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PubMed2026

Biocontrol efficacy of Bacillus albus SSR3 for controlling postharvest fungal pathogens and mycotoxin contamination.

Sweetpotato black rot, caused by Ceratocystis fimbriata, is a major postharvest disease that leads to substantial storage losses worldwide. In this study, a salt-tolerant rhizobacterial strain, Bacillus albus SSR3, was isolated from the rhizosphere of sweetpotato grown in saline-alkali soil, with broad-spectrum antagonistic activity against postharvest fungal pathogens. LC-MS/MS analysis revealed diverse bioactive metabolites associated with its antifungal activity. Integrated transcriptomic and metabolomic analyses showed that SSR3 bioactive metabolites extensively reprogrammed fungal metabolism, particularly pathways involved in carbohydrate and amino acid metabolism, antioxidant defense, and energy production. These alterations were accompanied by disruption of cell wall and membrane integrity, excessive reactive oxygen species accumulation, and mitochondrial dysfunction, ultimately inhibiting fungal growth. Here, we also found that SSR3 bioactive metabolites effectively inhibited aflatoxin B1 production by Aspergillus flavus and deoxynivalenol accumulation in Fusarium graminearum. In vivo assays further demonstrated that SSR3 bioactive metabolites significantly reduced sweetpotato black rot severity and effectively limited fungal colonization and mycotoxin contamination in stored agricultural commodities. Collectively, our findings demonstrate that B. albus SSR3 suppresses postharvest fungal pathogens through coordinated metabolic reprogramming, oxidative stress induction, and cellular integrity disruption, highlighting its potential as a sustainable biocontrol agent for postharvest disease management.

Bacillus albus↗

PubMed2026

Multi-omics and spatial transcriptomics reveal that S100A10 drives CD8+ T-cell exhaustion and immune evasion in hepatocellular carcinoma through cPLA2-5-LOX-mediated arachidonic acid metabolism and ferroptosis.

Immune evasion in hepatocellular carcinoma (HCC) represents a major biological barrier limiting the efficacy of immunotherapy, yet its molecular basis remains incompletely understood. Increasing evidence indicates that tumor metabolic reprogramming and ferroptosis-related signaling play critical roles in shaping an immunosuppressive tumor microenvironment (TME); however, the specific regulatory factors involved remain unclear. This study aims to systematically elucidate the functional role of S100 calcium-binding protein A10 (S100A10) in immune evasion in HCC, with a particular focus on the molecular mechanisms by which S100A10 regulates CD8+ T-cell exhaustion through arachidonic acid (AA) metabolism and ferroptosis, as well as its potential therapeutic implications. To this end, data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort are integrated to analyze the expression patterns of S100A10, its prognostic value, and its association with the immune microenvironment. S100A10 overexpression and knockout models are established in HCCLM3 and MHCC97L cell lines, and S100A10-mediated metabolic pathway reprogramming is characterized using transcriptomic profiling, untargeted metabolomics, and ferroptosis-related functional assays. In parallel, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics are employed to delineate the cell-type specificity and spatial distribution of S100A10. Furthermore, human CD8+ T-cell co-culture systems and orthotopic mouse HCC models are used to evaluate the impact of S100A10 on immune function and responsiveness to anti-programmed cell death protein 1 (anti-PD-1) therapy. The results demonstrate that S100A10 is significantly upregulated in HCC and is closely associated with poor prognosis and an immunosuppressive state. Mechanistically, S100A10 activates cytosolic phospholipase A2-arachidonate 5-lipoxygenase (cPLA2-5-LOX)-mediated AA oxidative metabolism, leading to the accumulation of lipid peroxidation products and ferroptosis-associated signals, thereby driving CD8+ T-cell exhaustion and promoting immune evasion. Significantly, inhibition of S100A10 reshapes the tumor immune microenvironment (TIME) and enhances the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify S100A10 as a critical regulator of metabolic-immune coupling in HCC and provide a theoretical basis for combinatorial strategies targeting metabolism and immunotherapy.

