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Results for “reprogramming”

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PubMed1986

Nuclear transplantation in the mouse: heritable differences between parental genomes after activation of the embryonic genome.

Paternal and maternal genomes apparently have complementary roles during embryogenesis in the mouse, and both are essential for development to term. However, there is no direct evidence to show that functional differences between parental genomes remain intact after activation of the embryonic genome at the 2-cell stage. In this study we demonstrate that transfer of paternal or maternal nuclei from early haploid preimplantation embryos back to fertilized eggs from which one pronucleus was removed resulted in development to term, but only if the remaining pronucleus was of the parental type opposite to the donor nucleus. Hence, functional differences between parental chromosomes are heritable and they survive activation of the embryonic genome and probable reprogramming of donor embryonic nuclei by epigenetic factors in the egg cytoplasm.

Animals↗

PubMed1992

Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture.

Steel factor (SF) and LIF (leukemia inhibitory factor) synergistically promote the proliferation and survival of mouse primordial germ cells (PGCs), but only for a limited time period in culture. We show here that addition of bFGF to cultures in the presence of membrane-associated SF and LIF enhances the growth of PGCs and allows their continued proliferation beyond the time when they normally stop dividing in vivo. They form colonies of densely packed, alkaline phosphatase-positive, SSEA-1-positive cells resembling undifferentiated embryonic stem (ES) cells in morphology. These cultures can be maintained on feeder layers for at least 20 passages, and under appropriate conditions give rise to embryoid bodies and to multiple differentiated cell phenotypes in monolayer culture and in tumors in nude mice. PGC-derived ES cells can also contribute to chimeras when injected into host blastocysts. The long-term culture of PGCs and their reprogramming to pluripotential ES cells has important implications for germ cell biology and the induction of teratocarcinomas.

Alkaline Phosphatase↗

PubMed1994

Specification of a single cell type by a Drosophila homeotic gene.

Homeotic genes function in blocks of cells along the body axis to specify diverse developmental pathways. Among the Drosophila homeotic genes, only one is known to be expressed in the endoderm. We show here that expression of this gene, labial (lab), coincides with copper cells, highly specialized cells of the larval midgut. lab is strictly required for copper cell formation, a requirement that starts in the embryo and extends through larval stages. This implies a function of lab not only in the determination and differentiation of copper cells, but also in the maintenance of their differentiated state. Ectopic expression of lab during embryogenesis reprograms other midgut cells within and outside the lab domain to become copper cell-like. Thus, lab functions in the larval midgut to specify a single cell type.

Animals↗

PubMed1993

Assessment of cytoplasmic effects on the development of mouse embryonic nuclei transferred to enucleated zygotes.

In this study, cytoplasmic effects on the development of nuclear transplant embryos were examined. In addition, the production of offspring from nuclear transplant embryos was attempted. Nuclei from cleavage-stage embryos were transplanted to enucleated zygotes at different cell cycle stages and with different cytoplasmic volumes. A greater developmental rate to the blastocyst stage was observed in reconstituted late stage zygotes that received nuclei from late 2-cell stage embryos than in early stage zygotes (46.3% vs. 16.9%). A further increase in developmental rate to the blastocyst stage (85.5%) and in cell number was obtained in reconstituted late stage zygotes with reduced cytoplasmic volume. However, developmental potential of nuclei from 4- and 8-cell stage embryos was very limited, although they were transferred to enucleated late stage zygotes with reduced cytoplasm. After the transfer of blastocysts derived from nuclear transplant embryos to recipient females, live young were obtained from reconstituted embryos that received nuclei from late 2-cell stage embryos (28.6%). These results confirm that the development of nuclear transplant embryos can be affected by recipient cell cycle stage and cytoplasmic volume. Furthermore, the nuclei from late 2-cell stage embryos in which activation of the embryonic genome had occurred can be reprogrammed to a certain extent when transplanted into enucleated zygotes, especially late stage zygotes with reduced cytoplasmic content.

Journal Article↗

PubMed1995

Genetic engineering of hybridoma glutamine metabolism.

