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PubMed1994

Long-term stability of P wave sensing in single lead VDDR pacing: clinical versus subclinical atrial undersensing.

Optimal function of a single lead P wave synchronous rate adaptive ventricular pacing system (VDDR) requires reliable P wave sensing over time and during daily activities. The stability of P wave sensing and the incidence of sensitivity reprogramming in a single pass lead with a diagonally arranged bipole was assessed in 30 patients with complete atrioventricular block over a follow-up period of 12 +/- 1 months (range 6 months to 3 years). Atrial sensing was assessed during clinic visits, by physical maneuvers (postural changes, breathing, Valsalva maneuver, walking and isometric exercise), maximum treadmill exercise and Holter recordings. P wave amplitude at implantation was 1.21 +/- 0.09 (0.5-3.6) mV, and the atrial sensing threshold remained stable over the entire period of follow-up. Using an atrial sensitivity based on twice the sensing threshold at 1 month, P wave undersensing was found in 2, 4, 3, and 7 patients during clinic visit, physical maneuvers, exercise, and Holter recordings, respectively. Atrial sensitivity reprogramming was performed in three patients based on the correction of undersensing during physical maneuvers. Although eight patients had atrial undersensing on Holter recordings, the number of undersensed P waves was small (total 101 beats or 0.013% +/- 0.001% of total ventricular beats) and no patient was symptomatic. One patient had intermittent atrial undersensing at the highest sensitivity, but the VDDR mode was still functional most of the time. No patient had myopotential interference at the programmed sensitivity. One patient developed chronic atrial fibrillation and was programmed to the VVIR mode. Thus, single lead VDDR pacing is a stable pacing mode in 97% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1996

Low-dose lipopolysaccharide (LPS) pretreatment of mouse macrophages modulates LPS-dependent interleukin-6 production in vitro.

Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Our laboratory previously reported that LPS-dependent macrophage-derived tumor necrosis factor alpha (TNF-alpha) production could be significantly potentiated by pretreatment with LPS at substimulatory LPS priming doses. The observed potentiation was shown to be coincident with a down-regulation of LPS-dependent nitric oxide (NO) production (X. Zhang and D. C. Morrison, J. Exp. Med. 177: 511-516, 1993). In order to determine whether these LPS reprogramming effects in mouse macrophages were selective for these two macrophage-derived mediators, we have examined the effects of LPS pretreatment on LPS-dependent interleukin 6 (IL-6) production. Thioglycolate-elicited mouse peritoneal macrophages were pretreated with various subthreshold stimulatory concentrations of LPS for 6 h, washed three times, and then stimulated with an effective stimulatory concentration of smooth LPS for 18 h. In confirmation of earlier studies, pretreatment of mouse macrophages with substimulatory doses of LPS inhibited the subsequent LPS-dependent NO production. This down-regulation was accompanied by a coordinate up-regulation of LPS-dependent IL-6 production, similar to what was shown earlier for TNF-alpha production. These priming effects with the substimulatory dose of smooth LPS are shown to be independent of doses of LPS used for subsequent activation and are not restricted to specific LPS stimulation. Moreover, the enhancement of the IL-6 response by LPS pretreatment is still observed in the presence of neutralizing antibody to TNF-alpha. These findings, therefore, provide further support for the conclusion that LPS-dependent macrophage reprogramming is likely to involve common regulatory pathways that control the secretion of both IL-6 and TNF-alpha.

Animals↗

PubMed1995

Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems.