Arachidonic acid metabolism↗

PubMed2025

Ischemic Injury Drives Nascent Tumor Growth Via Accelerated Hematopoietic Aging.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease and cancer, but their contributions to cardiovascular disease-driven tumor progression are unclear. OBJECTIVES: This study sought to study tumor growth after peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes cancer. METHODS: Mammary cancer (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and assay for transposase-accessible chromatin sequencing of bone marrow progenitors was performed to assess the distinct and synergistic transcriptomic and epigenetic changes of cancer and peripheral ischemia. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. RESULTS: Peripheral ischemia increased monocyte and neutrophil output at the expense of lymphocytes, driven by a shift toward CD150hi myeloid-biased hematopoietic stem cells. This was associated with accelerated cancer growth and enrichment of tumors with myeloid cells (monocytes, macrophages, neutrophils) and regulatory T cells. Increased myelopoiesis was also supported by sequencing analyses showing HLI and tumor-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated neogenin-1, thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. CONCLUSIONS: Peripheral ischemia enhances inflammaging of hematopoietic stem cells and long-lasting alterations to antitumoral immunity, accelerating breast tumor growth.

bone marrow transplantation↗

PubMed2025

Natural, safety immunomodulatory derivatives of lactobacillus biofilms promote diabetic wound healing by metabolically regulating macrophage phenotype and alleviating local inflammation.

INTRODUCTION: Long-term inflammatory microenvironment further impairs the healing process of diabetic wounds. Many studies have shown that Lactobacillus can regulate immune function and promote injured tissue repair. However, the immunomodulatory function and safety of Lactobacillus biofilm (LB) on wounds need further investigation. OBJECTIVES: In this present research, we proposed a "bacteria-free biofilm derivative therapy" and successfully extracted Lactobacillus biofilm derivatives (LBDs) by ultrasonic separation and filtration technology for the natural and safe treatment of diabetic wounds. METHODS: The study first cultured Lactobacillus anaerobically and extracted LBDs using ultrasound separation combined with filtration technology. LBDs were characterized via scanning electron microscopy, Concanavalin A fluorescence staining, and protein gel electrophoresis. In vivo diabetic wound model, wound closure rates were dynamically monitored, and tissue sections were analyzed using hematoxylin-eosin and immunofluorescence staining to evaluate LBDs' healing effects. An in vitro macrophage inflammation model was established, employing immunofluorescence, flow cytometry, and Western blotting techniques to explore the molecular mechanisms underlying LBDs' effects on macrophage phenotypes. Furthermore, whole-genome sequencing and proteomics of LBDs-treated macrophages were performed to further elucidate the intrinsic molecular mechanisms through which LBDs regulate macrophage phenotypes. RESULTS: LBDs were effectively extracted utilizing ultrasonic separation coupled with filtration technology. Studies revealed that LBDs modulate the systemic metabolic reprogramming in wound-site macrophages, suppress JAK-STAT1 signaling pathway, alleviate the local inflammatory microenvironment, promote neovascularization and ultimately accelerate wound healing. CONCLUSION: The LBDs retains most bioactive components of the LB. As a natural, safe and immunomodulatory agent, LBDs promote diabetic wound healing by metabolically reprogramming macrophage phenotypes and improving the local immune microenvironment, offering promising potential for regenerative applications in diabetic wound management.

Wound Healing↗

PubMed2026

Dynamic effects of short-term storage temperature and duration on the transcriptome and functional pathways of umbilical cord blood-derived NK cells.

OBJECTIVE: This study aims to elucidate the dynamic impact of different storage conditions (temperature and time) on the function of natural killer (NK) cells derived from umbilical cord blood (UCB) at the transcriptome level, providing a theoretical basis for optimizing the standardized post-collection processing protocol of UCB in clinical settings. METHODS: Four healthy full-term UCB samples were collected and assigned to a fresh control group (0H) and experimental groups stored at 4 °C (4C) or 25 °C (RT) for 24 h (24H) and 72 h (72H). Umbilical cord blood mononuclear cells (CBMCs) were isolated and expanded in vitro to derive NK cells. Using RNA sequencing (RNA-seq) technology, combined with principal component analysis (PCA), screening of differentially expressed genes (DEGs), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the effects of storage conditions on the transcriptome of NK cells were comprehensively analyzed. RESULTS: The results indicated that storage time was the primary factor causing transcriptomic differences. Compared to the 0H group, storage for 24 h induced a limited number of Differentially Expressed Genes (DEGs) (only 11 in the 24H-RT group), indicating overall transcriptome stability. In contrast, storage for 72 h triggered profound transcriptomic reprogramming, with DEGs significantly enriched in immune activation-related pathways. Specifically, at the 72-h time point, storage at 4 °C compared to 25 °C prevented the downregulation of key metabolic pathways such as 'response to decreased oxygen levels' and 'regulation of leukocyte cell-cell adhesion'. CONCLUSION: CBMC-derived NK cells can tolerate up to 24 h of ex vivo storage while maintaining transcriptome and core functional stability. However, extending the ex vivo storage period to 72 h leads to significant reprogramming in the expression of immune and metabolism-related genes. Notably, the degree of metabolic suppression under refrigerated conditions at 4 °C was less pronounced than that at 25 °C room temperature storage. This study recommends that the ex vivo storage time of UCB should ideally be limited to within 24 h, with room temperature storage being a viable option. If prolonged storage is necessary, refrigeration at 4 °C is advised.

