicating the hyperpolarization and increase of potential of the mitochondrial membrane (ΔΨm). Assessing the mitochondrial functional metabolism, we observed that in comparison to untreated parasites, heme-treated epimastigotes decreased their oxygen consumption, and increased the complex II-III activity. These changes allowed the electron flow into the electron transport system, even though the complex IV (cytochrome c oxidase) activity decreased

Donor, dad, or…? Young adults with lesbian parents' experiences with known donors.

PubMed

Goldberg, Abbie E; Allen, Katherine R

2013-06-01

In this exploratory qualitative study of 11 young adults, ages 19-29 years, we examine how young people who were raised by lesbian parents make meaning out of and construct their relationships with known donors. In-depth interviews were conducted to examine how participants defined their family composition, how they perceived the role of their donors in their lives, and how they negotiated their relationships with their donors. Findings indicate that mothers typically chose known donors who were family friends, that the majority of participants always knew who their donors were, and that their contact with donors ranged from minimal to involved. Further, participants perceived their donors in one of three ways: as strictly donors and not members of their family; as extended family members but not as parents; and as fathers. The more limited role of donors in participants' construction of family relationships sheds light on how children raised in lesbian, gay, and bisexual families are contributing to the redefinition and reconstruction of complex kinship arrangements. Our findings hold implications for clinicians who work with lesbian-mother families, and suggest that young adulthood is an important developmental phase during which interest in and contact with the donor may shift, warranting a transfer of responsibility from mother to offspring in terms of managing the donor-child relationship. © FPI, Inc.

Simultaneous detection of human mitochondrial DNA and nuclear-inserted mitochondrial-origin sequences (NumtS) using forensic mtDNA amplification strategies and pyrosequencing technology.

PubMed

Bintz, Brittania J; Dixon, Groves B; Wilson, Mark R

2014-07-01

Next-generation sequencing technologies enable the identification of minor mitochondrial DNA variants with higher sensitivity than Sanger methods, allowing for enhanced identification of minor variants. In this study, mixtures of human mtDNA control region amplicons were subjected to pyrosequencing to determine the detection threshold of the Roche GS Junior(®) instrument (Roche Applied Science, Indianapolis, IN). In addition to expected variants, a set of reproducible variants was consistently found in reads from one particular amplicon. A BLASTn search of the variant sequence revealed identity to a segment of a 611-bp nuclear insertion of the mitochondrial control region (NumtS) spanning the primer-binding sites of this amplicon (Nature 1995;378:489). Primers (Hum Genet 2012;131:757; Hum Biol 1996;68:847) flanking the insertion were used to confirm the presence or absence of the NumtS in buccal DNA extracts from twenty donors. These results further our understanding of human mtDNA variation and are expected to have a positive impact on the interpretation of mtDNA profiles using deep-sequencing methods in casework. © 2014 American Academy of Forensic Sciences.

First detection of Echinococcus multilocularis in rodent intermediate hosts in Turkey.

PubMed

Avcioglu, Hamza; Guven, Esin; Balkaya, Ibrahim; Kirman, Ridvan; Bia, Mohammed Mebarek; Gulbeyen, Hatice; Kurt, Ali; Yaya, Sali; Demirtas, Sadik

2017-11-01

Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a potentially fatal zoonotic disease. Large parts of Turkey are considered as endemic for E. multilocularis. The aim of this study was to determine the occurrence of metacestode of E. multilocularis in wild rodents in Erzurum, an endemic region for human AE in Turkey. During the sampling period, a total of 498 rodents were trapped in twenty counties of Erzurum Province. Suspected lesions were observed on the livers of 48 rodents, and then partial fragment of mitochondrial 12S rRNA gene was PCR-amplified. Five liver samples exhibited E. multilocularis infection. The prevalence of E. multilocularis for Microtus spp. was 1·3%. All of the infected rodents had fertile metacestodes. Infected rodents were morphologically and molecularly analysed and were confirmed to be Microtus irani by the mitochondrial cytochrome b gene sequence analysis. This is the first report of the presence of E. multilocularis in rodent intermediate hosts in Turkey. Our findings of infected M. irani with protoscoleces show that this rodent can act as suitable intermediate host for E. multilocularis' life cycle in Turkey. However, there was a complete lack of data on the infection of carnivores from the country. An extensive survey is recommended to determine the prevalence of E. multilocularis in definitive hosts in this endemic region.

Molecular systematics of pinniped hookworms (Nematoda: Uncinaria): species delimitation, host associations and host-induced morphometric variation.

PubMed

Nadler, Steven A; Lyons, Eugene T; Pagan, Christopher; Hyman, Derek; Lewis, Edwin E; Beckmen, Kimberlee; Bell, Cameron M; Castinel, Aurelie; Delong, Robert L; Duignan, Padraig J; Farinpour, Cher; Huntington, Kathy Burek; Kuiken, Thijs; Morgades, Diana; Naem, Soraya; Norman, Richard; Parker, Corwin; Ramos, Paul; Spraker, Terry R; Berón-Vera, Bárbara

2013-12-01

Hookworms of the genus Uncinaria have been widely reported from juvenile pinnipeds, however investigations of their systematics has been limited, with only two species described, Uncinaria lucasi from northern fur seals (Callorhinus ursinus) and Uncinaria hamiltoni from South American sea lions (Otaria flavescens). Hookworms were sampled from these hosts and seven additional species including Steller sea lions (Eumetopias jubatus), California sea lions (Zalophus californianus), South American fur seals (Arctocephalus australis), Australian fur seals (Arctocephalus pusillus), New Zealand sea lions (Phocarctos hookeri), southern elephant seals (Mirounga leonina), and the Mediterranean monk seal (Monachus monachus). One hundred and thirteen individual hookworms, including an outgroup species, were sequenced for four genes representing two loci (nuclear ribosomal DNA and mitochondrial DNA). Phylogenetic analyses of these sequences recovered seven independent evolutionary lineages or species, including the described species and five undescribed species. The molecular evidence shows that U. lucasi parasitises both C. ursinus and E. jubatus, whereas U. hamiltoni parasitises O. flavescens and A. australis. The five undescribed hookworm species were each associated with single host species (Z. californianus, A. pusillus, P. hookeri, M. leonina and M. monachus). For parasites of otarids, patterns of Uncinaria host-sharing and phylogenetic relationships had a strong biogeographic component with separate clades of parasites from northern versus southern hemisphere hosts. Comparison of phylogenies for these hookworms and their hosts suggests that the association of U. lucasi with northern fur seals results from a host-switch from Steller sea lions. Morphometric data for U. lucasi shows marked host-associated size differences for both sexes, with U. lucasi individuals from E. jubatus significantly larger. This result suggests that adult growth of U. lucasi is reduced within the

Sperm donor anonymity and compensation: an experiment with American sperm donors

PubMed Central

Cohen, Glenn; Coan, Travis; Ottey, Michelle; Boyd, Christina

2016-01-01

Abstract Most sperm donation that occurs in the USA proceeds through anonymous donation. While some clinics make the identity of the sperm donor available to a donor-conceived child at age 18 as part of ‘open identification’ or ‘identity release programs,’ no US law requires clinics to do so, and the majority of individuals do not use these programs. By contrast, in many parts of the world, there have been significant legislative initiatives requiring that sperm donor identities be made available to children after a certain age (typically when the child turns 18). One major concern with prohibiting anonymous sperm donation has been that the number of willing sperm donors will decrease leading to shortages, as have been experienced in some of the countries that have prohibited sperm donor anonymity. One possible solution, suggested by prior work, would be to pay current anonymous sperm donors more per donation to continue to donate when their anonymity is removed. Using a unique sample of current anonymous and open identity sperm donors from a large sperm bank in the USA, we test that approach. As far as we know, this is the first attempt to examine what would happen if the USA adopted a prohibition on anonymous sperm donation that used the most ecologically valid population, current sperm donors. We find that 29% of current anonymous sperm donors in the sample would refuse to donate if the law changed such that they were required to put their names in a registry available to donor-conceived children at age 18. When we look at the remaining sperm donors who would be willing to participate, we find that they would demand an additional $60 per donation (using our preferred specification). We also discuss the ramifications for the industry. PMID:28852536

HISTOCOMPATIBILITY STUDIES IN A CLOSELY BRED COLONY OF DOGS

PubMed Central

Rapaport, F. T.; Hanaoka, T.; Shimada, T.; Cannon, F. D.; Ferrebee, J. W.

1970-01-01

The establishment of a closely bred colony of beagles with known leukocyte group phenotypes has permitted an assessment of the role of leukocyte group antigens in conditioning the survival of renal allografts in the unmodified host. 22 kidney transplants obtained from leukocyte group-compatible donors were accorded a mean survival time of 25.5 days, as compared with 13.1 days for 27 transplants obtained from incompatible donors. Donor-recipient coefficients of correlation and Swisher erythrocyte group incompatibilities did not appear to affect the observed results. The mean survival time of 21 renal allografts performed in randomly selected mongrel dogs was 9.5 days. Availability of a carefully characterized and phenotyped canine population may be useful in further studies of the comparative immunogenicity of the major transplantable organs, and of methods designed to facilitate prolonged organ transplant survival in the mammalian host. PMID:4910142

Mitochondrial flash as a novel biomarker of mitochondrial respiration in the heart.