The murine hybridoma PQXB1/2 cannot be adapted to grow in culture media containing < 0.5 mM glutamine. Transformants selected following electroporation of PQXB1/2 cells with vectors containing a Chinese hamster glutamine synthetase (GS) cDNA under the control of the SV40 early promoter also failed to grow in the absence of glutamine in the culture medium. PQXB1/2 cells have, however, been transformed to glutamine independence following electroporation with a vector containing this glutamine synthetase cDNA under the control of the human cytomegalovirus immediate early promoter. In these cells, sufficient active glutamine synthetase was expressed from one vector per cell to enable growth in glutamine-free media. The specific activity of glutamine synthetase in two transformed cell lines producing parental levels of antibody was increased by 128 and 152%, respectively (0.57 and 0.63 mumol min-1 per 10(6) cells in transformants compared with parental levels of 0.25 mumol min-1 per 10(6) cells). This reprogramming of glutamine synthetase expression and glutamine metabolism is important for developing strategies to deal with ammonia toxicity and the production of cell lines with improved metabolic processes.

Animals↗

PubMed1995

The effects of 5-azacytidine and 5-azadeoxycytidine on chromosome structure and function: implications for methylation-associated cellular processes.

5-Azacytidine (5-aza-C) analogs demonstrate a remarkable ability to induce heritable changes in gene and phenotypic expression. These cellular processes are associated with the demethylation of specific DNA sequences. On the other hand, 5-aza-C analogs have dramatic effects on chromosomes, leading to decondensation of chromatin structure, chromosomal instability and an advance in replication timing. Condensation inhibition of genetically inactive chromatin occurs when the DNA is still hemimethylated or fully methylated. In cell cultures prolonged for several replication cycles, chromosomal rearrangements and instability affect the 5-aza-C-sensitive regions. Moreover, the normally late-replicating inactive chromatin undergoes a transient temporal shift to an earlier DNA replication, characteristic of activatable chromatin. zThe induced alterations of chromosome structure and behavior may trigger the 5-aza-C-dependent process of cellular reprogramming. Apart from their differentiating and gene-modifying effects, 5-aza-C analogs can tumorigenically transform cells and modulate their metastatic potential. High doses of 5-aza-C analogs have cytotoxic and antineoplastic activities.

Animals↗

PubMed1988

Data recording and playback on video tape--a multi-channel analog interface for a digital audio processor system.

The design of an analog interface to a digital audio signal processor (DASP)-video cassette recorder (VCR) system is described. The complete system represents a low-cost alternative to both FM instrumentation tape recorders and multi-channel chart recorders. The interface or DASP input-output unit described in this paper enables the recording and playback of up to 12 analog channels with a maximum of 12 bit resolution and a bandwidth of 2 kHz per channel. Internal control and timing in the recording component of the interface is performed using ROMs which can be reprogrammed to suit different analog-to-digital converter hardware. Improvement in the bandwidth specifications is possible by connecting channels in parallel. A parallel 16 bit data output port is provided for direct transfer of the digitized data to a computer.

Electrocardiography↗

PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short course of CD4/CD8 monoclonal antibody can be used to guide the immune system of experimental animals to accept organ grafts and to arrest autoimmunity. This reprogramming, reviewed by Herman Waldmann and Stephen Cobbold, is accompanied by potent T-cell dependent, 'infectious' regulatory mechanisms. A goal for therapeutic immunosuppression should be to understand and harness these innate immunoregulatory mechanisms.

Animals↗

PubMed1992

Myopotential inhibition of unipolar demand pacemakers: utility of provocative manoeuvres in assessment and management.

Fifty patients with permanent unipolar pacemakers (48 multiprogrammable, 2 non programmable) with protective insulating sheath placed against the muscular side of the pacemaker pocket were studied to determine the occurrence of inhibition of pacing by sensing of the myopotentials. All the patients were subjected to a combination of different provocative manoeuvres at their nominal R wave sensitivity settings. Myopotential inhibition was exhibited in 35 (70%) patients. Only 3 patients however had reported symptoms suggesting loss of pacing. The most useful provocative manoeuvre was shoulder flexion with adduction against resistance (94.3% positivity). Appropriate sensitivity adjustments resulted in amelioration of the problem in 86% of the patients while still retaining R wave sensing. Myopotential interference continues to be a frequently observed problem even in the present generation of unipolar pacemakers. Provocative tests and appropriate reprogramming should be done in all such patients as a routine.

