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Nguyen, K.

Publications and source records attributed to Nguyen, K..

At least 37 records · Page 2Linked to original sources

Rarity and reproductive biology drive population genomics of obligate symbioses

Modern perspectives on obligate symbioses increasingly recognize their dynamism, complexity, and global importance. Population genomics has been key to this advancement, yet the extension of existing frameworks to reproducibly integrate across multiple genotype-phenotype-environment relationships remains elusive. We generated 962 metagenomes for six lichens, obligate symbioses between fungi and algae, with contrasting traits sampled at a landscape scale. Core neutral population metrics were primarily driven by rarity and reproductive biology, while genes underlying expression regulation were under selection in response to land use and climate across all species. Examined within a comparative framework, these results illustrate that symbiont interactions are a major factor influencing microevolutionary trajectories, especially neutral processes. We present a conceptual framework for population-scale evolution in obligate symbioses that centers on biotic interactions.

evolutionary biology↗

Nascent CUT&Tag captures transcription factor binding after chromatin duplication

DNA replication strips off all chromatin proteins, which must be reassembled behind the replication fork. To track chromatin reassembly on newly synthesized DNA, we developed Nascent CUT&Tag, a chromatin profiling method that directly measures transcription factor (TF) binding on nascent chromatin. We tracked the recovery of GAGA factor (GAF) and Pleiohomeotic (PHO) in Drosophila Kc167 cells. Whereas both TFs are evicted following passage of the replication fork, GAF recovers on newly synthesized DNA over a minutes-to-hours range, whereas PHO generally requires hours to fully reestablish binding. Early recovering GAF peaks are characterized by shorter GAF motifs and are associated with functions related to cell cycle progression. Conversely, late recovering peaks are characterized by longer, degenerate GAF motifs and are associated with developmental functions. GAF recovery on newly synthesized DNA requires chromatin remodeling by Brahma Associated Factor (BAF), implying that nucleosome turnover is critical to fully reestablish GAF binding.

genomics↗

YAP/TEAD4-reagulated placental alkaline phosphatases ALPP and ALPPL2 are immunosuppressive ectonucleotidases modulated by MAPK inhibitors

Placental alkaline phosphatases ALPP and ALPPL2 (ALPP/L2) are promising clinical targets for therapies such as antibody-drug conjugates (ADCs). However, their regulation and biological functions remain unclear. Here, we identify the YAP/TEAD4 signaling axis as the primary regulator of ALPP/L2 expression in tumor cells. Importantly, we demonstrate that inhibitors targeting KRAS, MEK, and ERK upregulate ALPP/L2 expression in vitro and in vivo, thereby enhancing the efficacy of antibody-drug conjugates (ADCs) when used in combination. Moreover, our work reveals a novel immunomodulatory function of ALPP/L2 as cell surface ectonucleotidases that hydrolyze extracellular ATP, ADP, and AMP to adenosine, promoting regulatory T cell infiltration into the tumor microenvironment. Together, these findings reveal a biological function of ALPP/L2 and identify druggable regulators to enhance ALPP/L2-targeted therapies. SIGNIFICANCEThis study uncovers the YAP/TEAD pathway as a positive regulator of the clinically relevant tumor-associated antigens ALPP and ALPPL2. Kras, MEK, or ERK inhibitors enhance ALPP/L2 expression in tumor cells, thereby increasing the efficacy of ALPP/L2-targeted antibody-drug conjugates. These findings offer a promising combination strategy to overcome resistance to ALPP/L2-based therapies caused by low target expression.

cancer biology↗

Mycoelectronics: Bioprinted Living Fungal Bioelectronics for Artificial Sensation