PubMed

Gong, Guohua; Liu, Xiaoyun; Zhang, Huiliang; Sheu, Shey-Shing; Wang, Wang

2015-10-01

Mitochondrial respiration through electron transport chain (ETC) activity generates ATP and reactive oxygen species in eukaryotic cells. The modulation of mitochondrial respiration in vivo or under physiological conditions remains elusive largely due to the lack of appropriate approach to monitor ETC activity in a real-time manner. Here, we show that ETC-coupled mitochondrial flash is a novel biomarker for monitoring mitochondrial respiration under pathophysiological conditions in cultured adult cardiac myocyte and perfused beating heart. Through real-time confocal imaging, we follow the frequency of a transient bursting fluorescent signal, named mitochondrial flash, from individual mitochondria within intact cells expressing a mitochondrial matrix-targeted probe, mt-cpYFP (mitochondrial-circularly permuted yellow fluorescent protein). This mt-cpYFP recorded mitochondrial flash has been shown to be composed of a major superoxide signal with a minor alkalization signal within the mitochondrial matrix. Through manipulating physiological substrates for mitochondrial respiration, we find a close coupling between flash frequency and the ETC electron flow, as measured by oxygen consumption rate in cardiac myocyte. Stimulating electron flow under physiological conditions increases flash frequency. On the other hand, partially block or slowdown electron flow by inhibiting the F0F1 ATPase, which represents a pathological condition, transiently increases then decreases flash frequency. Limiting electron entrance at complex I by knocking out Ndufs4, an assembling subunit of complex I, suppresses mitochondrial flash activity. These results suggest that mitochondrial electron flow can be monitored by real-time imaging of mitochondrial flash. The mitochondrial flash frequency could be used as a novel biomarker for mitochondrial respiration under physiological and pathological conditions. Copyright © 2015 the American Physiological Society.

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

PubMed Central

Tan, Dun-Xian; Manchester, Lucien C.; Qin, Lilan; Reiter, Russel J.

2016-01-01

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. PMID:27999288

Is the red fox (Vulpes vulpes) a competent definitive host for Taenia multiceps?

PubMed

Varcasia, Antonio; Tamponi, Claudia; Tosciri, Gabriele; Pipia, Anna Paola; Dore, Francesco; Schuster, Rolf Karl; Kandil, Omnia Mohamed; Manunta, Maria Lucia; Scala, Antonio

2015-09-25

Shepherd and stray dogs are thought to represent the primary definitive hosts of Coenurosis by Taenia multiceps, due to their feeding habits which translate into high chances of coming into contact with infected intermediate hosts. Nonetheless, little attention has been paid to the role of the red fox (Vulpes vulpes) in the epidemiology of coenurosis. In fact a knowledge gap exists on the role played by red foxes in the epidemiology of Taenia multiceps and the capability of this parasite to produce fertile and viable eggs in this wild canid, i.e. on the occurrence of a sylvatic cycle. This study investigates the role of the red fox (Vulpes vulpes) in the epidemiology of T. multiceps and related metacestodoses. The small intestine of 63 red foxes was macroscopically examined for the presence of cestodes. Adult parasites were identified morphologically as being T. multiceps. Tapeworm eggs were counted and stored at 4 °C in physiological saline solution prior to experimental infection of four sheep and one goat. Sheep were inoculated orally on Day 0 with 3000 (sheep 1), 5000 (sheep 2 and 3) or 7000 eggs (sheep 4), while the goat was infected with 5000 eggs of T. multiceps. The animals were followed-up regularly by MRI and underwent surgical treatment between days 180 to day 240 post infection. Collected coenuri were identified using morphological and molecular methods. A total of 6.3 % of red foxes were found infected with T. multiceps and the eggs obtained from the worms were determined to have a viability of 45.4 %. Two of the challenged sheep and the goat developed disease compatible with T. multiceps. Morphometrical features of the cysts were consistent with those of T. multiceps; nucleotide amplification and sequencing of mitochondrial genes (i.e., cox1 and Nd1) from the metacestode material confirmed the identification. The present study is the first to provide evidence of the role of the red fox as a competent definitive host for T. multiceps, thus changing

Elimination of mitochondrial DNA is not required for herpes simplex virus 1 replication.

PubMed

Duguay, Brett A; Saffran, Holly A; Ponomarev, Alina; Duley, Shayla A; Eaton, Heather E; Smiley, James R

2014-03-01

Infection with herpes simplex virus type 1 (HSV-1) results in the rapid elimination of mitochondrial DNA (mtDNA) from host cells. It is known that a mitochondrial isoform of the viral alkaline nuclease (UL12) called UL12.5 triggers this process. However, very little is known about the impact of mtDNA depletion on viral replication or the biology of HSV-1 infections. These questions have been difficult to address because UL12.5 and UL12 are encoded by overlapping transcripts that share the same open reading frame. As a result, mutations that alter UL12.5 also affect UL12, and UL12 null mutations severely impair viral growth by interfering with the intranuclear processing of progeny viral genomes. Therefore, to specifically assess the impact of mtDNA depletion on viral replication, it is necessary to eliminate the activity of UL12.5 while preserving the nuclear functions of UL12. Previous work has shown that the human cytomegalovirus alkaline nuclease UL98 can functionally substitute for UL12 during HSV-1 replication. We found that UL98 is unable to deplete mtDNA in transfected cells and therefore generated an HSV-1 variant in which UL98 coding sequences replace the UL12/UL12.5 open reading frame. The resulting virus was severely impaired in its ability to trigger mtDNA loss but reached titers comparable to those of wild-type HSV-1 in one-step and multistep growth experiments. Together, these observations demonstrate that the elimination of mtDNA is not required for HSV-1 replication in cell culture. Herpes simplex virus types 1 and 2 destroy the DNA of host cell mitochondria, the powerhouses of cells. Epstein-Barr virus, a distantly related herpesvirus, has a similar effect, indicating that mitochondrial DNA destruction is under positive selection and thus confers a benefit to the virus. The present work shows that mitochondrial DNA destruction is not required for efficient replication of herpes simplex virus type 1 in cultured Vero kidney epithelial cells

Mitochondrial threshold effects.

PubMed Central

Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry

2003-01-01

The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the 'phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the 'biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a 'translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases. PMID:12467494

CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease

PubMed Central

Alexander, Kylie A.; Flynn, Ryan; Lineburg, Katie E.; Kuns, Rachel D.; Teal, Bianca E.; Olver, Stuart D.; Lor, Mary; Raffelt, Neil C.; Koyama, Motoko; Leveque, Lucie; Le Texier, Laetitia; Melino, Michelle; Markey, Kate A.; Varelias, Antiopi; Engwerda, Christian; Serody, Jonathan S.; Janela, Baptiste; Ginhoux, Florent; Clouston, Andrew D.; Blazar, Bruce R.; Hill, Geoffrey R.; MacDonald, Kelli P.A.

2014-01-01

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17–dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS–). Cutaneous cGVHD developed in a CSF-1/CSF-1R–dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r–/– mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti–CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD. PMID:25157821

Donor selection for adult-to-adult living donor liver transplantation: well begun is half done.

PubMed

Sharma, Amit; Ashworth, April; Behnke, Martha; Cotterell, Adrian; Posner, Marc; Fisher, Robert A

2013-02-15

Donor selection criteria for adult-to-adult living donor liver transplantation vary with the medical center of evaluation. Living donor evaluation uses considerable resources, and the nonmaturation of potential into actual donors may sometimes prove fatal for patients with end-stage liver disease. On the contrary, a thorough donor evaluation process is mandatory to ensure safe outcomes in otherwise healthy donors. We aimed to study the reasons for nonmaturation of potential right lobe liver donors at our transplant center. A retrospective data analysis of all potential living liver donors evaluated at our center from 1998 to 2010 was done. Overall, 324 donors were evaluated for 219 potential recipients, and 171 (52.7%) donors were disqualified. Common reasons for donor nonmaturation included the following: (1) donor reluctance, 21%; (2) greater than 10% macro-vesicular steatosis, 16%; (3) assisted donor withdrawal, 14%; (4) inadequate remnant liver volume, 13%; and (5) psychosocial issues, 7%, and thrombophilia, 7%. Ten donors (6%) were turned down because of anatomic variations (8 biliary and 2 arterial anomalies). Donors older than 50 years and those with body mass index of more than 25 were less likely to be accepted for donation. We conclude that donor reluctance, hepatic steatosis, and assisted donor withdrawal are major reasons for nonmaturation of potential into actual donors. Anatomic variations and underlying medical conditions were not a major cause of donor rejection. A system in practice to recognize these factors early in the course of donor evaluation to improve the efficiency of the selection process and ensure donor safety is proposed.