Humans↗

PubMed2026

Proteomic and phosphoproteomic profiles of time-dependent dynamic changes in LPS-induced macrophage polarization.

The temporal proteomic and phosphoproteomic reprogramming during early M1 macrophage polarization (0-6 h) remains poorly understood. We performed time-resolved proteomic and phosphoproteomic analyses of LPS-stimulated RAW264.7 macrophages at seven time points within 6 h. Time-clustering of differentially expressed molecules revealed two patterns: initial change with partial recovery, and sustained dysregulation. Upregulated proteins and phosphorylation sites were enriched in the Rho GTPase signaling pathway, T-cell receptor signaling pathway, NF-κB cascade, osteoclast differentiation pathway, and antiviral immune pathway. Downregulated pathways were associated with cell cycle regulation, chromatin remodeling, RNA metabolism, and mRNA processing, indicating resource reallocation to prioritize acute inflammatory responses. Kinase-substrate network analysis confirmed the mitogen-activated protein kinase (MAPK), cyclin-dependent kinase (CDK), protein kinase B (AKT), and ribosomal S6 kinase (RSK) families as core upstream phosphorylation regulators. Integrated analysis revealed synergistic and antagonistic relationships between proteomic and phosphoproteomic changes. This study provides a temporal molecular atlas of M1 polarization, delineating inflammatory signaling dynamics and offering a basis for therapeutic target discovery in inflammatory diseases. SIGNIFICANCE: Macrophage M1 polarization is a central event in innate immune defense against pathogenic invasion, yet its dysregulation is a pivotal driver of the onset and progression of a broad spectrum of inflammation-associated disorders, spanning autoimmune diseases, infectious conditions and inflammatory bone diseases, making the dissection of its molecular regulatory mechanisms an urgent research priority in immunology and translational medicine. Dynamic molecular events within 0-6 h after LPS stimulation are critical for initiating and shaping M1 inflammatory activation, yet systematic time-resolved proteomic and phosphoproteomic profiling remains insufficient.In this study, we comprehensively characterized temporal proteome and phosphoproteome changes at seven consecutive time points during macrophage polarization, clarified two distinct dynamic molecular patterns, identified core signaling pathways and key kinase regulators involved in inflammatory reprogramming, and uncovered the leading role of post-translational phosphorylation modifications in initiating polarization. This work delineates the time-series molecular atlas of early macrophage activation, provides novel insights into the temporal regulatory mechanism of inflammatory signaling networks, and lays a solid experimental foundation for exploring new intervention targets and regulatory nodes in clinical translational research.

Lipopolysaccharides↗

PubMed2026

Molecular mechanisms of natural de novo shoot organogenesis and their applications.

Natural de novo shoot organogenesis (DNSO) is the spontaneous regeneration of shoots from wound sites outside the shoot apical region through endogenous developmental programs. This regenerative capacity enables plants to recover from severe tissue damage by re-establishing the shoot-root axis. Here, we review current knowledge about the molecular mechanisms of natural DNSO, focusing on transcriptomic and physiological studies in model plants. Accumulating evidence suggests that natural DNSO proceeds through three sequential phases: (i) early wound responses, characterized by the activation of the WIND1-ESR1 module and the establishment of apical-basal auxin asymmetry; (ii) cellular proliferation driven by metabolic and cell-cycle reprogramming; and (iii) cytokinin-mediated establishment of shoot apical meristem identity. We also discuss how these mechanistic insights have been harnessed for practical applications, including tissue culture-free transformation systems such as the cut-dip-budding (CDB) method, and developmental reprogramming strategies that employ ectopic expression of developmental regulator (DR) genes to induce DNSO in otherwise recalcitrant species. Together, these advances illustrate how understanding natural regeneration can guide the development of simplified, broadly applicable plant transformation technologies.