The intelligence of the human biological system is enabled by the highly distributed sensing receptors on soft skin that can distinguish various stimulations or environmental cues, thus establishing the fundamental logic of sensing and physiological regulation or response. To replicate biological perception, two approaches have emerged: artificial nervous systems that utilize soft electronics as biomimetic receptors to convert external stimuli into frequency-encoded signals, and biohybrid solutions that integrate living cells, plants, or even live animals with electronic components to decode environmental cues for life-like sensations. However, most current biohybrid approaches for artificial sensation are based on eukaryotic cells, which suffer from slow growth, stringent culture conditions, environmental susceptibility, and short lifespans, thus limiting their integration into practical wearables or robotic sensory skins. Here, we introduce fungi-based printable "Mycoelectronics", which are created by additive bioprinting of living fungal mycelium networks onto stretchable electronics, as a practical living thermo-responsive sensory platform. This Mycoelectronics approach leverages fungis capacity for rapid biological responsiveness, cultivability with exponential growth, stability and self-healing in ambient conditions, bioprintability for scalable manufacturing, and mechanical flexibility for seamless integration with soft electronics. Critically, we discovered that the thermal responsiveness of the fungal network arises from intrinsic cellular processes--specifically, heat-induced vacuole remodeling and fusion, which modulate ionic transport and thus the electrical conductivity of the mycelial cells and networks, enabling a rapid temperature response. By bridging the gap between cell biology and soft electronics, the Mycoelectronics device with a living mycelium network functions as a thermal sensation system with rapid response and intrinsic self-healing properties, autonomously restoring sensing capabilities after damage or autonomously establishing sensor pathways in hard-to-reach locations. Furthermore, by integrating fungal thermal sensing with electronic circuits, we established a hybrid bioelectronic reflex arc that can actuate muscles and initiate diverse actions, suggesting promising applications in future neurorobotics and neuroprosthetics.

bioengineering↗

Multi-platform framework for mapping somatic retrotransposition in human tissues

Mobile element insertions (MEI) shape the human genome in both germline and somatic tissues. While inherited MEIs are well characterized, mapping somatic MEIs (sMEI) in non-cancer tissues remains challenging due to their low allelic fraction and repetitive nature. We established an integrative framework for sMEI analysis leveraging modern sequencing technologies and analytical innovations. We first benchmarked sMEI detection and demonstrated advantages of long-read and MEI-targeted sequencing for ultra-low-frequency events using a mixture of well-established cell lines. We then showed that haplotype phasing and donor-specific assemblies refine sMEI detection, effectively distinguishing from germline and false signals in in-silico tumor-normal mixtures. We further developed a source-tracing strategy based on internal sequence variation, expanding the catalogue of active source elements beyond traditional transduction-based methods. Applying this framework to donor tissues, we identified 18 rare somatic L1 insertions, revealing structural and source diversity. Our work provides a foundational framework and biological insight into sMEIs.

genomics↗

Cellular and Molecular Architecture of Renin-Angiotensin System Signaling in the PVN Under Cardiometabolic Stress

The hypothalamic paraventricular nucleus (PVN) integrates neuroendocrine and autonomic signals that regulate blood pressure and metabolism. Although the renin- angiotensin system (RAS) is implicated in neurogenic hypertension and obesity, cell-type- specific expression and regulation of its components within the PVN remain poorly understood. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to profile the transcriptomic landscape of the PVN in male mice under baseline conditions and in models of DOCA-salt-induced hypertension and high-fat diet (HFD)-induced obesity. We identified major PVN cell types, including neurons, astrocytes, precursor oligodendrocytes, oligodendrocytes, microglia and endothelial cells, and further resolved eight transcriptionally distinct neuronal subtypes. Expression of RAS-related genes was highly cell-type specific: Agt (angiotensinogen) was enriched in astrocytes, whereas Ace (angiotensin-converting enzyme), Atp6ap2 (also known as the (pro)renin receptor [PRR]), Agtr1a (angiotensin II type 1a receptor, aka AT1aR), Lnpep (leucyl/cystinyl aminopeptidase, aka angiotensin 4 receptor [AT4R]), and the Mas1 proto-oncogene were predominantly expressed in neurons. DOCA-salt treatment increased the proportion of GABAergic and vasopressin neurons and enhanced neuronal Agt and Atp6ap2 expression, while reducing astrocytic Agt, suggesting activation of a vasoconstrictive RAS axis. HFD exposure increased excitatory and stress-responsive neuronal subtypes (glutamatergic, vasopressin, corticotropin-releasing hormone) and upregulated Atp6ap2, Agtr1b, Lnpep, and Mas1 in vasopressin neurons, while downregulating multiple RAS genes in GABAergic neurons. These findings reveal dynamic, cell-type-specific remodeling of RAS signaling in the PVN in response to hypertensive and metabolic stress, providing a transcriptomic atlas of RAS expression in the PVN and identifying potential cellular targets for therapeutic strategies addressing cardiometabolic disorders.