Donor Selection for Adult- to- Adult Living Donor Liver Transplantation: Well Begun is Half Done

PubMed Central

Sharma, Amit; Ashworth, April; Behnke, Martha; Cotterell, Adrian; Posner, Marc; Fisher, Robert A.

2012-01-01

Background Donor selection criteria for adult-to-adult living donor liver transplantation vary with the medical center of evaluation. Living donor evaluation utilizes considerable resources and the non-maturation of potential into actual donors may sometimes prove fatal for patients with end stage liver disease. On the contrary, a thorough donor evaluation process is mandatory to ensure safe outcomes in otherwise healthy donors. We aimed to study the reasons for non-maturation of potential right lobe liver donors at our transplant center. Methods A retrospective data analysis of all potential living liver donors evaluated at our center from 1998 to 2010 was done. Results Overall 324 donors were evaluated for 219 potential recipients and 171 (52.7%) donors were disqualified. Common reasons for donor non-maturation included: (1) Donor reluctance, 21% (2) >10% macro-vesicular steatosis, 16% (3) assisted donor withdrawal, 14% (4) inadequate remnant liver volume, 13% (5) psychosocial issues, 7% and thrombophilia, 7%. Ten donors (6%) were turned down due to anatomical variations (8 biliary and 2 arterial anomalies). Donors older than 50 years and those with BMI over 25 were less likely to be accepted for donation. Conclusions We conclude that donor reluctance, hepatic steatosis and assisted donor withdrawal are major reasons for non-maturation of potential into actual donors. Anatomical variations and underlying medical conditions were not a major cause of donor rejection. A system in practice to recognize these factors early in the course of donor evaluation to improve the efficiency of the selection process and ensure donor safety is proposed. PMID:23128999

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

PubMed

Fukunaga, Kohji; Shinoda, Yasuharu; Tagashira, Hideaki

2015-01-01

Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Considering Tangible Benefit for Interdependent Donors: Extending a Risk-Benefit Framework in Donor Selection.

PubMed

Van Pilsum Rasmussen, S E; Henderson, M L; Kahn, J; Segev, D

2017-10-01

From its infancy, live donor transplantation has operated within a framework of acceptable risk to donors. Such a framework presumes that risks of living donation are experienced by the donor while all benefits are realized by the recipient, creating an inequitable distribution that demands minimization of donor risk. We suggest that this risk-tolerance framework ignores tangible benefits to the donor. A previously proposed framework more fully considers potential benefits to the donor and argues that risks and benefits must be balanced. We expand on this approach, and posit that donors sharing a household with and/or caring for a potential transplant patient may realize tangible benefits that are absent in a more distantly related donation (e.g. cousin, nondirected). We term these donors, whose well-being is closely tied to their recipient, "interdependent donors." A flexible risk-benefit model that combines risk assessment with benefits to interdependent donors will contribute to donor evaluation and selection that more accurately reflects what is at stake for donors. In so doing, a risk-benefit framework may allow some donors to accept greater risk in donation decisions. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Marginal donors: can older donor hearts tolerate prolonged cold ischemic storage?

PubMed

Korkmaz, Sevil; Bährle-Szabó, Susanne; Loganathan, Sivakkanan; Li, Shiliang; Karck, Matthias; Szabó, Gábor

2013-10-01

Both advanced donor age and prolonged ischemic time are significant risk factors for the 1-year mortality. However, its functional consequences have not been fully evaluated in the early-phase after transplantation; even early graft dysfunction is the main determinant of long-term outcome following transplantation. We evaluated in vivo left-ventricular (LV) cardiac and coronary vascular function of old-donor grafts after short and prolonged cold ischemic times in rats 1 h after heart transplantation. The hearts were excised from young donor (3-month-old) or old donor (18-month-old) rats, stored in cold preservation solution for either 1 or 8 h, and heterotopically transplanted. After 1 h of ischemic period, in the old-donor group, LV pressure, maximum pressure development (dP/dt max), time constant of LV pressure decay (τ), LV end-diastolic pressure and coronary blood flow did not differ compared with young donors. However, endothelium-dependent vasodilatation to acetylcholine resulted in a significantly lower response of coronary blood flow in the old-donor group (33 ± 4 vs. 51 ± 15 %, p < 0.05). After 8 h preservation, two of the old-donor hearts showed no mechanical activity upon reperfusion. LV pressure (55 ± 6 vs. 72 ± 5 mmHg, p < 0.05), dP/dt max (899 ± 221 vs. 1530 ± 217 mmHg/s, p < 0.05), coronary blood flow and response to acetylcholine were significantly reduced and τ was increased in the old-donor group in comparison to young controls. During the early-phase after transplantation, the ischemic tolerance of older-donor hearts is reduced after prolonged preservation time and the endothelium is more vulnerable to ischemia/reperfusion.

Donor-transmitted, donor-derived, and de novo cancer after liver transplant.

PubMed

Chapman, Jeremy R; Lynch, Stephen V

2014-03-01

Cancer is the third most common cause of death (after cardiovascular disease and infection) for patients who have a functioning kidney allograft. Kidney and liver transplant recipients have similar cancer risks because of immunosuppression but different risks because of differences in primary diseases that cause renal and hepatic failure and the inherent behavior of cancers in the liver. There are 4 types of cancer that may develop in liver allograft recipients: (1) recurrent cancer, (2) donor-transmitted cancer, (3) donor-derived cancer, and (4) de novo cancer. Identification of potential donor cancer transmission may occur at postmortem examination of a deceased donor or when a probable donor-transmitted cancer is identified in another recipient. Donor-transmitted cancer after liver transplant is rare in Australia, the United Kingdom, and the United States. Aging of the donor pool may increase the risk of subclinical cancer in donors. Liver transplant recipients have a greater risk of de novo cancer than the general population, and risk factors for de novo cancer in liver transplant recipients include primary sclerosing cholangitis, alcoholic liver disease, smoking, and increased age. Liver transplant recipients may benefit from cancer screening because they have a high risk, are clearly identifiable, and are under continuous medical supervision.

Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast Candida glabrata

PubMed Central

Nagi, Minoru; Tanabe, Koichi; Nakayama, Hironobu; Ueno, Keigo; Yamagoe, Satoshi; Umeyama, Takashi; Ohno, Hideaki; Miyazaki, Yoshitsugu

2016-01-01

ABSTRACT Candida glabrata, a haploid budding yeast, is the cause of severe systemic infections in immune-compromised hosts. The amount of free iron supplied to C. glabrata cells during systemic infections is severely limited by iron-chelating proteins such as transferrin. Thus, the iron-deficiency response in C. glabrata cells is thought to play important roles in their survival inside the host's body. In this study, we found that mitophagy was induced under iron-depleted conditions, and that the disruption of a gene homologous to ATG32, which is responsible for mitophagy in Saccharomyces cerevisiae, blocked mitophagy in C. glabrata. The mitophagic activity in C. glabrata cells was not detected on short-period exposure to nitrogen-starved conditions, which is a mitophagy-inducing condition used in S. cerevisiae. The mitophagy-deficient atg32Δ mutant of C. glabrata also exhibited decreased longevity under iron-deficient conditions. The mitochondrial membrane potential in Cgatg32Δ cells was significantly lower than that in wild-type cells under iron-depleted conditions. In a mouse model of disseminated infection, the Cgatg32Δ strain resulted in significantly decreased kidney and spleen fungal burdens compared with the wild-type strain. These results indicate that mitophagy in C. glabrata occurs in an iron-poor host tissue environment, and it may contribute to the longevity of cells, mitochondrial quality control, and pathogenesis. PMID:27347716

Host partitioning by parasites in an intertidal crustacean community.

PubMed

Koehler, Anson V; Poulin, Robert

2010-10-01

Patterns of host use by parasites throughout a guild community of intermediate hosts can depend on several biological and ecological factors, including physiology, morphology, immunology, and behavior. We looked at parasite transmission in the intertidal crustacean community of Lower Portobello Bay, Dunedin, New Zealand, with the intent of: (1) mapping the flow of parasites throughout the major crustacean species, (2) identifying hosts that play the most important transmission role for each parasite, and (3) assessing the impact of parasitism on host populations. The most prevalent parasites found in 14 species of crustaceans (635 specimens) examined were the trematodes Maritrema novaezealandensis and Microphallus sp., the acanthocephalans Profilicollis spp., the nematode Ascarophis sp., and an acuariid nematode. Decapods were compatible hosts for M. novaezealandensis, while other crustaceans demonstrated lower host suitability as shown by high levels of melanized and immature parasite stages. Carapace thickness, gill morphology, and breathing style may contribute to the differential infection success of M. novaezealandensis and Microphallus sp. in the decapod species. Parasite-induced host mortality appears likely with M. novaezealandensis in the crabs Austrohelice crassa, Halicarcinus varius, Hemigrapsus sexdentatus, and Macrophthalmus hirtipes, and also with Microphallus sp. in A. crassa. Overall, the different parasite species make different use of available crustacean intermediate hosts and possibly contribute to intertidal community structure.