OBJECTIVE: To evaluate the incidence of intraoperative and early postoperative complications (up to two months after implant) of endocardial permanent pacemaker insertion in all patients under-going a first implant at a referral centre. METHODS: Prospective evaluation of all endocardial pacemaker implantation procedures performed from April 1992 to January 1994 carried out by completion of standard audit form at implant. Patients' demographic data, medical history, details of pacemaker hardware used, and any complications were noted. Follow up information was also collected prospectively onto standard forms at pacemaker outpatient clinic. SETTING: United Kingdom tertiary referral cardiothoracic centre. PATIENTS: 1088 consecutive patients underwent implantation of their first endocardial permanent pacemaker from April 1992 to January 1994. Implant and follow up data were available for 1059 (97.3%) patients at analysis. The median (range) age was 77 years (16-99); 51.2 % were male. RESULTS: Dual chamber units were implanted in 54.1% of patients, single chamber atrial in 5.2%, and ventricular in 40.7%. A temporary pacing lead was present at implant in 22.9% of patients. Most (93.6%) implants were performed via the subclavian vein. Immediate complications were rare: eight (0.8%) patients developed pneumothorax requiring medical treatment and 11 (1.0%) an insignificant pneumothorax. There was no significant difference in the pneumothorax rate for dual chamber (DDD) compared with single chamber systems. Arterial puncture without sequelae was documented in 2.7% of attempts at subclavian vein cannulation. A total of 35 patients (3.3%) required reoperation; the reoperation rate for dual chamber (3.5%) was similar to that for single chamber (3.1%) systems. Electrode displacement (n = 15, 1.4%) was the most common reason for reoperation. Atrial lead displacement (n = 10, 1.6% of atrial leads) was significantly more common than ventricular lead displacement (n = 5, 0.5% of ventricular leads, P = 0.047). There was no difference in electrode displacement rates for dual (1.6%) compared with single (1.2%) chamber systems. Pacemaker pocket infection led to reoperation in 10 patients (six dual, four single chamber, P = not significant) and was significantly more common in patients who had a temporary pacing lead in place at implant (2.9%) than in those who did not (0.4%, P = 0.0014). Five patients (0.5%) required reoperation for generator erosion (two dual, three single chamber, P = not significant). and a further five for drainage of haematoma or a serous fluid collection (three dual, two single chamber, P = not significant). Complications that did not require reoperation were also rare. Undersensing occurred in 10 patients (0.9%). Atrial undersensing (n = 8) was significantly more common than ventricular undersensing (n = 2, P = 0.017). All patients were successfully treated by reprogramming of sensitivity. Superficial wound infection was treated successfully with antibiotics in nine patients (six dual, three single chamber, P = not significant). Three patients with DDD generators developed sustained atrial fibrillation: two required reprogramming to VVI mode and one required cardioversion. CONCLUSIONS: Permanent pacing in a large tertiary referral centre with experienced operators carries a low risk. Infection rates are low, < 1% overall but significantly higher in patients who undergo temporary pacing before implantation. Lead displacement and undersensing are more likely to occur with atrial than ventricular leads. The overall complication rate for dual chamber pacing, however, is no higher than for single chamber pacing.

Adolescent↗

PubMed1993

Coding of movement direction and amplitude in Parkinson's disease: are they differentially impaired (or unimportant)?

A recent study suggested that the preparation of movement direction, but not amplitude, may be selectively impaired by Parkinson's disease (PD). The authors examined the reprogramming of direction only, amplitude only, and direction and amplitude together, and included a control condition in which neither parameter was reprogrammed. The findings suggested that neither direction nor amplitude coding was differentially impaired in PD. Thus the structures affected by PD may not be uniquely involved in specifying only the direction or the amplitude of future movements; these structures probably have more complex higher-level roles.

Aged↗

PubMed2025

Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.