genomics↗

Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity

The DNA-incorporating nucleoside analogs azacytidine (AZA) and decitabine (DEC) have clinical efficacy in blood cancers, yet the precise mechanism by which these agents kill cancer cells has remained unresolved - specifically, whether their anti-tumor activity arises from conventional DNA damage or DNA hypomethylation via DNA methyltransferase 1 (DNMT1) inhibition. This incomplete mechanistic understanding has limited their broader therapeutic application, particularly in solid tumors, where early clinical trials showed limited efficacy. Here, through the assessment of drug sensitivity in over 600 human cancer models and comparison to a non-DNA-damaging DNMT1 inhibitor (GSK-3685032), we establish DNA hypomethylation, rather than DNA damage, as the primary killing mechanism of AZA and DEC across diverse cancer types. In further support of an epigenetic killing mechanism, CRISPR drug modifier screens identified a core set of chromatin regulators, most notably the histone deubiquitinase USP48, as AZA and DEC protective factors. We show that USP48 is recruited to newly hypomethylated CpG islands and deubiquitinates non-canonical histones, establishing USP48 as a key molecular link between the two components of epigenetic gene regulation: DNA methylation and chromatin modification. Furthermore, loss of USP48, which occurs naturally through biallelic deletions in human cancers, sensitized both hematologic and solid tumors to DNMT1 inhibition in vitro and in vivo. Our findings elucidate the epigenetic mechanism of action of AZA and DEC and identify a homeostatic link between DNA methylation and chromatin state, revealing new therapeutic opportunities for DNMT1 inhibitors in solid tumors.

cancer biology↗

THE IMPACT OF ARTIFICIAL INTELLIGENCE ON UNIVERSITY STUDENTS PERCEPTIONS OF ENVIRONMENTAL CHALLENGES AND SUSTAINABLE SOLUTIONS

In the context of Vietnams higher education strongly transforming towards digitalization and sustainability, this study aims to analyze the impact of artificial intelligence (AI) on students awareness and intention to act for the environment. Based on the Extended Planned Behavior (TPB) model, the research model integrates two input factors: environmental awareness (EA) and the level of interaction with AI in environmental learning (AEEL), affecting three mediating factors: attitude (AT), subjective norm (SN) and perceived behavioral control (PBC), thereby predicting students green action intention (GAI). Data collected from 521 students at private university in Vietnam were processed using EFA, CFA and SEM. The results showed that both EA and AEEL had positive effects on AT, SN and PBC (p < 0.001). Among them, AEEL had the strongest influence on SN ({beta} = 0.281) and PBC ({beta} = 0.252). PBC had the strongest influence on GAI ({beta} = 0.312), followed by AT ({beta} = 0.274) and SN ({beta} = 0.267). Bootstrapping mediation analysis confirmed that the mediating variables (AT, SN, PBC) played an important role in linking EA and AEEL with GAI. In addition, cluster analysis showed that female students and senior students had significantly higher levels of AI engagement and action intention. These results suggest that AI not only serves as a learning support tool but also as a catalyst for sustainable behavior in higher education.

scientific communication and education↗

Biologically Guided Variational Inference for Interpretable Multimodal Single-Cell Integration and Mechanistic Discovery

