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PubMed2003

The role of electrodiagnostic techniques in the reprogramming of patients with a delayed suboptimal response to sacral nerve stimulation.

Sacral neuromodulation is an approved therapy for frequency, urgency, urge incontinence and non-obstructive urinary retention. There are several recent reports on a subgroup of patients who are 'Iate failures' to therapy. This descriptive study aimed to determine whether the use of electrodiagnosis during reprogramming could provide objective data on device function in these patients and help direct therapy. We employed electrodiagnostic techniques to differentiate between those patients who could be reprogrammed in the office to a site of maximal response, those that required reoperation, and those in whom reoperation was unlikely to be successful. Our findings suggest that electrodiagnostic monitoring may help to direct future therapy in this group of patients who currently present a management challenge.

Action Potentials↗
PubMed1998

The effects of competition and motor reprogramming on visuomotor selection in unilateral neglect.

Patients with unilateral neglect following right hemisphere damage may have difficulty in moving towards contralesional targets. To test the hypothesis that this impairment arises from competing motor programs triggered by irrelevant ipsilesional stimuli, we examined 16 right hemisphere patients, eight with left visual neglect and eight without, in addition to eight healthy control subjects. In experiment 1 subjects performed sequences of movements using their right hand to targets on the contralesional or ipsilesional side of the responding limb. The locations of successive targets in each sequence were either predictable or unpredictable. In separate blocks of trials, targets appeared either alone or with a simultaneous distractor located at the immediately preceding target location. Neglect patients were significantly slower to execute movements to contralesional targets, but only for unpredictable movements and in the presence of a concurrent ipsilesional distractor. In contrast, healthy controls and right hemisphere patients without neglect showed no directional asymmetries of movement execution. In experiment 2 subjects were required to interrupt a predictable, reciprocating sequence of leftward and rightward movements in order to move to an occasional, unpredictable target that occurred either in the direction opposite to that expected, or in the same direction but twice the extent. Neglect patients were significantly slower in reprogramming the direction and extent of movements towards contralesional versus ipsilesional targets, and they also made significantly more errors when executing such movements. Right hemisphere patients without neglect showed a similar bias in reprogramming direction (but not extent) for contralesional targets, whereas healthy controls showed no directional asymmetry in either condition. On the basis of these findings we propose that neglect involves a competitive bias in favour of motor programs for actions directed towards ipsilesional versus contralesional events. We suggest that programming errors and increased latencies for contralesional movements arise because the damaged right hemisphere can no longer effectively inhibit the release of inappropriate motor programs towards ipsilesional events.

Aged↗
PubMed2004

Using a quantitative blueprint to reprogram the dynamics of the flagella gene network.

Detailed understanding and control of biological networks will require a level of description similar to that of electronic engineering blueprints. Currently, however, even the best-studied systems are usually described using qualitative arrow diagrams. A quantitative blueprint requires in vivo measurements of (1) the relative strength of the interactions (numbers on the arrows) and (2) the functions that integrate multiple inputs. Here, we address this using a well-studied system, the flagella biosynthesis transcription network in Escherichia coli. We use theory and high-resolution experiments to obtain a quantitative blueprint with (1) numbers on the arrows, finding different hierarchies of activation coefficients for the two regulators, FlhDC and FliA; and (2) cis-regulatory input functions, which summate the input from the two regulators (SUM gates). We then demonstrate experimentally how this blueprint can be used to reprogram temporal expression patterns in this system, using controlled expression of the regulators or point mutations in their binding sites. The present approach can be used to define blueprints of other gene networks and to quantitatively reprogram their dynamics.

Algorithms↗
PubMed2003

Reprogramming in nuclear transfer.