Molecular diversification of Trichuris spp. from Sigmodontinae (Cricetidae) rodents from Argentina based on mitochondrial DNA sequences.

PubMed

Callejón, Rocío; Robles, María Del Rosario; Panei, Carlos Javier; Cutillas, Cristina

2016-08-01

A molecular phylogenetic hypothesis is presented for the genus Trichuris based on sequence data from mitochondrial cytochrome c oxidase 1 (cox1) and cytochrome b (cob). The taxa consisted of nine populations of whipworm from five species of Sigmodontinae rodents from Argentina. Bayesian Inference, Maximum Parsimony, and Maximum Likelihood methods were used to infer phylogenies for each gene separately but also for the combined mitochondrial data and the combined mitochondrial and nuclear dataset. Phylogenetic results based on cox1 and cob mitochondrial DNA (mtDNA) revealed three clades strongly resolved corresponding to three different species (Trichuris navonae, Trichuris bainae, and Trichuris pardinasi) showing phylogeographic variation, but relationships among Trichuris species were poorly resolved. Phylogenetic reconstruction based on concatenated sequences had greater phylogenetic resolution for delimiting species and populations intra-specific of Trichuris than those based on partitioned genes. Thus, populations of T. bainae and T. pardinasi could be affected by geographical factors and co-divergence parasite-host.

Marginal kidney donor

PubMed Central

Gopalakrishnan, Ganesh; Gourabathini, Siva Prasad

2007-01-01

Renal transplantation is the treatment of choice for a medically eligible patient with end stage renal disease. The number of renal transplants has increased rapidly over the last two decades. However, the demand for organs has increased even more. This disparity between the availability of organs and waitlisted patients for transplants has forced many transplant centers across the world to use marginal kidneys and donors. We performed a Medline search to establish the current status of marginal kidney donors in the world. Transplant programs using marginal deceased renal grafts is well established. The focus is now on efforts to improve their results. Utilization of non-heart-beating donors is still in a plateau phase and comprises a minor percentage of deceased donations. The main concern is primary non-function of the renal graft apart from legal and ethical issues. Transplants with living donors outnumbered cadaveric transplants at many centers in the last decade. There has been an increased use of marginal living kidney donors with some acceptable medical risks. Our primary concern is the safety of the living donor. There is not enough scientific data available to quantify the risks involved for such donation. The definition of marginal living donor is still not clear and there are no uniform recommendations. The decision must be tailored to each donor who in turn should be actively involved at all levels of the decision-making process. In the current circumstances, our responsibility is very crucial in making decisions for either accepting or rejecting a marginal living donor. PMID:19718332

Successful enrichment and recovery of whole mitochondrial genomes from ancient human dental calculus.

PubMed

Ozga, Andrew T; Nieves-Colón, Maria A; Honap, Tanvi P; Sankaranarayanan, Krithivasan; Hofman, Courtney A; Milner, George R; Lewis, Cecil M; Stone, Anne C; Warinner, Christina

2016-06-01

Archaeological dental calculus is a rich source of host-associated biomolecules. Importantly, however, dental calculus is more accurately described as a calcified microbial biofilm than a host tissue. As such, concerns regarding destructive analysis of human remains may not apply as strongly to dental calculus, opening the possibility of obtaining human health and ancestry information from dental calculus in cases where destructive analysis of conventional skeletal remains is not permitted. Here we investigate the preservation of human mitochondrial DNA (mtDNA) in archaeological dental calculus and its potential for full mitochondrial genome (mitogenome) reconstruction in maternal lineage ancestry analysis. Extracted DNA from six individuals at the 700-year-old Norris Farms #36 cemetery in Illinois was enriched for mtDNA using in-solution capture techniques, followed by Illumina high-throughput sequencing. Full mitogenomes (7-34×) were successfully reconstructed from dental calculus for all six individuals, including three individuals who had previously tested negative for DNA preservation in bone using conventional PCR techniques. Mitochondrial haplogroup assignments were consistent with previously published findings, and additional comparative analysis of paired dental calculus and dentine from two individuals yielded equivalent haplotype results. All dental calculus samples exhibited damage patterns consistent with ancient DNA, and mitochondrial sequences were estimated to be 92-100% endogenous. DNA polymerase choice was found to impact error rates in downstream sequence analysis, but these effects can be mitigated by greater sequencing depth. Dental calculus is a viable alternative source of human DNA that can be used to reconstruct full mitogenomes from archaeological remains. Am J Phys Anthropol 160:220-228, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

L Band Service Compatibility : Part II: Optimum GPS Receiver ABI Compatibility

DOT National Transportation Integrated Search

2015-03-12

Workshop Objectives. This is the Second of Two Parts on Compatibility. Last time, OOBE. Today examine mitigation of Adjacent Band Interference, ABI. Apply Relevant TWG and NPEF (2011) data to engage compatibility analysis. Assert Principle: Dr. Brad ...

Safely expanding the donor pool: brain dead donors with history of temporary cardiac arrest.

PubMed

Hoyer, Dieter P; Paul, Andreas; Saner, Fuat; Gallinat, Anja; Mathé, Zoltan; Treckmann, Juergen W; Schulze, Maren; Kaiser, Gernot M; Canbay, Ali; Molmenti, Ernesto; Sotiropoulos, Georgios C

2015-06-01

Cardiac arrest (CA) in deceased organ donors can potentially be associated with ischaemic organ injury, resulting in allograft dysfunction after liver transplantation (LT). The aim of this study was to analyse the influence of cardiac arrest in liver donors. We evaluated 884 consecutive adult patients undergoing LT at our Institution from September 2003 to December 2011. Uni- and multivariable analyses was performed to identify predictive factors of outcome and survival for organs from donors with (CA donor) and without (no CA donor) a history of cardiac arrest. We identified 77 (8.7%) CA donors. Median resuscitation time was 16.5 (1-150) minutes. Allografts from CA donors had prolonged CIT (p = 0.016), were obtained from younger individuals (p < 0.001), and had higher terminal preprocurement AST and ALT (p < 0.001) than those of no CA donors. 3-month, 1-year and 5-year survival for recipients of CA donor grafts was 79%, 76% and 57% and 72.1%, 65.1% and 53% for no CA donor grafts (log rank p = 0.435). Peak AST after LT was significantly lower in CA donor organs than in no CA donor ones (886U/l vs 1321U/l; p = 0.031). Multivariable analysis identified CIT as a risk factor for both patient and graft survival in CA donors. This analysis represents the largest cohort of liver donors with a history of cardiac arrest. Reasonable selection of these donors constitutes a safe approach to the expansion of the donor pool. Rapid allocation and implantation with diminution of CIT may further improve the outcomes of livers from CA donors. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mitochondrial tRNA cleavage by tRNA-targeting ribonuclease causes mitochondrial dysfunction observed in mitochondrial disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, Tetsuhiro, E-mail: atetsu@mail.ecc.u-tokyo.ac.jp; Shimizu, Ayano; Takahashi, Kazutoshi

2014-08-15

Highlights: • MTS-tagged ribonuclease was translocated successfully to the mitochondrial matrix. • MTS-tagged ribonuclease cleaved mt tRNA and reduced COX activity. • Easy and reproducible method of inducing mt tRNA dysfunction. - Abstract: Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrialmore » dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ{sup 0} cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.« less

Production and release of acylcarnitines by primary myotubes reflect the differences in fasting fat oxidation of the donors.