Multi-omics technologies allow detailed characterization of cell types and states across omics layers as well as chemical and genetic perturbations. Variational autoencoders have become a cornerstone of single-cell data integration; however, they are often implemented as black-box models, requiring post hoc interpretation using known markers, pathways, or regulators to make sense of their latent representations. NetworkVI fundamentally flips this paradigm by incorporating biological knowledge directly into the model architecture. By embedding co-regulation networks derived from topologically associated domains and structured ontologies such as the Gene Ontology (GO), NetworkVI introduces a biologically-informed inductive bias that promotes the preservation of meaningful variation during integration while enforcing interpretability at both the gene and GO levels. NetworkVI achieves state-of-the-art data integration, modality imputation, and cell label transfer across bimodal and trimodal datasets. Beyond integration, here we show that NetworkVI facilitates ontology-guided hypothesis generation by exploiting established associations between genes, structured cellular programs, and regulatory domains to interpretably model cellular identities. Furthermore, decomposition of GO activation spaces resolves lineage-specific functional states within immune cell types, including quiescent, inflammatory, and transitional monocyte subpopulations, that are invisible to transcriptomic clustering. NetworkVI prioritizes GO-term programs associated with immunosenescence, consistent with age-associated immune dysregulation and reveals candidate immune evasion mechanisms consistent with CD58 loss in a Perturb-CITE-seq melanoma dataset.

bioinformatics↗

Oocyte mitochondria link maternal environment to offspring phenotype

During oogenesis and maturation oocytes undergo a recently discovered mitochondrial electron transport chain (ETC) remodeling in flies1, frogs1, and humans2. This conserved oocyte ETC remodeling is regulated by maternal insulin signaling, but its role in biology remains unclear. In the model animal Caenorhabditis elegans, we previously found that insulin signaling to oocytes regulates offsprings ability to adapt to future osmotic stress by altering offspring metabolism. However, the molecular mechanisms that function in oocytes to mediate this intergenerational stress response are similarly unknown. Here, we developed a low-input oocyte proteomics workflow and combined it with our C. elegans intergenerational stress response model to find that both a mothers environment and maternal insulin signaling regulate the abundance of ETC proteins in oocytes - particularly the abundance of proteins involved in the transfer of electrons from QH2 to cytochrome C by ETC Complex III. Using genetic perturbations of ETC function we further found that promoting ETC Complex III function in oocytes was both necessary and sufficient to link a mothers environment to adaptive changes in offspring metabolism. Lastly, we found that the effects of Complex III dysfunction in oocytes on offspring were mediated via an AMP-kinase (AAK-2) dependent mechanism and that AAK-2 functions in offspring to promote ATP preservation and glycerol metabolism in response to stress. Collectively, our data suggest that the role of oocyte ETC remodeling in biology includes linking maternal environments to changes in offspring metabolism that promote offspring survival in the environment experienced by their mother.

genetics↗

CytoAnalyst: A web-based platform for comprehensive single-cell RNA sequencing analysis

Single-cell technologies have revolutionized our ability to study cellular heterogeneity and dynamics at unprecedented resolutions. In this fast-growing field, it becomes increasingly challenging to navigate the vast amount of tools and steps for analysis. It is particularly difficult to integrate and analyze large datasets that require extensive collaborations and customized pipelines to obtain robust results. We present CytoAnalyst, a web-based platform that offers a number of important advantages over existing tools for single-cell analysis. First, the platform enables custom pipeline configuration using an efficient study management system and a broad range of analysis modules. Second, the platform supports parallel analysis instances, facilitating the comprehensive comparison of different methods or parameter settings available at each analysis step. Third, the advanced sharing system facilitates real-time synchronization among team members and seamless analysis continuation across different devices. Finally, the multi-grid visualization system supports simultaneous display of different data aspects, allowing for the comparison of multiple labels and plots side-by-side for comprehensive data insights, with the ability to save and reload visualization settings at any analysis step. The platform incorporates multiple blending modes, allowing users to combine plots in various ways for comprehensive data exploration. CytoAnalyst supports a high level of analytical rigor while providing user-friendly and flexible operations through its carefully designed interface and extensive documentation. The platform supports all major web browsers and is freely available at https://cytoanalyst.tinnguyen-lab.com.