UNLABELLED: Parkin (PRKN) is a mitochondria-associated E3 ubiquitin ligase that mediates mitophagy and organelle quality control. More recently, PRKN has been implicated in stimulating antitumor immunity and reprogramming the tumor immune microenvironment. In this study, we showed that PRKN ubiquitinates the alarmin molecule, high-mobility group box-1 (HMGB1) on Lys146 (K146) using predominantly K48 linkages. By molecular modeling, the in-between-ring domain of PRKN (Gln326-Leu358) made extensive contacts with the amino-terminus A-box of HMGB1 (Met1-Ser42), forming a mitochondria-associated PRKN-HMGB1 complex that juxtaposes K146 to ubiquitin active site residues Gly76 and Arg74. Instead of proteasomal degradation, PRKN ubiquitination of K146 enabled the loading of HMGB1 but not HMGB1 K146A mutant, onto autophagy- and mitochondria-derived large extracellular vesicles (LEV). In turn, released PRKN-HMGB1-LEV stimulated a potent IFN and cytokine response in recipient cells, expanding CD8+ T-cell subsets with effector (CD69+/KLRG1+), self-renewal (TCF1+/PD-1+), and cytotoxic (KLRG1+/GrzB+) properties. Conditional expression of PRKN induced HMGB1 release, activated intratumoral CD8+ T cells, and suppressed syngeneic tumor growth in vivo in a response that was abolished by HMGB1 silencing. These data identify that PRKN-LEV-regulated release of HMGB1 reprograms antitumor immunity via stimulation of IFN signaling and expansion of specialized CD8+ T-cell subsets. SIGNIFICANCE: Parkin ubiquitinates the alarmin molecule HMGB1 to enable its regulated release in large extracellular vesicles that activate interferon signaling, expand specialized CD8+ T-cell subsets, and promote antitumor immunity.

HMGB1 Protein↗

PubMed2026

Machine Learning and Metabolomics to Characterize Warburg-Like Metabolic Subtypes in Human Retinal Endothelial Cells Exposed to Risk Factors Associated With Proliferative Diabetic Retinopathy.

PURPOSE: High glucose (HG), hypoxia (Hyp), and their combination are major risk factors for proliferative diabetic retinopathy (PDR). Although these conditions induce features of the Warburg-like metabolic reprogramming in human retinal endothelial cells (HRECs), it remains unclear whether they produce distinct metabolic and angiogenic subtypes. This study aimed to characterize the Warburg-like-associated metabolic heterogeneity induced by these PDR-related risk factors and evaluate the ability of supervised machine-learning models to distinguish these subtypes. METHODS: HRECs were cultured under normoglycemic, HG, Hyp (2% O2), and combined HG-Hyp conditions. Untargeted LC-MS/MS metabolomics quantified metabolites spanning carbohydrates, amino acids, nucleotides, and lipids. Principal component analysis (PCA) assessed overall metabolic variation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified metabolic pathways associated with angiogenesis. In vitro angiogenesis assays measured endothelial tube formation and branching. Nine supervised classifiers (decision tree, logistic regression, naïve Bayes, random forest, K-Nearest Neighbors, neural network, gradient boosting, AdaBoost, and Support Vector Machine) were trained on the highest-ranked metabolites selected by the Information Gain Ratio feature-ranking approach. Model performance was evaluated using 10-fold cross-validation, leave-one-out cross-validation (LOOCV), permutation testing, and a classifier stability analysis under biologically meaningful distributional shift using an independent chemically induced hypoxia model (CoCl2). RESULTS: PCA revealed partial separation of metabolic profiles across conditions, indicating different Warburg-like metabolic subtypes. The combined HG-Hyp condition exhibited enhanced angiogenic potential relative to either HG or Hyp alone. KEGG pathway enrichment analysis identified fatty acid biosynthesis and elongation among the most significantly enriched pathways in HRECs under combined HG-Hyp conditions, alongside amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, the pentose phosphate pathway, and glycolysis/gluconeogenesis. Supervised machine-learning classifiers distinguished these metabolic subtypes, with AdaBoost and gradient Boosting showing the most balanced, reproducible performance across 10-fold cross-validation, LOOCV, and permutation testing, and remaining the most reliable classifiers under domain-shift testing (area under the curve = 0.88, P = 0.0061). CONCLUSIONS: In this exploratory analysis, HG, Hyp, and their combination drive metabolically and functionally distinct subtypes of Warburg-like metabolic reprogramming in HRECs, with HG-Hyp in combination producing a highly angiogenic phenotype. Boosting-based ensemble classifiers provide a promising framework for detecting these subtypes even under domain-shift conditions, warranting validation in larger independent datasets. TRANSLATIONAL RELEVANCE: Integrating metabolomics with machine-learning classification offers a strategy to identify Warburg-like metabolic subtypes in retinal endothelial cells, providing insights into angiogenic mechanisms and guiding the development of targeted diagnostics or therapeutics for PDR.