PubMed

Wolf, Magnus; Chen, Shili; Zhao, Xinjie; Scheler, Mika; Irmler, Martin; Staiger, Harald; Beckers, Johannes; de Angelis, Martin Hrabé; Fritsche, Andreas; Häring, Hans-Ulrich; Schleicher, Erwin D; Xu, Guowang; Lehmann, Rainer; Weigert, Cora

2013-06-01

Acylcarnitines are biomarkers of incomplete β-oxidation and mitochondrial lipid overload but indicate also high rates of mitochondrial fatty acid oxidation. It is unknown whether the production of acylcarnitines in primary human myotubes obtained from lean, metabolically healthy subjects reflects the fat oxidation in vivo. Our objective was to quantify the acylcarnitine production in myotubes obtained from subjects with low and high fasting respiratory quotient (RQ). Fasting RQ was determined by indirect calorimetry. Muscle biopsies from the vastus lateralis muscle were taken from 6 subjects with low fasting RQ (mean 0.79 ± 0.03) and 6 with high fasting RQ (0.90 ± 0.03), and satellite cells were isolated, cultured, and differentiated to myotubes. Myotubes were cultivated with 125 μM (13)C-labeled palmitate for 30 minutes and 4 and 24 hours. Quantitative profiling of 42 intracellular and 31 extracellular acylcarnitines was performed by stable isotope dilution-based metabolomics analysis by liquid chromatography coupled to mass spectrometry. Myotubes from donors with high fasting RQ produced and released significant higher amounts of medium-chain acylcarnitines. High (13)C8 and (13)C10 acylcarnitine levels in the extracellular compartment correlated with high fasting RQ. The decreased expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD) in these myotubes can explain the higher rate of incomplete fatty acid oxidation. A lower intracellular [(13)C]acetylcarnitine to carnitine and lower intracellular (13)C16/(13)C18 acylcarnitine to carnitine ratio indicate reduced fatty acid oxidation capacity in these myotubes. Mitochondrial DNA content was not different. Acylcarnitine production and release from primary human myotubes of donors with high fasting RQ indicate a reduced fatty acid oxidation capacity and a higher rate of incomplete fatty acid oxidation. Thus, quantitative profiling of acylcarnitine production in human myotubes can be a suitable tool to

Targeted Transgenic Overexpression of Mitochondrial Thymidine Kinase (TK2) Alters Mitochondrial DNA (mtDNA) and Mitochondrial Polypeptide Abundance

PubMed Central

Hosseini, Seyed H.; Kohler, James J.; Haase, Chad P.; Tioleco, Nina; Stuart, Tami; Keebaugh, Erin; Ludaway, Tomika; Russ, Rodney; Green, Elgin; Long, Robert; Wang, Liya; Eriksson, Staffan; Lewis, William

2007-01-01

Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-γ. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity. PMID:17322372

Donor Retention in Online Crowdfunding Communities: A Case Study of DonorsChoose.org

PubMed Central

Althoff, Tim; Leskovec, Jure

2016-01-01

Online crowdfunding platforms like DonorsChoose.org and Kick-starter allow specific projects to get funded by targeted contributions from a large number of people. Critical for the success of crowdfunding communities is recruitment and continued engagement of donors. With donor attrition rates above 70%, a significant challenge for online crowdfunding platforms as well as traditional offline non-profit organizations is the problem of donor retention. We present a large-scale study of millions of donors and donations on DonorsChoose.org, a crowdfunding platform for education projects. Studying an online crowdfunding platform allows for an unprecedented detailed view of how people direct their donations. We explore various factors impacting donor retention which allows us to identify different groups of donors and quantify their propensity to return for subsequent donations. We find that donors are more likely to return if they had a positive interaction with the receiver of the donation. We also show that this includes appropriate and timely recognition of their support as well as detailed communication of their impact. Finally, we discuss how our findings could inform steps to improve donor retention in crowdfunding communities and non-profit organizations. PMID:27077139

Donor Retention in Online Crowdfunding Communities: A Case Study of DonorsChoose.org.

PubMed

Althoff, Tim; Leskovec, Jure

2015-05-01

Online crowdfunding platforms like DonorsChoose.org and Kick-starter allow specific projects to get funded by targeted contributions from a large number of people. Critical for the success of crowdfunding communities is recruitment and continued engagement of donors. With donor attrition rates above 70%, a significant challenge for online crowdfunding platforms as well as traditional offline non-profit organizations is the problem of donor retention. We present a large-scale study of millions of donors and donations on DonorsChoose.org, a crowdfunding platform for education projects. Studying an online crowdfunding platform allows for an unprecedented detailed view of how people direct their donations. We explore various factors impacting donor retention which allows us to identify different groups of donors and quantify their propensity to return for subsequent donations. We find that donors are more likely to return if they had a positive interaction with the receiver of the donation. We also show that this includes appropriate and timely recognition of their support as well as detailed communication of their impact. Finally, we discuss how our findings could inform steps to improve donor retention in crowdfunding communities and non-profit organizations.

Compatibility: drugs and parenteral nutrition

PubMed Central

Miranda, Talita Muniz Maloni; Ferraresi, Andressa de Abreu

2016-01-01

ABSTRACT Objective Standardization and systematization of data to provide quick access to compatibility of leading injectable drugs used in hospitals for parenteral nutrition. Methods We selected 55 injectable drugs analyzed individually with two types of parenteral nutrition: 2-in-1 and 3-in-1. The following variables were considered: active ingredient, compatibility of drugs with the parenteral nutrition with or without lipids, and maximum drug concentration after dilution for the drugs compatible with parenteral nutrition. Drugs were classified as compatible, incompatible and untested. Results After analysis, relevant information to the product’s compatibility with parental nutrition was summarized in a table. Conclusion Systematization of compatibility data provided quick and easy access, and enabled standardizing pharmacists work. PMID:27074235

Complete mitochondrial genome sequences from five Eimeria species (Apicomplexa; Coccidia; Eimeriidae) infecting domestic turkeys

PubMed Central

2014-01-01

; Eimeria dispersa may have arisen via host switching from another avian host. Phylogenetic analyses suggest E. necatrix and E. tenella are related distantly to other Eimeria of chickens. Conclusions Mitochondrial genomes of Eimeria species sequenced to date are highly conserved with regard to gene content and structure. Nonetheless, complete mitochondrial genome sequences and, particularly the three CDS, possess sufficient sequence variability for differentiating Eimeria species of poultry. The mitochondrial genome sequences are highly suited for molecular diagnostics and phylogenetics of coccidia and, potentially, genetic markers for molecular epidemiology. PMID:25034633

Donor Conception and "Passing," or; Why Australian Parents of Donor-Conceived Children Want Donors Who Look Like Them.

PubMed

Wong, Karen-Anne

2017-03-01

This article explores the processes through which Australian recipients select unknown donors for use in assisted reproductive technologies and speculates on how those processes may affect the future life of the donor-conceived person. I will suggest that trust is an integral part of the exchange between donors, recipients, and gamete agencies in donor conception and heavily informs concepts of relatedness, race, ethnicity, kinship, class, and visibility. The decision to be transparent (or not) about a child's genetic parentage affects recipient parents' choices of donor, about who is allowed to "know" children's genetic backgrounds, and how important it is to be able to "pass" as an unassisted conception. In this way, recipients must trust the process, institutions, and individuals involved in their treatment, as well as place trust in the future they imagine for their child. The current market for donor gametes reproduces normative conceptions of the nuclear family, kinship, and relatedness by facilitating "matching" donors to recipients by phenotype and cultural affinities. Recipient parents who choose not to prioritize "matching," and actively disclose the process of children's conceptions, may embark on a project of queering heteronormative family structures and place great trust in both their own children and changing social attitudes to reduce stigma and generate acceptance for non-traditional families.

Beet yellow stunt virus in cells of Sonchus oleraceus L. and its relation to host mitochondria.

PubMed

Esau, K

1979-10-15

In Sonchus oleraceus L. (Asteraceae) infected with the beet yellow stunt virus (BYSV) the virions are found in phloem cells, including the sieve elements. In parenchymatous phloem cells, the virus is present mainly in the cytoplasm. In some parenchymatous cells, containing massive accumulations of virus, the flexuous rodlike virus particles are found partly inserted into mitochondrial cristae. The mitochondrial envelope is absent where virus is present in the cristae. A similar relation between virus and host mitochondria apparently has not been recorded for any other plant virus.

Recurrence of chronic active Epstein-Barr virus infection from donor cells after achieving complete response through allogeneic bone marrow transplantation.

PubMed

Arai, Ayako; Imadome, Ken-ichi; Wang, Ludan; Wu, Nan; Kurosu, Tetsuya; Wake, Atsushi; Yamamoto, Hisashi; Ota, Yasunori; Harigai, Masayoshi; Fujiwara, Shigeyoshi; Miura, Osamu

2012-01-01

We report the case of a 35-year-old woman with chronic active Epstein-Barr virus (EBV) infection (CAEBV). She underwent allogeneic bone marrow transplantation (BMT) from an unrelated male donor and achieved a complete response. However, her CAEBV relapsed one year after BMT. EBV-infected cells proliferated clonally and revealed a 46XY karyotype. In addition, the infecting EBV strain differed from that detected before BMT. These findings indicated that her disease had developed from donor cells. This is the first report of donor cell-derived CAEBV that recurred after transplantation, suggesting that host factors may be responsible for the development of this disease.

Repeated sequence sets in mitochondrial DNA molecules of root knot nematodes (Meloidogyne): nucleotide sequences, genome location and potential for host-race identification.