Reprogramming a nucleus by transferring it to oocyte cytoplasm triggers epigenetic changes that eventually lead to the restoration of a totipotent state and the birth of a viable animal. A simplified way of studying this complex process is to study cell hybrids. These studies suggest that the pluripotent character of one nucleus is dominant over that of the other nucleus. The development of nuclear transfer embryos shows that there are several restriction points and that the extra-embryonic lineages may be the primary source of death. Successful reprogramming depends on the balance between epigenetic modifications and the regulative properties of development.

Animals↗
PubMed2006

Reprogramming of the tumour B-cell phenotype in Hodgkin lymphoma.

Hodgkin and Reed-Sternberg (HRS) cells, the tumour cells in classical Hodgkin lymphoma, derive from mature B cells but have largely lost their B-cell phenotype. This extensive reprogramming is unique among B-cell lymphomas. A recent study by Dörken and colleagues provides an interesting insight into the mechanisms for this reprogramming by demonstrating that the key B-cell-determining transcription factor E2A is inhibited in HRS cells by the deregulated expression of its inhibitors activated B-cell factor (ABF)-1 and inhibitor of differentiation and DNA binding (Id)2.

Cell Differentiation↗
PubMed2004

Transcriptional reprogramming in murine liver defines the physiologic consequences of biliary obstruction.

BACKGROUND/AIMS: While the metabolic and histological responses to cholestasis are recognized, the consequences of impaired biliary flow on liver gene expression are largely undefined. We hypothesized that biliary obstruction results in transcriptional reprogramming that dictates the physiologic response. METHODS: We determined global gene expression in murine livers 1-21 days following bile duct ligation. Total hepatic cRNA from experimental and sham mice was hybridized to Affymetrix gene chips. Gene expression data was analyzed by GeneSpring software and validated by Northern analysis. RESULTS: We found 92 genes over-expressed > or =2-fold at one or more time points following bile duct ligation. Functional classification of these genes revealed the activation of three main biological processes in a sequential and time-restricted fashion. At day 1, genes involved in sterol metabolism were uniquely over-expressed, including HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. This was followed by an increased expression of growth-promoting genes at day 7, the time point coinciding with peak cholangiocyte proliferation. In later phases (days 14-21), the liver over-expressed genes encoding structural proteins and proteases. CONCLUSIONS: Transcriptional reprogramming in the liver following biliary obstruction favors the activation of genes regulating metabolism, cell proliferation, and matrix remodeling in a time-restricted and sequential fashion.

Animals↗
PubMed2006

Self-paced and reprogrammed saccades: differences between melancholic and non-melancholic depression.

Motor disturbances in major depressive disorder (MDD) are increasingly recognized and may differentiate melancholic, from non-melancholic depression. Motor impairments in melancholic depression have been likened to Parkinson's disease and proposed to have a frontostriatal basis. This study investigated self-pacing and reprogramming skills, thought to rely on frontostriatal functioning, in groups of healthy individuals (n=15), non-melancholic depression patients (n=10) and melancholic depression patients (n=9) using ocular motor tasks. Self-paced saccades were requested to be performed at a rhythm of 1 Hz between two continuously illuminated targets, before and after external cueing. Saccade reprogramming, for direction and amplitude, was explored using a saccadic "oddball" task. Results indicated no group differences for accuracy, intersaccadic intervals (during the self-paced task), latency or peak velocity. However, the melancholic group showed greater intrasubject variability of latencies than the control group, lower peak saccade velocities compared to the non-melancholic group, and reduced accuracy of the primary saccade when compared to the control and the non-melancholic groups. These findings provide further support for distinct motor impairments associated with melancholia that may reflect frontostriatal abnormalities.

Adult↗
PubMed2026

Next-generation macrophage engineering in cancer therapy: From TAM reprogramming to CAR-macrophages.