Action Potentials↗

PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short courses of CD4/CD8 monoclonal antibody can be used to guide the immune system of experimental animals to accept organ grafts and to arrest autoimmunity. This reprogramming is accompanied by potent T-cell dependent, 'infectious' regulatory mechanisms. A goal for therapeutic immunosuppression should be to understand and harness these innate immunoregulatory mechanisms.

Animals↗

PubMed1994

Heterochronic genes and the temporal control of C. elegans development.

The heterochronic genes of Caenorhabditis elegans encode part of a regulatory system that controls the temporal component of cell fates in development. The genes have been characterized genetically and molecularly, and their study has so far revealed a genetic hierarchy that specifies sequences of developmental events, a novel RNA-mediated mechanism of gene regulation and a reprogramming phenomenon associated with arrested development.

Animals↗

PubMed1992

Exemplary data: sample size and power in the design of event-time clinical trials.

In planning a complex clinical trial with time to event as the outcome, it is difficult to derive the power of the test statistic analytically. In this paper we describe an algorithm for generating exemplary data from an alternative hypothesis that can be used to compute the expected value of a logrank test statistic and its power under that alternative. Exemplary data are nonrandomly computer-generated data that are constructed from a complex stochastic process and have desirable characteristics such as distributional moments similar to those of the process. An algorithm for generating exemplary timed events data is presented and its use in evaluating power for the planning of clinical trials demonstrated. These data represent "expectations" of outcome, data censoring, and censoring event times. A test statistic, z, such as the logrank can be computed from the data. It is distributed asymptotically, N(mu A, 1), under the alternative hypothesis and its value is used to estimate mu A and the power of the test for a given trial scenario. The results compare favorably to results from analytical methods and Monte Carlo simulations published in the literature. The advantages of the method lie in the degree of flexibility in study design, choice of models that describe the timing of events, and the range of testing methods that can be used. Although Monte Carlo methods may appear to have similar flexibility, the exemplary algorithm is more practical because only one data set need be analyzed and the modifications can be achieved without reprogramming.

Algorithms↗

PubMed1993

Oral administration of insulin in winter-acclimatized carp (Cyprinus carpio) induces hepatic ultrastructural changes.

1. The intestinal absorption of insulin in carps was assessed examining the transepithelial passage of ingested gold-labeled hormone by electron microscopy. Insulin transfer occurred mainly through the intercellular spaces between the enterocytes. 2. When reaching the lamina propria, the gold-labeled hormone gathered predominantly around the granules of the granular cells, and therefore can enter the circulatory system via the blood capillaries which are found in close contact with these cells. 3. Winter-acclimatized carp were also capable of internalizing the hormone when fed with insulin. 4. Furthermore, the absorbed hormone revealed full activity in regard to the observed changes in the ultrastructure of the liver cells of the treated cold-adapted fish. 5. The fish ingesting the hormone underwent the same type of hepatic ultrastructure reprogramming observed when winter-acclimatized carps are injected intraperitoneally with insulin, i.e. conversion to a phenotype corresponding to hepatocytes from summer-adapted carp. 6. The oral absorption of insulin by winter-acclimatized fish and its effect in reversing the cold-adaptive state might be useful for the fish culturing industry.

Acclimatization↗

PubMed1993

Observations on the treatment of autochthonous tumors in mice with an enterovirus and cyclophosphamide.

Significant remissions in autochthonous mammary tumors in A/Strong mice were effected in 45% of treated animals with a vaccine prepared with an enterovirus plus cyclophosphamide. Three methods of vaccine preparation were examined. Only one was effective although all three contained viable viruses. The data are consistent with the interpretation that the effective vaccine stimulated the host reticuloendothelial (RE) system differentially so that partial destruction with cyclophosphamide resulted in the reprograming of the RE system in favor of host control.

Animals↗

PubMed1986

The nature of the scrapie agent.

There now seems little doubt that the infective agent of scrapie cannot be accommodated within current concepts of virology/molecular biology. It is proposed: that the basic infective entity is a nucleic acid fragment (oligonucleotide) of some 40 bp coupled with specific (but host encoded) protein totalling approximately 10(5) daltons, a significant proportion of which is in the form of proteolipid; that the nucleic acid fragment reprograms the host cell on the chemically switched microprocessor network analogy already proposed; that the nucleic acid fragment has no initiation sequence for replication: it is therefore non-infective; that the nucleic acid fragment can replicate when associated with the specific protein component because the resulting complex is able to displace mobile genetic element flanking sequences (similar to the yeast delta sequence). The function of the protein is to provide a scaffolding which allows the nucleic acid fragment to be assimilated into the replication cycle of the mobile genetic element as a whole.