Plant Shoots↗

PubMed2026

Paternal exposure to polystyrene nanoplastics induces inter- and transgenerational bronchopulmonary dysplasia-like damage in male offspring by FtMt hypermethylation-mediated ferroptosis.

Bronchopulmonary dysplasia (BPD) is a major cause of chronic lung disease in both preterm infants and adults, but its etiology remains incompletely understood. In this study, F0 generation mice were exposed to polystyrene nanoplastics (PS-NPs), and F1 to F3 generations were obtained by breeding. Multi-omics sequencing including whole genome methylation sequencing, single cell transcriptome sequencing and transcriptome sequencing was performed on the lungs of offspring. The levels of Fe2+, lipid peroxidation products and key gene expression were determined. Male mice exposed to PS-NPs at environmentally relevant doses produced offspring (F1 and F2) that exhibited a typical BPD-like phenotype. Meanwhile, the F0 males showed diminished sperm motility, demonstrating that paternal PS-NPs exposure constituted an etiological factor for BPD in descendants. Mechanistic studies showed that PS-NPs exposure upregulated the expression of DNA methyltransferase Dnmt3a, leading to global hypermethylation of the sperm genome. Importantly, the hypermethylated promoter signature of the mitochondrial ferritin (FtMt) gene partially resisted epigenetic reprogramming and was transmitted to the lungs of offspring, resulting in persistently low FtMt expression in F1 and F2 lungs. This led to increased intracellular Fe2+ levels, subsequently triggered ferroptosis in alveolar epithelial cells, and ultimately impaired alveolarization. Knockdown of FtMt confirmed that FtMt deficiency was sufficient to induce ferroptosis and BPD-like lung injury both in vitro and in vivo. Furthermore, using in vitro fertilization of F0 sperm combined with Dnmt3a siRNA microinjection, we directly demonstrated that Dnmt3a is a key driver for FtMt to escape reprogramming and maintain its hypermethylation. In summary, this study reveals for the first time that paternal PS-NPs exposure causes BPD through a Dnmt3a-FtMt hypermethylation intergenerational and transgenerational axis, providing an epigenetic basis for understanding paternal derived chronic lung disease and potential targets for early intervention.

Animals↗

PubMed2026

Establishment of a human induced pluripotent stem cell line, KMUGMCi011-A, from a patient bearing a frameshift mutation in the KMT2D gene leading Kabuki syndrome 1.

Kabuki syndrome 1 is a rare genetic disorder typically characterized by facial abnormalities, cognitive impairment, developmental delay and organ dysfunction. It is caused by a loss-of-function mutation in the KMT2D gene. The peripheral blood mononuclear cells from a patient carrying frameshift mutation in the KMT2D gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. This frameshift mutation results in a truncated protein. This established human induced pluripotent cell line will allow proper in vitro disease modelling of Kabuki syndrome 1.

Journal Article↗

PubMed2022

In vitro germ cell induction from fertile and infertile monozygotic twin research participants.

Human induced pluripotent stem cells (hiPSCs) enable reproductive diseases to be studied when the reproductive health of the participant is known. In this study, monozygotic (MZ) monoamniotic (MA) twins discordant for primary ovarian insufficiency (POI) consent to research to address the hypothesis that discordant POI is due to a shared primordial germ cell (PGC) progenitor pool. If this is the case, reprogramming the twin's skin cells to hiPSCs is expected to restore equivalent germ cell competency to the twins hiPSCs. Following reprogramming, the infertile MA twin's cells are capable of generating human PGC-like cells (hPGCLCs) and amniotic sac-like structures equivalent to her fertile twin sister. Using these hiPSCs together with genome sequencing, our data suggest that POI in the infertile twin is not due to a genetic barrier to amnion or germ cell formation and support the hypothesis that during gestation, amniotic PGCs are likely disproportionately allocated to the fertile twin with embryo splitting.

Humans↗

PubMed2025

Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing.

Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control the expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.

Prader-Willi Syndrome↗

PubMed2026

Directing fratricide within T cell products using an anti-uPAR chimeric antigen receptor to drive the production of potent therapeutic cells.