Humans↗

PubMed2024

TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.

Humans↗

PubMed1994

Benefits of rate-responsive pacing in patients with sick sinus syndrome.

The effect of changing a rate-responsive pacemaker program (which reacts to evoked QT interval) to fixed-rate ventricular pacing was studied in 10 patients with sick sinus syndrome (SSS). After the patients had been in the rate-responsive mode (VVIR) for at least one year, the exercise capacity (maximal oxygen consumption [peak VO2], anaerobic threshold [AT], and cardiac output [CO] at these points) was examined. Three hours later on the same day, the pacemaker was reprogrammed to the fixed-rate pacing (VVI) and the exercise capacity was examined again (VVI-S). One month later, a similar exercise test was also done in the VVI mode (VVI-L). There was no significant difference in peak VO2 and AT between VVIR and VVI-S, but both peak VO2 and AT were significantly lower in VVI-L than in VVIR. However, there were no significant differences in the CO at peak VO2 or AT between any of the pacing modes. These findings indicate that a VVIR pacemaker should not be reprogrammed to the VVI mode in SSS patients, because the change can cause the exercise capacity to deteriorate.

Aged↗

PubMed2025

Transposition element MERVL regulates DNA demethylation through TET3 in oxidative-damaged mouse preimplantation embryos.

Transposable elements (TEs) comprise approximately half of eukaryotic genomes and significantly contribute to genome plasticity. In this study, we focused on a specific TE, MERVL, which exhibits particular expression during the 2-cell stage and commonly serves as an indicator of embryonic totipotency. However, its precise role in embryo development remains mysterious. We utilized DRUG-seq to investigate the effects of oxidative damage on genes and TEs expression. Our findings revealed that exposure to hydrogen peroxide (H2O2) could induce DNA damage, apoptosis, and incomplete DNA demethylation in embryos, which were potentially associated with MERVL expression. To further explore its function, antisense nucleotides (ASO) targeting MERVL were constructed to knockdown the expression in early embryos. Notably, this knockdown led to the occurrence of DNA damage and apoptosis as early as the 2-cell stage, consequently reducing the number of embryos that could progress to the blastocyst stage. Moreover, we discovered that MERVL exerted an influence on the reprogramming of embryonic DNA methylation. In MERVL-deficient embryos, the activity of the DNA demethylase ten-eleven translocation 3 (TET3) was suppressed, resulting in impaired demethylation when compared to normal development. This impairment might underpin the mechanism that impacts embryonic development. Collectively, our study not only verified the crucial role of MERVL in embryonic development but also probed its regulatory function in DNA methylation reprogramming, thereby laying a solid foundation for further investigations into MERVL's role.

Animals↗

PubMed2025

Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions.