Macrophages are central regulators of the tumor microenvironment (TME), shaping immune suppression, angiogenesis, metabolism, and therapeutic resistance in solid cancers. While early strategies sought to deplete tumor-associated macrophages (TAMs) or block monocyte recruitment, limited efficacy and compensatory mechanisms revealed the need for functional reprogramming rather than elimination. Recent advances in viral vectors, CRISPR-Cas genome editing, and RNA-based delivery platforms have enabled precise genetic modification of macrophages, giving rise to chimeric antigen receptor macrophages (CAR-Ms) and related engineered products. Beyond antigen targeting, effective macrophage engineering requires stabilization of pro-inflammatory identity, resistance to tumor-induced repolarization, metabolic reinforcement, and integration of checkpoint modulation pathways. This review synthesizes current strategies across DNA, mRNA, and siRNA-based platforms, highlighting convergent design principles that connect TAM reprogramming with CAR-M development. We discuss reshaping phagocytosis checkpoints, metabolic and transcriptional stabilization, cytokine augmentation, and synthetic receptor architecture, emphasizing combinatorial and context-aware engineering, while proposing new candidate gene targets. Engineered macrophages are thus evolving from simple effector cells into programmable immune coordinators capable of converting immunologically "cold" tumors into inflamed, therapy-responsive niches.

CAR-M↗
PubMed2006

AOX--a functional marker for efficient cell reprogramming under stress?

Functional markers for stress tolerance can be used in plant breeding to identify genotypes with high yield stabilities under various conditions. Thus, a good marker should show a strong correlation with favourable adaptive plant behaviour. The efficient reprogramming of target cells for yield determination is currently considered to be the most important step towards defining abiotic stress tolerance. In this Opinion article, we propose a role for the alternative oxidase (AOX) gene as a marker for genetic variation in cell reprogramming and yield stability. Evidence to support this idea comes from the metabolic role of alternative respiration under stress, the link between AOX activity and differential growth, and the single nucleotide polymorphism recently observed in AOX genes. We propose an innovative, interdisciplinary and global research strategy for future experimentation on AOX genes that could have an application in plant breeding.

Arabidopsis Proteins↗
PubMed2005

Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice.

Induction of mouse germ cells occurs from the proximal epiblast at around embryonic day (E) 7.0. These germ cells then migrate to, and enter the gonads at about E10.5 after which they undergo epigenetic reprogramming including erasure of parental imprints. However, the epigenetic properties acquired by nascent germ cells and the potential remodeling of these epigenetic marks in the subsequent migratory period have been largely unexplored. Here we have used immunohistochemistry to examine several genome-wide epigenetic modifications occurring in germ cells from their specification to their colonization of the genital ridges. We show that at around E8.0, germ cells concomitantly and significantly reduce H3-K9 dimethylation and DNA methylation, two major repressive modifications for gene expression. These events are preceded by the transient loss of all the DNA methyltransferases from their nuclei. By contrast, germ cells substantially increase the levels of H3-K27 trimethylation, another repressive modification with more plasticity, at E8.5-9.0 and maintain this state until at least E12.5. H3-K4 methylation and H3-K9 acetylation, modifications associated with transcriptionally permissive/active chromatin, are similar in germ and surrounding somatic cells but germ cells transiently increase these marks sharply upon their entry into the genital ridge. H3-K9 trimethylation, a hallmark of centromeric heterochromatin, is kept relatively constant during the periods examined. We suggest that this orderly and extensive epigenetic reprogramming in premigratory and migratory germ cells might be necessary for their reacquisition of underlying totipotency, for subsequent specific epigenetic remodeling, including the resetting of parental imprints, and for the production of gametes with an appropriate epigenotype for supporting normal development.

Animals↗
PubMed2006

Genome restructuring in mouse embryos during reprogramming and early development.