PubMed Central

Okimoto, R; Chamberlin, H M; Macfarlane, J L; Wolstenholme, D R

1991-01-01

Within a 7 kb segment of the mtDNA molecule of the root knot nematode, Meloidogyne javanica, that lacks standard mitochondrial genes, are three sets of strictly tandemly arranged, direct repeat sequences: approximately 36 copies of a 102 ntp sequence that contains a TaqI site; 11 copies of a 63 ntp sequence, and 5 copies of an 8 ntp sequence. The 7 kb repeat-containing segment is bounded by putative tRNAasp and tRNAf-met genes and the arrangement of sequences within this segment is: the tRNAasp gene; a unique 1,528 ntp segment that contains two highly stable hairpin-forming sequences; the 102 ntp repeat set; the 8 ntp repeat set; a unique 1,068 ntp segment; the 63 ntp repeat set; and the tRNAf-met gene. The nucleotide sequences of the 102 ntp copies and the 63 ntp copies have been conserved among the species examined. Data from Southern hybridization experiments indicate that 102 ntp and 63 ntp repeats occur in the mtDNAs of three, two and two races of M.incognita, M.hapla and M.arenaria, respectively. Nucleotide sequences of the M.incognita Race-3 102 ntp repeat were found to be either identical or highly similar to those of the M.javanica 102 ntp repeat. Differences in migration distance and number of 102 ntp repeat-containing bands seen in Southern hybridization autoradiographs of restriction-digested mtDNAs of M.javanica and the different host races of M.incognita, M.hapla and M.arenaria are sufficient to distinguish the different host races of each species. Images PMID:2027769

A simplified donor risk index for predicting outcome after deceased donor kidney transplantation.

PubMed

Watson, Christopher J E; Johnson, Rachel J; Birch, Rhiannon; Collett, Dave; Bradley, J Andrew

2012-02-15

We sought to determine the deceased donor factors associated with outcome after kidney transplantation and to develop a clinically applicable Kidney Donor Risk Index. Data from the UK Transplant Registry on 7620 adult recipients of adult deceased donor kidney transplants between 2000 and 2007 inclusive were analyzed. Donor factors potentially influencing transplant outcome were investigated using Cox regression, adjusting for significant recipient and transplant factors. A United Kingdom Kidney Donor Risk Index was derived from the model and validated. Donor age was the most significant factor predicting poor transplant outcome (hazard ratio for 18-39 and 60+ years relative to 40-59 years was 0.78 and 1.49, respectively, P<0.001). A history of donor hypertension was also associated with increased risk (hazard ratio 1.30, P=0.001), and increased donor body weight, longer hospital stay before death, and use of adrenaline were also significantly associated with poorer outcomes up to 3 years posttransplant. Other donor factors including donation after circulatory death, history of cardiothoracic disease, diabetes history, and terminal creatinine were not significant. A donor risk index based on the five significant donor factors was derived and confirmed to be prognostic of outcome in a validation cohort (concordance statistic 0.62). An index developed in the United States by Rao et al., Transplantation 2009; 88: 231-236, included 15 factors and gave a concordance statistic of 0.63 in the UK context, suggesting that our much simpler model has equivalent predictive ability. A Kidney Donor Risk Index based on five donor variables provides a clinically useful tool that may help with organ allocation and informed consent.

Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease.

PubMed

Arbez, Jessy; Saas, Philippe; Lamarthée, Baptiste; Malard, Florent; Couturier, Mélanie; Mohty, Mohamad; Gaugler, Béatrice

2015-07-01

This study aimed to characterize the immune effectors contained in the grafts from donor mice mobilized by granulocyte colony-stimulating factor (G-CSF) and plerixafor and to evaluate their impact on the development of acute graft-versus-host-disease (aGVHD). Mobilization was done with G-CSF alone or G-CSF plus plerixafor (G+P). In grafts collected after G+P mobilization, we observed a significantly higher proportion of c-kit(+)Sca-1(+) hematopoietic stem cells compared with G-CSF. A significant increase in the percentage of plasmacytoid dendritic cells was detected in the G+P graft compared with G-CSF graft. We also studied the ability of stem cell grafts mobilized with G+P to induce GVHD in a mouse model. We observed higher mortality (P < 0.001) associated with increased aGVHD clinical score (P < 0.0001) as well as higher pathology score in the intestine of mice receiving G+P as compared with G-CSF grafts (P < 0.001). Moreover, the exacerbated aGVHD severity was associated with upregulation of CCR6 expression on both CD4(+) and CD8(+) T cells from the G+P grafts, as well as on T cells from mice transplanted with G+P grafts. In conclusion, we showed that grafts mobilized with G+P exhibited functional features different from those mobilized with G-CSF alone, which increase the severity of aGVHD in the recipients. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Spatial compatibility and affordance compatibility in patients with chronic schizophrenia.

PubMed

Kume, Yu; Sato, Fumiyasu; Hiraoka, Yuya; Suzuki, Shingo; Niyama, Yoshitsugu

2016-12-01

A deterioration in information-processing performance is commonly recognized in patients with chronic schizophrenia. Although the enhancement of cognitive skills in patients with schizophrenia is important, the types of external stimuli that influence performance have not received much attention. The aim of present study was to clarify the effects of spatial and affordance compatibility in patients with schizophrenia, compared with those in healthy people. The subjects (25 patients with schizophrenia and 25 healthy controls) participated in two experiment examining the effects of the spatial location of stimuli and the action-relevance of objects. The results showed that the effect of spatial compatibility was similar in both the patients and the controls, whereas the influence of action-relevant objects was not highlighted in either patients with chronic schizophrenia or healthy controls. These findings provide important evidence of a normal spatial compatibility effect in patients with chronic schizophrenia. However, further research examining the affordance compatibility effect is needed, taking into consideration the symptomatology and the severity of the social functioning level in patients with schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Factors influencing donor return.

PubMed

Schlumpf, Karen S; Glynn, Simone A; Schreiber, George B; Wright, David J; Randolph Steele, Whitney; Tu, Yongling; Hermansen, Sigurd; Higgins, Martha J; Garratty, George; Murphy, Edward L

2008-02-01

To predict future blood donation behavior and improve donor retention, it is important to understand the determinants of donor return. A self-administered questionnaire was completed in 2003 by 7905 current donors. With data mining methods, all factors measured by the survey were ranked as possible predictors of actual return within 12 months. Significant factors were analyzed with logistic regression to determine predictors of intention and of actual return. Younger and minority donors were less likely to return in 12 months. Predictors of donor return were higher prior donation frequency, higher intention to return, a convenient place to donate, and having a good donation experience. Most factors associated with actual donor return were also associated with a high intention to return. Although not significant for actual return, feeling a responsibility to help others, higher empathetic concern, and a feeling that being a blood donor means more than just donating blood were related to high intention to return. Prior donation frequency, intention to return, donation experience, and having a convenient location appear to significantly predict donor return. Clearly, donor behavior is dependent on more than one factor alone. Altruistic behavior, empathy, and social responsibility items did not enter our model to predict actual return. A donor's stated intention to give again is positively related to actual return and, while not a perfect measure, might be a useful proxy when donor return cannot be determined.

Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division

PubMed Central

Cho, Bongki; Cho, Hyo Min; Jo, Youhwa; Kim, Hee Dae; Song, Myungjae; Moon, Cheil; Kim, Hyongbum; Kim, Kyungjin; Sesaki, Hiromi; Rhyu, Im Joo; Kim, Hyun; Sun, Woong

2017-01-01

Mitochondrial division is critical for the maintenance and regulation of mitochondrial function, quality and distribution. This process is controlled by cytosolic actin-based constriction machinery and dynamin-related protein 1 (Drp1) on mitochondrial outer membrane (OMM). Although mitochondrial physiology, including oxidative phosphorylation, is also important for efficient mitochondrial division, morphological alterations of the mitochondrial inner-membrane (IMM) have not been clearly elucidated. Here we report spontaneous and repetitive constriction of mitochondrial inner compartment (CoMIC) associated with subsequent division in neurons. Although CoMIC is potentiated by inhibition of Drp1 and occurs at the potential division spots contacting the endoplasmic reticulum, it appears on IMM independently of OMM. Intra-mitochondrial influx of Ca2+ induces and potentiates CoMIC, and leads to K+-mediated mitochondrial bulging and depolarization. Synergistically, optic atrophy 1 (Opa1) also regulates CoMIC via controlling Mic60-mediated OMM–IMM tethering. Therefore, we propose that CoMIC is a priming event for efficient mitochondrial division. PMID:28598422

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

PubMed

Styczynski, Jan; Tridello, Gloria; Gil, Lidia; Ljungman, Per; Hoek, Jennifer; Iacobelli, Simona; Ward, Katherine N; Cordonnier, Catherine; Einsele, Hermann; Socie, Gerard; Milpied, Noel; Veelken, Hendrik; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Maertens, Johan; Blaise, Didier; Cornelissen, Jan; Michallet, Mauricette; Daguindau, Etienne; Petersen, Eefke; Passweg, Jakob; Greinix, Hildegard; Duarte, Rafael F; Kröger, Nicolaus; Dreger, Peter; Mohty, Mohamad; Nagler, Arnon; Cesaro, Simone

2016-07-01

We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. © 2016 by American Society of Clinical Oncology.

Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases

PubMed Central

Swerdlow, Russell H.