Upon infection, human papillomavirus (HPV) manipulates host cell gene expression to create an environment that is supportive of a productive and persistent infection. The virus-induced changes to the host cell's transcriptome are thought to contribute to carcinogenesis. Here, we show by RNA-sequencing that oncogenic HPV18 episome replication in primary human foreskin keratinocytes (HFKs) drives host transcriptional changes that are consistent between multiple HFK donors. We have previously shown that HPV18 recruits the host protein CTCF to viral episomes to control the differentiation-dependent viral transcriptional programme. Since CTCF is an important regulator of host cell transcription via coordination of epigenetic boundaries and long-range chromosomal interactions, we hypothesised that HPV18 may also manipulate CTCF to contribute to host transcription reprogramming. Analysis of CTCF binding in the host cell genome by ChIP-Seq revealed that while the total number of CTCF binding sites is not altered by the virus, there are a sub-set of CTCF binding sites that are either enriched or depleted of CTCF. Many of these altered sites are clustered within regulatory elements of differentially expressed genes, including the tumour suppressor gene cell adhesion molecule 1 (CADM1), which supresses epithelial cell growth and invasion. We show that HPV18 establishment results in reduced CTCF binding at the CADM1 promoter and upstream enhancer. Loss of CTCF binding is coincident with epigenetic repression of CADM1, in the absence of CpG hypermethylation, while adjacent genes including the transcriptional regulator ZBTB16 are activated. These data indicate that the CADM1 locus is subject to topological rearrangement following HPV18 establishment. We tested this hypothesis using 4C-Seq (circular chromosome confirmation capture-sequencing) and show that HPV18 establishment causes a loss of long-range chromosomal interactions between the CADM1 transcriptional start site and the upstream transcriptional enhancer. These data show that HPV18 manipulates host cell promoter-enhancer interactions to drive transcriptional reprogramming that may contribute to HPV-induced disease progression.

Humans↗

PubMed2026

Lipid Metabolism-related lncRNA Model Identifies AC026412.3 as a Driver of Fatty Acid β-oxidation in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Dysregulated lipid metabolism contributes to hepatocellular carcinoma (HCC) progression, but the prognostic value and mechanistic roles of lipid metabolism-related long noncoding RNAs (LRLs) remain insufficiently characterized. This study aimed to construct and validate an LRL-based prognostic model and to investigate the biological function and metabolic mechanism of AC026412.3 in HCC. METHODS: Transcriptomic and clinical data from the The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort were analyzed to identify LRLs based on their correlation with curated lipid metabolism genes. Differential expression, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a prognostic signature, which was evaluated using Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) analyses. Functional enrichment analyses Gene Ontology [GO], Kyoto Encyclopedia of Genes and Genomes [KEGG] and gene set enrichment analysis [GSEA], mutation profiling, tumor mutational burden, immune infiltration estimation, and consensus clustering were applied to characterize associated features. A key LRL was identified through integrated bioinformatic screening and prioritization. Its biological role was assessed by quantitative reverse transcription polymerase chain reactionq (RT-PCR), western blotting, BODIPY staining, colony formation, Transwell assays, and xenograft models. RNA sequencing followed by pathway enrichment analysis was conducted to explore underlying mechanisms. RESULTS: A three-LRL signature (AL031985.3, NRAV, and AC026412.3) stratified HCC patients into distinct risk groups with significantly different survival outcomes and demonstrated independent prognostic value. AC026412.3 was markedly upregulated in HCC and associated with poor prognosis. Functional assays demonstrated that AC026412.3 promoted proliferation, invasion, and tumor growth while reducing lipid accumulation. Mechanistically, AC026412.3 upregulated solute carrier family 22 member 5 (SLC22A5), enhanced fatty acid β-oxidation, and increased adenosine triphosphate (ATP) production, thereby driving metabolic reprogramming. CONCLUSIONS: This study establishes a robust LRL-based prognostic model and identifies AC026412.3 as a key regulator of lipid metabolic reprogramming via the SLC22A5-fatty acid β-oxidation axis, highlighting its potential as a biomarker and therapeutic target in HCC.

HCC↗

PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗

PubMed2026

Molecular mechanisms underlying drug resistance in protozoan parasites: emerging mechanisms and therapeutic perspectives.