Although a growing number of studies investigates functional genome organization in somatic cell nuclei, it is largely unknown how mammalian genome organization is established during embryogenesis. To address this question, we investigated chromo center formation and the peculiar arrangements of chromosome domains in early mouse embryos. At the one-cell stage, we observed characteristic arrangements of chromosomes and chromo center components. Subsequently, starting with the burst of zygotic genome transcription major rearrangements led to the establishment of somatic type chromo centers with a defined spatio-temporal organization. These processes appeared to be completed at the blastocyst stage with the onset of cell differentiation. During the same developmental period, a fraction of pericentric heterochromatin that was late replicating in the first cycle underwent switches in replication timing, spatial organization and epigenetic marks. Cloning experiments revealed that the genome organization typical for more advanced stages was quickly reverted into the one-cell stage-specific form after nuclear transfer, supporting the idea that reprogramming associated genome remodeling in normal and cloned embryos is determined by cytoplasmic factors. Together, the results suggest that distinct but characteristic forms of nuclear genome organization are required for genome reprogramming in early embryos and for proper regulation of differential gene expression patterns at later stages.

Animals↗
PubMed2005

Long-term in vitro, cell-type-specific genome-wide reprogramming of gene expression.

We demonstrate a cell extract-based, genome-wide and heritable reprogramming of gene expression in vitro. Kidney epithelial 293T cells have previously been shown to take on T cell properties following a brief treatment with an extract of Jurkat T cells. We show here that 293T cells exposed for 1 h to a Jurkat cell extract undergo genome-wide, target cell-type-specific and long-lasting transcriptional changes. Microarray analyses indicate that on any given week after extract treatment, approximately 2500 genes are upregulated >3-fold, of which approximately 900 are also expressed in Jurkat cells. Concomitantly, approximately 1500 genes are downregulated or repressed, of which approximately 500 are also downregulated in Jurkat cells. Gene expression changes persist for over 30 passages ( approximately 80 population doublings) in culture. Target cell-type specificity of these changes is shown by the lack of activation or repression of Jurkat-specific genes by extracts of 293T cells or carcinoma cells. Quantitative RT-PCR analysis confirms the long-term transcriptional activation of genes involved in key T cell functions. Additionally, growth of cells in suspended aggregates, expression of CD3 and CD28 T cell surface markers, and interleukin-2 secretion by 293T cells treated with extract of adult peripheral blood T cells illustrate a functional nuclear reprogramming. Therefore, target cell-type-specific and heritable changes in gene expression, and alterations in cell function, can be promoted by extracts derived from transformed cells as well as from adult primary cells.

Adult↗
PubMed2002

Reprogramming of vascular smooth muscle alpha-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant.

OBJECTIVE: Chronic rejection in cardiac allografts depletes vascular smooth muscle (VSM) alpha-actin from the coronary arterial smooth muscle bed while promoting its abnormal accumulation in cardiomyocytes and myofibroblasts. The objective was to determine if the newly discovered TEF1, MSY1, Puralpha and Purbeta VSM alpha-actin transcriptional reprogramming proteins (TRPs) were associated with development of chronic rejection histopathology in accepted murine cardiac allografts. METHODS: A mouse heterotopic cardiac transplant model was employed using H2 locus-mismatched mouse strains (DBA/2 or FVB/N to C57BL/6). Recipients were immunosuppressed to promote long-term allograft acceptance and emergence of chronic rejection. Explanted grafts and isolated heart cells were evaluated for changes in the DNA-binding activity and subcellular distribution of VSM alpha-actin transcriptional regulatory proteins. RESULTS: The DNA-binding activity of all four TRPs was high in the developing mouse ventricle, minimal in adult donor hearts and increased substantially within 30 days after transplantation. Immunohistologic analysis revealed nuclear localization of Purbeta and MSY1 particularly in fibrotic areas of the allograft myocardium demonstrating extravascular accumulation of VSM alpha-actin. Cardiomyocytes isolated from adult, non-transplanted mouse hearts not only exhibited less VSM alpha-actin expression and lower levels of TRPs compared to isolated cardiac fibroblasts or neonatal cardiomyocytes, but also contained a novel size variant of the MSY1 protein. CONCLUSION: Accumulation of TRPs in cardiac allografts, particularly within the fibroblast-enriched myocardial interstitium, was consistent with their potential role in VSM alpha-actin gene reprogramming, fibrosis and dysfunctional remodeling following transplant. These nuclear protein markers could help stage peri-transplant cellular events that precede formation of graft-destructive fibrosis and coronary vasculopathy during chronic rejection.