Cell therapy manufacturing of primary T cells often results in heterogeneous cell populations in the final product, with many cells lacking desired receptor expression or exhausted and other dysfunctional phenotypes. Here, we design a novel cell-intrinsic strategy to genetically reprogram primary human T cells to autonomously detect and eliminate dysfunctional cells. This integrated detection and elimination process, known as directed fratricide, is programmed via non-viral CRISPR genome editing to eliminate the T cell receptor (TCR) alpha chain (TRAC gene knockout) and integrate a chimeric antigen receptor (CAR) against the urokinase-type plasminogen activator receptor (uPAR), also known as CD87. In these cell products, strong T cell stimulation or activation during manufacturing causes a small subset of cells to express uPAR, which triggers CAR-mediated killing within the product. This fratricide induces proliferation in the desired cells and destroys undesired cells, a process that could be modeled computationally and controlled robustly via supplements to the culture media. The strategy enabled enrichment of anti-uPAR and anti-disialoganglioside (GD2) CAR-T cell products up to ≥99% CAR+/TCR-, favoring a memory-like phenotype. Understanding growth dynamics among T cell subsets and reprogramming them via CRISPR could accelerate the biomanufacturing of potent cell products without extensive selection methods.

Humans↗

PubMed1992

Long-term multicenter experience with a second-generation implantable pacemaker-defibrillator in patients with malignant ventricular tachyarrhythmias. The Guardian Multicenter Investigators Group.

A second-generation implantable pacemaker-cardioverter-defibrillator was evaluated in 200 patients with sustained ventricular tachycardia, ventricular fibrillation or prior cardiac arrest. The device permits demand ventricular pacing for bradyarrhythmias and for long QT interval or tachycardia suppression, uses programmable (3 to 30 J) energy shocks for conversion of ventricular tachycardia and ventricular fibrillation and is used with conventional pacing and defibrillation leads. Ventricular tachycardia/fibrillation recognition is based on the ventricular electrogram rate and requires reconfirmation before shock delivery. Two hundred patients (mean age 62 years, mean left ventricular ejection fraction 36%) were enrolled and followed up for 0 to 23 months (mean 12). Epicardial lead system implantation was performed with use of an anterolateral thoracotomy (38%), median sternotomy (26%) and subxiphoid (20%) or subcostal (16%) approach. Perioperative mortality rate was 5.5% (all nonarrhythmic deaths). Implant defibrillation threshold ranged from 3 to 30 J (mean 15), with initial programmed shock energy ranging from 3 to 30 J (mean 22). Ventricular tachycardia/fibrillation sensing threshold ranged from 0.7 to 1.8 mV (median 1) and the tachycardia detection interval from 288 to 416 ms (median 320). Reprogramming of implant variables was necessary for reliable electrographic sensing (54 patients), programmed shock therapy (61 patients) and tachycardia detection rate (63 patients). Device activation for potential shock delivery occurred in 111 patients (55.5%) with actual shock delivery after ventricular tachycardia/fibrillation reconfirmation in 66 patients (33%). During follow-up study, there was a 1% arrhythmia mortality rate, 6.5% cardiac mortality rate and 10.5% total mortality rate. This study demonstrates that the programmable implantable pacemaker-cardioverter-defibrillator is effective in preventing arrhythmic death, yet reduces patient exposure to repeated shock therapy. Reprogramming is usually necessary during follow-up for optimal function.

Adolescent↗

PubMed1985

Long-term assessment of unipolar and bipolar stimulation and sensing thresholds using a lead configuration programmable pacemaker.

Acute and long-term pacing thresholds were measured prospectively in 74 patients with a unipolar/bipolar multiprogrammable pacemaker. At implantation, mean current threshold was 0.48 +/- 0.16 mA with unipolar mode and 0.55 +/- 0.16 mA bipolar mode (p less than 0.01). R wave amplitude at implantation was 7.78 +/- 2.4 mV with unipolar and 7.67 +/- 2.1 mV in bipolar mode (p = NS). During long-term follow-up (mean 9.3 months; range 3 to 24), no clinically significant differences in pacing or sensing thresholds were observed between bipolar and unipolar configurations. Lead configuration was changed 23 times in 11 patients. Symptomatic myopotential inhibition was corrected in two patients by reprogramming to the bipolar pacing mode. High thresholds and loss of capture were corrected in two patients by reprogramming to the unipolar pacing mode. The remaining configurational changes were made for improved sensing or pacing thresholds. This study documents, in a large group of patients, the equivalence of long-term unipolar and bipolar pacing and sensing thresholds and, in addition, demonstrates that lead configuration programmability offered some advantage in a subgroup of patients and may have prevented reoperation in five patients.