Protozoan parasitic infections, including malaria, leishmaniasis, and human African trypanosomiasis, remain major global public health challenges. In the absence of highly effective vaccines, disease control relies primarily on chemotherapy; however, the emergence and spread of drug-resistant parasite populations increasingly threaten treatment efficacy. This review synthesizes current evidence on the molecular mechanisms underlying drug resistance in Plasmodium, Leishmania, and Trypanosoma species through a systematic analysis of literature. The review identifies four interconnected mechanisms that drive the evolution of drug resistance. First, altered drug transport enables parasites to regulate intracellular drug concentrations through mutations, loss, or amplification of membrane transporters, including PfCRT in Plasmodium and AQP2 in Trypanosoma brucei. Second, target modification and genomic plasticity promote resistance through point mutations in drug targets, such as dhfr and dhps in Plasmodium, while kinetoplastids, particularly Leishmania, exploit extensive genomic plasticity, including aneuploidy, gene amplification, and translational reprogramming, to facilitate rapid adaptation under drug pressure. Third, metabolic reprogramming enhances parasite survival by increasing intracellular thiol production, strengthening antioxidant defense systems, and reshaping central carbon and lipid metabolism to mitigate drug-induced stress. Finally, stress response and persistence mechanisms enable subpopulations of parasites to enter dormant, persister-like states characterized by reduced metabolic activity and slowed proliferation, thereby evading both host immune responses and chemotherapeutic agents. Collectively, these findings demonstrate that drug resistance is a dynamic, multifactorial evolutionary process rather than a single molecular event. Addressing this growing challenge requires integrating genomic surveillance, molecular diagnostics, mathematical modeling of resistance transmission, and mechanistic insights into parasite persistence into future drug discovery and disease control strategies. Such an integrated approach is essential for improving the durability of antiprotozoal therapies and advancing global efforts to control neglected protozoan diseases.

antiprotozoal therapy↗

PubMed2026

Exogenous ABA enhances cold tolerance of Rhododendron yedoense var. poukhanense under subzero temperature: integrating physiology, transcriptome, and proteome.

Low temperature limits the growth and ornamental value of evergreen shrubs. Rhododendron yedoense var. poukhanense, an important ornamental shrub from Northeast China, frequently suffers freezing damage during winter. While exogenous abscisic acid (ABA) enhances cold tolerance in many plants, its molecular mechanisms at subzero temperatures remain poorly understood in non-model species lacking chromosome-level reference genomes. This study investigated the effects of exogenous ABA on freezing tolerance in R. yedoense var. poukhanense at -4 °C using an integrated physiological, transcriptomic, and proteomic approach. Cutting seedlings were subjected to four treatments: CK (22°C control), A (22°C + ABA), LT (-4°C), and ALT (-4°C + ABA). Photosynthetic pigments, osmotic regulation substances, antioxidant enzyme activities, and malondialdehyde (MDA) content were measured. Transcriptome sequencing and quantitative proteomics were performed, and transcriptome data were validated by quantitative real-time PCR (qRT-PCR) of 15 selected genes. ABA pretreatment reduced visible cold injury severity, partially preserved photosynthetic pigments, decreased MDA content by 28.7%, and promoted recovery of catalase (+43.6%), superoxide dismutase (+31.1%), and peroxidase (+20.0%) activities under freezing stress. Transcriptome analysis revealed 8, 444 differentially expressed genes (DEGs) in LT versus CK and 6, 481 DEGs in ALT versus CK, representing a 23% reduction in transcriptional reprogramming scope attributable to ABA priming. The ALT versus LT comparison identified only 1, 690 additional DEGs, indicating that most cold-responsive genes were pre-activated during the ABA priming phase. Proteome analysis identified 1, 461 differentially expressed proteins (DEPs) in ALT versus CK. Integrated analysis revealed extensive post-transcriptional regulation, with transcript-protein concordance of only 1.0-4.1%, and co-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in both omics layers. qRT-PCR validation confirmed high reliability of the transcriptome data (R2 = 0.8500). These findings demonstrate that exogenous ABA enhances freezing tolerance through multi-layered molecular regulation encompassing transcriptional buffering, translational reprogramming, and functional reallocation from photosynthesis to stress protection. This study provides the first integrated physiology-transcriptome-proteome framework for ABA-mediated freezing tolerance in an evergreen ornamental shrub and offers theoretical support for ABA-based winter protection strategies.

Rhododendron yedoense var. Poukhanense↗

PubMed1991

[Hazards of radiotherapy in the presence of a cardiac pacemaker].