Animals↗

PubMed1987

Successful selection for increased longevity in Drosophila: analysis of the survival data and presentation of a hypothesis on the genetic regulation of longevity.

Long lived strains of Drosophila melanogaster have been generated via 25 generations of artificial selection. The mean and the maximum lifespans have been increased both absolutely as well as relative to the controls. The mean lifespan of the selected line now exceeds the maximum lifespan of the controls. The data shows that this increase is entirely accounted for by a genetically based delay in the onset of senescence. Identification and analysis of biomarker data involving reproductive functions supports this interpretation and leads to a suggestion of the processes involved in the lifespan extension. This increase in the duration of the pre-senescent period is under both genetic and environmental control. Senescence itself is not under genetic control and appears to occur stochastically. Selection for decreased longevity was unsuccessful, supporting the concept of a minimum species specific lifespan. A testable hypothesis regarding the biphasic mode of gene regulation of senescence is presented in which a gene-environment interaction takes place in larval life that results in a temporal reprogramming of other, presumably structural, genes which act in adult life at a time prior to the onset of senescence.

Aging↗

PubMed1990

Clinical interactions between pacemakers and automatic implantable cardioverter-defibrillators.

Concomitant use of a pacemaker and an automatic implantable cardioverter-defibrillator (AICD) is common. Seventeen percent of patients receiving an AICD at The Johns Hopkins Hospital also had a permanent pacemaker implanted before (16 patients), at the same time as (2 patients) or after (12 patients) AICD implantation. Four types of interactions were noted: 1) transient failure to sense or capture immediately after AICD discharge (seven patients); 2) oversensing of the pacemaker stimulus by the AICD, leading to double counting (one patient); 3) AICD failure to sense ventricular fibrillation resulting from pacemaker stimulus oversensing (three patients, one only at high asynchronous output); and 4) pacemaker reprogramming caused by AICD discharge (three patients). No clinical sequelae of these interactions were noted during follow-up study. Thus, potentially adverse clinical interactions are common and routine screening is recommended. With proper attention to lead placements and programming of the devices, clinical consequences of these interactions can be avoided.

Anti-Arrhythmia Agents↗

PubMed1994

Underdetection of ventricular tachycardia by algorithms to enhance specificity in a tiered-therapy cardioverter-defibrillator.

OBJECTIVES: The goal of this study was to determine the incidence and clinical significance of underdetection in 125 patients treated with a tiered-therapy cardioverter-defibrillator, the Medtronic PCD. BACKGROUND: Underdetection, distinct from undersensing, is a unique, potential complication of new algorithms that enhance specificity in tiered-therapy cardioverter-defibrillators. These algorithms may delay or prevent recognition of ventricular tachycardia even though electrograms are sensed accurately and RR intervals meet the programmed interval criterion. METHODS: Underdetection was defined as delay in detection > 5 s at electrophysiologic study or symptomatic delay or detection failure at follow-up of 15 +/- 8 months. RESULTS: We identified six specific mechanisms of underdetection caused by algorithms to discriminate sustained ventricular tachycardia from sinus tachycardia, atrial fibrillation, ventricular fibrillation and nonsustained ventricular tachycardia. Underdetection caused detection delays in 13 (1.9%) of 677 induced ventricular tachyarrhythmia episodes in 12 patients (9.6%). During follow-up, underdetection occurred in 7 (9.9%) of 71 patients in whom ventricular tachycardia therapies were programmed. Failure to detect ventricular tachycardia occurred in 6 (0.6%) of 988 spontaneous ventricular tachycardia episodes in four patients (5.6%); 2 episodes required external cardioversion. After defibrillator reprogramming, underdetection did not occur. CONCLUSIONS: Algorithms to enhance specificity cause underdetection of ventricular tachycardia in a significant minority of patients with tiered-therapy cardioverter-defibrillators. Optimal programming can minimize underdetection.

Algorithms↗