Cardiac Pacing, Artificial↗

PubMed1985

Noninvasive evaluation of retrograde conduction times to avoid pacemaker-mediated tachycardia.

Pacemaker-mediated tachycardia is a potential complication of atrioventricular (AV) universal DDD pacemakers when retrograde ventriculoatrial (VA) conduction is slower than the postventricular-atrial refractory period of the pulse generator. The propensity for pacemaker-mediated tachycardia was noninvasively assessed in 17 patients with a unipolar DDD pacemaker using chest wall stimulation. Low amplitude stimuli were delivered to chest wall electrodes through a programmed stimulator. Using this method, 13 of the 17 patients were found to have absent VA conduction or VA conduction time less than the postventricular-atrial refractory period. In the four patients with noninvasively measured VA conduction time greater than the postventricular-atrial refractory period, sustained pacemaker-mediated tachycardia was induced. Reprogramming of pacemaker parameters prevented repeat induction of pacemaker-mediated tachycardia in only one of four patients. The three remaining patients had clinical pacemaker-mediated tachycardia and underwent pacemaker programming to the DVI mode. A total of 13 patients continue to use DDD mode after a mean follow-up period of 9.5 +/- 5.4 months. Invasive measurement of VA conduction was performed in 13 of the 17 patients. The noninvasive method accurately predicted the invasive measurement in each case. Noninvasive evaluation of VA conduction accurately predicts the propensity for pacemaker-mediated tachycardia under a variety of clinical conditions. Serial testing can be performed after pacemaker reprogramming or drug intervention. Noninvasive evaluation of retrograde VA conduction should predict most clinical episodes of pacemaker-mediated tachycardia.

Adult↗

PubMed1988

Is the Suppressor-mutator element controlled by a basic developmental regulatory mechanism?

We report the results of genetic studies on derivatives of two different alleles of the maize a locus with an insertion of the Suppressor-mutator (Spm) transposable element in which the element is inactive, but can be reactivated readily. We present evidence that the mechanism that determines whether the element is in an active or inactive phase has two genetically distinguishable components. One determines whether or not the element is genetically active (the phase setting) and the other determines the stability of the setting in development, its heritability, and its phase in the next generation (the phase program). We show that the element's phase can be reset in a reproducible pattern during plant development. We also show that the Spm element can be reprogrammed to undergo a subsequent phase change without a concomitant phase change. The capacity to reset and reprogram the Spm element is differentially expressed within the plant in a pattern that is correlated with the developmental fate of apical and lateral meristems, suggesting the involvement of a basic developmental determination mechanism.

Alleles↗

PubMed2026

Transient YAP activation uncovers the neurogenic potential of proliferative mammalian Müller glia.

The Hippo pathway effector YAP promotes spontaneous proliferation of Müller glia (MG), suggesting that bypassing Hippo signaling and activating YAP could enhance retinal regeneration. However, whether proliferative adult MGs retain meaningful neurogenic competence remains unclear. Here, using viral delivery of a Hippo-resistant YAP variant to wild-type adult MGs, we achieved transient YAP activation in adult MGs, inducing proliferation followed by cell-cycle withdrawal and differentiation. Intersectional genetic lineage tracing and EdU labeling, combined with transcriptomic analyses, revealed that YAP-activated MGs predominantly regenerate MGs, whereas only a subset gives rise to bipolar cell-like neurons. These results indicate that proliferative MGs acquire a state resembling that of late-stage retinal progenitors, with limited neurogenic lineage potential. We conclude that YAP-activated cell-cycle reentry inefficiently reprograms adult MGs toward photoreceptor or ganglion cell fates. These findings define the limited competence of proliferative adult MGs to contribute to neurogenic fates and provide a rigorous framework for assessing in vivo glial reprogramming strategies.

AAV↗

PubMed2025

Hormetic nutrient stress promotes longevity by orchestrating histone acetylation on key lipid catabolism and antioxidant defense genes.

Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. In this study, we identified histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. The increase in H3K27ac, mediated by pioneer factor PHA-4/FOXA and cooperating transcription factor NHR-49/HNF4, is crucial for lifespan extension under hermetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch that bridges nutrient status with transcriptomic reprogramming, underpinning the pro-longevity effects of hormetic fasting through orchestrating lipid catabolism and antioxidative defenses.

Journal Article↗