2012-01-01

Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed. PMID:21902672

Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction.

PubMed Central

Oliver, N A; Wallace, D C

1982-01-01

Two mitochondrially synthesized marker polypeptides, MV-1 and MV-2, were found in human HeLa and HT1080 cells. These were assigned to the mitochondrial DNA in HeLa-HT1080 cybrids and hybrids by demonstrating their linkage to cytoplasmic genetic markers. These markers include mitochondrial DNA restriction site polymorphisms and resistance to chloramphenicol, an inhibitor of mitochondrial protein synthesis. In the absence of chloramphenicol, the expression of MV-1 and MV-2 in cybrids and hybrids was found to be directly proportional to the ratio of the parental mitochondrial DNAs. In the presence of chloramphenicol, the marker polypeptide linked to the chloramphenicol-sensitive mitochondrial DNA continued to be expressed. This demonstrated that resistant and sensitive mitochondrial DNAs can cooperate within a cell for gene expression and that the CAP-resistant allele was dominant or codominant to sensitive. Such cooperation suggests that mitochondrial DNAs can be exchanged between mitochondria. Images PMID:6955589

Successful ABO-Incompatible Renal Transplantation:  Blood Group A1B Donor Into A2B Recipient With Anti-A1 Isoagglutinins.

PubMed

Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

2016-08-01

Transplantation of the blood group A2B in a recipient was successfully performed in the setting of receiving a deceased donor kidney from an "incompatible" A1B donor. The donor and recipient were both typed for ABO blood group, including ABO genotyping. The donor and recipient were tested for ABO, non-ABO, and human leukocyte antigen (HLA) antibodies. The donor and recipient were typed for HLA antigens, including T- and B-flow cytometry crossmatch tests. The recipient's RBCs were negative with A1 lectin, and immunoglobulin G anti-A1 was demonstrated in the recipient's plasma. The donor-recipient pair was a four-antigen HLA mismatch, but final T- and B-flow cytometry crossmatch tests were compatible. The transplant procedure was uneventful; the patient experienced immediate graft function with no episodes of rejection or readmissions more than 2 years later. It may be safe to transplant across the A1/A2 blood group AB mismatch barrier in the setting of low titer anti-A1 isoagglutinins without the need for pretransplant desensitization even if the antibody produced reacts with anti-human globulin. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Compatibility Conditions of Structural Mechanics

NASA Technical Reports Server (NTRS)

Patnaik, Surya N.; Coroneos, Rula M.; Hopkins, Dale A.

1999-01-01

The theory of elasticity has camouflaged a deficiency in the compatibility formulation since 1860. In structures the ad hoc compatibility conditions through virtual "cuts" and closing "gaps" are not parallel to the strain formulation in elasticity. This deficiency in the compatibility conditions has prevented the development of a direct stress determination method in structures and in elasticity. We have addressed this deficiency and attempted to unify the theory of compatibility. This work has led to the development of the integrated force method for structures and the completed Beltrami-Michell formulation for elasticity. The improved accuracy observed in the solution of numerical examples by the integrated force method can be attributed to the compliance of the compatibility conditions. Using the compatibility conditions allows mapping of variables and facile movement among different structural analysis formulations. This paper reviews and illustrates the requirement of compatibility in structures and in elasticity. It also describes the generation of the conditions and quantifies the benefits of their use. The traditional analysis methods and available solutions (which have been obtained bypassing the missed conditions) should be verified for compliance of the compatibility conditions.

α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice.

PubMed

Uryu, Hidetaka; Hashimoto, Daigo; Kato, Koji; Hayase, Eiko; Matsuoka, Satomi; Ogasawara, Reiki; Takahashi, Shuichiro; Maeda, Yoshinobu; Iwasaki, Hiromi; Miyamoto, Toshihiro; Saijo, Shinobu; Iwakura, Yoichiro; Hill, Geoffrey R; Akashi, Koichi; Teshima, Takanori

2015-05-07

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT. © 2015 by The American Society of Hematology.

Hepatitis C Virus Induces the Mitochondrial Translocation of Parkin and Subsequent Mitophagy

PubMed Central

Kim, Seong-Jun; Syed, Gulam H.; Siddiqui, Aleem

2013-01-01

Hepatitis C Virus (HCV) induces intracellular events that trigger mitochondrial dysfunction and promote host metabolic alterations. Here, we investigated selective autophagic degradation of mitochondria (mitophagy) in HCV-infected cells. HCV infection stimulated Parkin and PINK1 gene expression, induced perinuclear clustering of mitochondria, and promoted mitochondrial translocation of Parkin, an initial event in mitophagy. Liver tissues from chronic HCV patients also exhibited notable levels of Parkin induction. Using multiple strategies involving confocal and electron microscopy, we demonstrated that HCV-infected cells display greater number of mitophagosomes and mitophagolysosomes compared to uninfected cells. HCV-induced mitophagy was evidenced by the colocalization of LC3 puncta with Parkin-associated mitochondria and lysosomes. Ultrastructural analysis by electron microscopy and immunoelectron microscopy also displayed engulfment of damaged mitochondria in double membrane vesicles in HCV-infected cells. The HCV-induced mitophagy occurred irrespective of genotypic differences. Silencing Parkin and PINK1 hindered HCV replication suggesting the functional relevance of mitophagy in HCV propagation. HCV-mediated decline of mitochondrial complex I enzyme activity was rescued by chemical inhibition of mitophagy or by Parkin silencing. Overall our results suggest that HCV induces Parkin-dependent mitophagy, which may have significant contribution in mitochondrial liver injury associated with chronic hepatitis C. PMID:23555273

Donor B cells in Transplants Augment Clonal Expansion and Survival of Pathogenic CD4+ T cells That Mediate Autoimmune-like Chronic GVHD

PubMed Central

Young, James S; Wu, Tao; Chen, Yuhong; Zhao, Dongchang; Liu, Hongjun; Yi, Tangsheng; Johnston, Heather; Racine, Jeremy; Li, Xiaofan; Wang, Audrey; Todorov, Ivan; Zeng, Defu

2013-01-01

We reported that both donor CD4+ T and B cells in transplants were required for induction of an autoimmune-like chronic graft versus host disease (cGVHD) in a murine model of DBA/2 donor to BALB/c recipient, but mechanisms whereby donor B cells augment cGVHD pathogenesis remain unknown. Here, we report that, although donor B cells have little impact on acute GVHD (aGVHD) severity, they play an important role in augmenting the persistence of tissue damage in the acute and chronic GVHD overlapping target organs (i.e. skin and lung); they also markedly augment damage in a prototypical cGVHD target organ- the salivary gland. During cGVHD pathogenesis, donor B cells are activated by donor CD4+ T cells to upregulate MHC II and co-stimulatory molecules. Acting as efficient APCs, donor B cells augment donor CD4+ T clonal expansion, autoreactivity, IL-7Rα expression, and survival. These qualitative changes markedly augment donor CD4+ T cells' capacity in mediating autoimmune-like cGVHD, so that they mediate disease in the absence of donor B cells in secondary recipients. Therefore, a major mechanism whereby donor B cells augment cGVHD is through augmenting the clonal expansion, differentiation and survival of pathogenic CD4+ T cells. PMID:22649197

Risk Factors for Bartonella species Infection in Blood Donors from Southeast Brazil.

PubMed

Diniz, Pedro Paulo Vissotto de Paiva; Velho, Paulo Eduardo Neves Ferreira; Pitassi, Luiza Helena Urso; Drummond, Marina Rovani; Lania, Bruno Grosselli; Barjas-Castro, Maria Lourdes; Sowy, Stanley; Breitschwerdt, Edward B; Scorpio, Diana Gerardi

2016-03-01

Bacteria from the genus Bartonella are emerging blood-borne bacteria, capable of causing long-lasting infection in marine and terrestrial mammals, including humans. Bartonella are generally well adapted to their main host, causing persistent infection without clinical manifestation. However, these organisms may cause severe disease in natural or accidental hosts. In humans, Bartonella species have been detected from sick patients presented with diverse disease manifestations, including cat scratch disease, trench fever, bacillary angiomatosis, endocarditis, polyarthritis, or granulomatous inflammatory disease. However, with the advances in diagnostic methods, subclinical bloodstream infection in humans has been reported, with the potential for transmission through blood transfusion been recently investigated by our group. The objective of this study was to determine the risk factors associated with Bartonella species infection in asymptomatic blood donors presented at a major blood bank in Southeastern Brazil. Five hundred blood donors were randomly enrolled and tested for Bartonella species infection by specialized blood cultured coupled with high-sensitive PCR assays. Epidemiological questionnaires were designed to cover major potential risk factors, such as age, gender, ethnicity, contact with companion animals, livestock, or wild animals, bites from insects or animal, economical status, among other factors. Based on multivariate logistic regression, bloodstream infection with B. henselae or B. clarridgeiae was associated with cat contact (adjusted OR: 3.4, 95% CI: 1.1-9.6) or history of tick bite (adjusted OR: 3.7, 95% CI: 1.3-13.4). These risk factors should be considered during donor screening, as bacteremia by these Bartonella species may not be detected by traditional laboratory screening methods, and it may be transmitted by blood transfusion.