Actins↗
PubMed1987

[Reprogramming of a pacemaker induced by electrocautery].

A case is reported of reprogramming of a ventricular unipolar permanent pacemaker induced by electrocautery during biliary surgery. After skin incision and use of the unipolar electrosurgery unit, the CPI model 505 multiprogrammable pulse generator previously set at 70 b X min-1 abruptly fired at 120 b X min-1. Application of a magnet over the pacemaker reduced the heart rate to 100 b X min-1. After surgery, the pulse generator was successfully reprogrammed to a rate of 65 b X min-1. Based on the analysis of this case and of previous reports, it is suggested, so as to avoid such complications, that the unipolar electrocautery be avoided when the surgical field is near the pulse generator or lead: that the bipolar electrocautery be preferred; that a magnet and non-invasive programmer be available during and after surgery; and that a postoperative assessment of the pulse generator be carried out.

Aged↗
PubMed2006

On the way to reprogramming cells to pluripotency using cell-free extracts.

The functional reprogramming of a differentiated cell to pluripotency may present beneficial applications in regenerative medicine. Somatic cell nuclear transfer may offer this possibility, but technical hurdles and ethical guidelines currently prevent application of this technology in several countries. As a result, alternative approaches are being developed for altering cell fate. Recent non-nuclear transfer-based approaches for reprogramming somatic cells are discussed as well as ways to enhance their differentiation potential. These approaches include the fusion of differentiated cells with embryonic stem cells and the use of extract from pluripotent cells to reprogramme differentiated cells into multipotent or pluripotent cells.

Animals↗
PubMed2002

Chromatin modification and epigenetic reprogramming in mammalian development.

The developmental programme of embryogenesis is controlled by both genetic and epigenetic mechanisms. An emerging theme from recent studies is that the regulation of higher-order chromatin structures by DNA methylation and histone modification is crucial for genome reprogramming during early embryogenesis and gametogenesis, and for tissue-specific gene expression and global gene silencing. Disruptions to chromatin modification can lead to the dysregulation of developmental processes, such as X-chromosome inactivation and genomic imprinting, and to various diseases. Understanding the process of epigenetic reprogramming in development is important for studies of cloning and the clinical application of stem-cell therapy.

Animals↗
PubMed2026

Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

Animals↗
PubMed2003

Epigenetic reprogramming in mammalian nuclear transfer.

With the exception of lymphocytes, the various cell types in a higher multicellular organism have basically an identical genotype but are functionally and morphologically different. This is due to tissue-specific, temporal, and spatial gene expression patterns which are controlled by genetic and epigenetic mechanisms. Successful cloning of mammals by transfer of nuclei from differentiated tissues into enucleated oocytes demonstrates that these genetic and epigenetic programs can be largely reversed and that cellular totipotency can be restored. Although these experiments indicate an enormous plasticity of nuclei from differentiated tissues, somatic cloning is a rather inefficient and unpredictable process, and a plethora of anomalies have been described in cloned embryos, fetuses, and offspring. Accumulating evidence indicates that incomplete or inappropriate epigenetic reprogramming of donor nuclei is likely to be the primary cause of failures in nuclear transfer. In this review, we discuss the roles of various epigenetic mechanisms, including DNA methylation, chromatin remodeling, imprinting, X chromosome inactivation, telomere maintenance, and epigenetic inheritance in normal embryonic development and in the observed abnormalities in clones from different species. Nuclear transfer represents an invaluable tool to experimentally address fundamental questions related to epigenetic reprogramming. Understanding the dynamics and mechanisms underlying epigenetic control will help us solve problems inherent in nuclear transfer technology and enable many applications, including the modulation of cellular plasticity for human cell therapies.

Animals↗