A patient with cardiac pacing operated for cancer of the breast received subsequent radiotherapy, first with a linear accelerator, then with a betatron. The pacemaker was found deprogrammed as a sequel to irradiation although care was taken to keep it outside the irradiation field. After reprogramming the pacemaker changed a second time spontaneously the given parameters indicating permanent damage by the irradiation. In such cases the exchange of the pacemaker is recommended. Precautionary measures ranging from surveillance to possibilities for reprogramming and even reanimation or pacemaker replacement should be assured prior to irradiation of patients with cardiac pacing.

Breast Neoplasms↗

PubMed1990

Nuclear protein modifications in vitellogenic rooster liver.

The estrogenic regulation of vitellogenesis in chicken liver provides an unique perspective on cellular reprogramming because males can be induced experimentally. Transient exposure to estradiol (ES) completely alters established patterns of gene expression in rooster hepatocytes within 6 hrs., and triggers major structural and compositional changes in cell nuclei by 24 hrs. Concurrently, the total protein content of nuclei increases nearly 50% and the relative proportion of protein within the nucleoplasmic, chromatin and residual compartments, shifts markedly. These bulk quantitative changes in nuclear composition are accompanied by marked alterations in 2-D electrophoretic patterns of cytoplasmic, nuclear and nuclear matrix polypeptides. Although most individual proteins remain unidentified, several components clearly overlap both the cytoplasmic and nuclear compartments. Reciprocal changes in the 2-D patterns are also evident after ES stimulation, with progressive decline in some and relative increase in other proteins. Among known species, the lamins (La and Lb) decrease in prominence after hormone, while RNP-associated polypeptides become increasingly pronounced in the residual matrix fraction. The results are discussed in relation to other systems where large-scale nuclear reprogramming is known to occur.

Animals↗

PubMed1990

Cardiac pacemaker inhibition by transcutaneous electrical nerve stimulation.

The use of transcutaneous electrical nerve stimulation (TENS) has increased in recent years for the management of chronic pain. One of its few contraindications is the presence of a cardiac pacemaker. Clinicians have recommended that cardiac monitoring be performed for a short interrupted period during the first application of TENS to ensure safety. We present two patients who were given trials of TENS for different chronic pain complaints. In both cases, electrocardiograms during the TENS trial did not reveal cardiac pacemaker dysfunction, but extended cardiac monitoring with the Holter monitor showed interference with pacemaker function. The abnormalities did not recur after reprogramming the sensitivity of the pacemakers. We suggest the use of extended cardiac monitoring for patients with cardiac pacemakers during the prolonged use of TENS to ensure safety and to determine any need for reprogramming of the pacemakers. Patients with cardiac pacemakers should not be excluded from the use of TENS, but careful evaluation and extended cardiac monitoring should be performed.

Aged↗

PubMed1985

[Reevaluation of pacemaker-induced reentry tachycardias: incidence, mechanisms and therapy].

To reassess incidence, mechanisms and therapeutic possibilities in the treatment of pacemaker-induced reentry tachycardias (RT) in patients with the second generation of DDD-pacemakers, 35 consecutive patients were studied prospectively by measuring VA conduction at implant and searching for RT clinically and by repeat 24-hour ECG monitoring. Reprogramming to the VVI mode because of atrial flutter and to the AAI mode because of lead displacement was necessary in 2 and 1 of the patients respectively. RT were detected in 7/32 patients (22%), 4 of whom were symptomatic. The triggering mechanism of RT was premature ventricular contraction in 4 patients, premature atrial contractions in 1, loss of atrial sensing in 1, and remained unclear in 1. Unlike the 30% of patients of an earlier consecutive series with first generation of physiologic PM who had RT and required permanent reprogramming to VVI stimulation in 10% of cases, RT was abolished in all patients maintaining physiologic pacing by prolonging the atrial refractory period, shortening the av delay, adjusting atrial output or atrial sensing, or by antiarrhythmic therapy.

Aged↗