[Blood donor hemovigilance: impact for donor and recipient safety].

PubMed

Hauser, L; Beyloune, A; Simonet, M; Bierling, P

2013-05-01

Since its creation in 1993, hemovigilance has an important place for blood safety. The part concerning donors, as the name suggests, targeted on improvement of donor's safety covers in fact the two points of the transfusion chain with serious adverse events in donor, epidemiologic survey for recipients and post-donation information on the two sides. Organized management and close collaboration between the actors of the transfusion chain are necessary to ensure the effectiveness of the system. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.

PubMed

Sonoda, Junichiro; Laganière, Josée; Mehl, Isaac R; Barish, Grant D; Chong, Ling-Wa; Li, Xiangli; Scheffler, Immo E; Mock, Dennis C; Bataille, Alain R; Robert, Francois; Lee, Chih-Hao; Giguère, Vincent; Evans, Ronald M

2007-08-01

Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.

[Assessment of mitochondrial metabolic oxidative state in living cardiomyocytes with spectrally-resolved fluorescence lifetime spectroscopy of NAD(P)H].

PubMed

Cheng, Ying; Ren, Mingming; Niu, Yanyan; Qiao, Jianhua; Aneba, S; Chorvat, D; Chorvatova, A

2009-12-01

The primary function of cardiac mitochondria is the production of ATP to support heart contraction. Examination of the mitochondrial redox state is therefore crucially important to sensitively detect early signs of mitochondrial function in pathophysiological conditions, such as ischemia, diabetes and heart failure. We study fingerprinting of mitochondrial metabolic oxidative state in living cardiomyocytes with spectrally-resolved fluorescence lifetime spectroscopy of NAD(P)H, the principal electron donor in mitochondrial respiration responsible for vital ATP supply. Here NAD(P)H is studied as a marker for non-invasive fluorescent probing of the mitochondrial function. NAD(P) H fluorescence is recorded in cardiac cells following excitation with 375nm UV-light and detection by spectrally-resolved time-correlated single photon counting (TCSPC), based on the simultaneous measurement of the fluorescence spectra and fluorescence lifetimes. Modulation of NADH production and/or mitochondrial respiration is tested to study dynamic characteristics of NAD(P) H fluorescence decay. Our results show that at least a 3-exponential decay model, with 0.4-0.7ns, 1.2-1.9ns and 8.0-13. Ons lifetime pools is necessary to describe cardiomyocyte autofluorescence (AF) within 420-560nm spectral range. Increased mitochondrial NADH production by ketone bodies enhanced the fluorescence intensity, without significant change in fluorescent lifetimes. Rotenone, the inhibitor of Complex I of the mitochondrial respiratory chain, increased AF intensity and shortened the average fluorescence lifetime. Dinitrophenol (DNP), an uncoupling agent of the mitochondrial oxidative phosphorylation, lowered AF intensity, broadened the spectral shoulder at 520 nm and increased the average fluorescence lifetime. These effects are comparable to the study of NADH fluorescence decay in vitro. In the present contribution we demonstrated that spectrally-resolved fluorescence lifetime technique provides promising new

Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade.

PubMed

Ezzelarab, Mohamed B; Lu, Lien; Shufesky, William F; Morelli, Adrian E; Thomson, Angus W

2018-01-01

Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4 + T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4 + T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4 + CTLA4 hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4 + CTLA4 hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

Method for Controlled Mitochondrial Perturbation during Phosphorus MRS in Children

PubMed Central

Cree-Green, Melanie; Newcomer, Bradley R.; Brown, Mark; Hull, Amber; West, Amy D.; Singel, Debra; Reusch, Jane E.B.; McFann, Kim; Regensteiner, Judith G.; Nadeau, Kristen J.

2014-01-01

Introduction Insulin resistance (IR) is increasingly prevalent in children, and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used 31Phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive technique appealing for clinical research. 31P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly with disease, is problematic due to variability in perception of effort and motivation. We therefore developed a method to predict MVC, using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations. Methods Data were collected from 66 sedentary 12–20 year-olds. Plantar flexion-volitional MVC was assessed using a MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from MRI images. Data from the first 26 participants were utilized to model the relationship between MVC and MCSA (predicted MVC = 24.763+0.0047*MCSA). This model was then applied to the subsequent 40 participants. Results Volitional vs. model-predicted mean MVC was 43.9±0.8 kg vs. 44.2±1.81 (P=0.90). 31P-MRS results when predicted and volitional MVC were similar showed expected changes during volitional MVC-based exercise. In contrast, volitional MVC was markedly lower than predicted in 4 participants, and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations. Conclusions Compared to using MVC testing alone, utilizing MRI to predict muscle strength allows for a more accurate and standardized 31P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youth. These studies have importance as we seek to determine the role of mitochondrial function in youth with IR and diabetes

Quality of life of liver donors following donor hepatectomy.

PubMed

Chandran, Biju; Bharathan, Viju Kumar; Shaji Mathew, Johns; Amma, Binoj Sivasankara Pillai Thankamony; Gopalakrishnan, Unnikrishnan; Balakrishnan, Dinesh; Menon, Ramachandran Narayana; Dhar, Puneet; Vayoth, Sudheer Othiyil; Surendran, Sudhindran

2017-03-01

Although morbidity following living liver donation is well characterized, there is sparse data regarding health-related quality of life (HRQOL) of donors. HRQOL of 200 consecutive live liver donors from 2011-2014 performed at an Indian center were prospectively collected using the SF-36 version 2, 1 year after surgery. The effect of donor demographics, operative details, post-operative complications (Clavien-Dindo and 50-50 criteria), and recipient mortality on the quality-of-life (QOL) scoring was analyzed. Among 200 donors (female/male=141:59), 77 (38.5%) had complications (14.5%, 16.5%, 4.5%, and 3.5%, Clavien-Dindo grades I-IV, respectively). The physical composite score (PCS) of donors 1 year after surgery was less than ideal (48.75±9.5) while the mental composite score (MCS) was good (53.37±6.16). Recipient death was the only factor that showed a statistically significant correlation with both PCS (p<0.001) and MCS (p=0.05). Age above 50 years (p<0.001), increasing body mass index (BMI) (p=0.026), and hospital stay more than 14 days ( p= 0.042) negatively affected the physical scores while emergency surgery (p<0.001) resulted in lower mental scores. Gender, postoperative complications, type of graft, or fulfillment of 50-50 criteria did not influence HRQOL. On asking the hypothetical question whether the donors would be willing to donate again, 99% reiterated there will be no change in their decision. Recipient death, donation in emergency setting, age above 50, higher BMI, and prolonged hospital stay are factors that lead to impaired HRQOL following live liver donation. Despite this, 99% donors did not repent the decision to donate.

Probability of Finding Marrow Unrelated Donor (MUD) for an Indian patient in a Multi-national Human Leukocyte Antigen (HLA) Registry.

PubMed

Tiwari, Aseem K; Bhati-Kushwaha, Himakshi; Kukreja, Pooja; Mishra, Vikash C; Tyagi, Neetu; Sharma, Ashish; Raina, Vimarsh

2015-06-01

With an increase in the number of transplants happening globally, hematopoietic stem cells (HSC) transplantation from matched unrelated donor (MUD) has begun. The increasing trend of MUD transplants across countries has been largely facilitated with the conspicuous growth of volunteer HSC donor noted in the last decade i.e. 8 million HSC donors in 2002 to more than 22 million in 2013 registered in 71 member registries of the Bone Marrow Donor Worldwide (BMDW). Some populations of the world are still very poorly represented in these registries. Since, the chances of successful engraftment and disease free survival are directly proportional to the HLA compatibility between the recipient and the prospective donor, the diversity of the HLA system at the antigenic and allelic level and the heterogeneity of HLA data of the registered donors has a bearing on the probability of finding a volunteer unrelated HSC donor for patients from such populations. In the present study 126 patients were identified suffering from hematological diseases requiring MUD transplant. Their HLA typing was performed and search was done using BMDW database. The search results for these Indian patients in the multinational registry as well as in the Indian Registries were analyzed using mean, range, standard deviation and finally evaluated in terms of probability for finding matched donor (MUD). Total Asian population is only 11 % in the BMDW making it difficult to find a MUD for an Asian patient. The current study supports this, experimentally; revealing that the probability of finding an allele match for an Indian patient in the multinational Human Leukocyte Antigen (HLA) registries is 16 % and a dismal 0.008 % in the Indian registries (donors in Indian registries is just 33,678 as compared to 22.5 million in BMDW). This greatly, emphasizes on enhancing the number of Indian donors in Indian and multi-national registries.