bioinformatics↗

Distinct yet Overlapping Functions of VMP1 and TMEM41B in Modulating Hepatic Lipoprotein Secretion and Autophagy in MASH

BackgroundTransmembrane protein 41B (TMEM41B) and vacuolar membrane protein 1 (VMP1) are endoplasmic reticulum (ER) scramblases that shuttle phospholipids between the inner and outer leaflets of the ER membrane. Both TMEM41B and VMP1 also play critical roles in regulating hepatic lipoprotein secretion and autophagy. Despite these similarities, whether TMEM41B and VMP1 exhibit different roles in very low-density lipoprotein (VLDL) secretion and autophagy in the pathogenesis of metabolic-associated steatotic liver disease (MASLD) remains unclear. MethodsWe created liver- and hepatocyte-specific single knockout (KO) and double knockout (DKO) mice for Tmem41b and Vmp1, as well as overexpression knock-in (KI) mice with hepatic overexpression of TMEM41B, Tmem41b KO/Vmp1 KI, and Vmp1 KO/Tmem41b KI. We conducted lipidomic, metabolomic, biochemical, and functional studies in these mice, fed either a chow diet or a MASLD diet. ResultsTMEM41B protein levels were decreased in the livers of human subjects with MASLD. The loss of hepatic Tmem41b impaired VLDL secretion, resulting in steatosis, inflammation, and fibrosis. Vmp1 KO mice exhibited similar phenotypes to DKO mice, displaying a more severe defect in VLDL secretion and greater liver injury than Tmem41b KO mice. Lipidomic analysis revealed decreased levels of phosphatidylcholine and phosphatidylethanolamine, along with increased neutral lipids in both Tmem41b KO and Vmp1 KO mice; however, these changes were generally more pronounced in Vmp1 KO mice. VMP1 and TMEM41B localized at the mitochondrial-associated membrane (MAM), and a reduction in mitochondria-ER contact was observed in hepatocytes deficient in either VMP1 or TMEM41B. Ultrastructural electron microscopy analysis showed increased accumulation of "lipid droplet" in the ER membrane bilayer and ER lumen in both Vmp1 KO and Tmem41b KO hepatocytes, with greater ER luminal "lipid droplet" accumulation in Tmem41b KO hepatocytes. The loss of hepatic Vmp1 or Tmem41b led to elevated levels of LC3-II and p62, with significantly higher levels of both markers in Vmp1 KO and DKO mouse livers compared to Tmem41b KO mouse livers. Restoring Vmp1 in Tmem41b KO mice partially improved defective VLDL secretion; however, high expression levels of VMP1 did not correct the hepatic autophagy defect. In contrast, restoring Tmem41b in Vmp1 KO mice dose-dependently enhanced both defective VLDL secretion and autophagy. Importantly, overexpression of hepatic TMEM41B mitigated diet-induced MASLD in mice. ConclusionThe loss of hepatic Vmp1 or Tmem41b decreases hepatic MAM and phospholipid content, leading to decreased VLDL secretion and promoting MASLD. While VMP1 and TMEM41B have overlapping functions, VMP1 appears to play a more critical role in regulating VLDL secretion and autophagy in mouse livers than TMEM41B.

cell biology↗

Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS)

BackgroundPatients with recalcitrant enterococcal bloodstream infections are at greater risk of adverse outcomes. We identified patients in the 2016-2022 Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS) cohort experiencing recalcitrant bloodstream infections for further clinical and genomic characterization. MethodsBacteremia episodes were considered "persistent" if there was a lack of clearance on day four while receiving [&ge;] 48 hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, "recalcitrant" bacteremia). A matched comparison group of non-recalcitrant bacteremia patients was chosen in a 2:1 control:case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline. Findings. A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the ICU upon admission relative to controls. E. faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between E. faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation. DiscussionEnterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index vs. persistent isolates revealed that E. faecium may be genetically pre-adapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. This data lays groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.

genomics↗

Therapeutic CD8+T cell tissue retention and immunomodulation during ART interruption fails to prevent SIV rebound

A primary obstacle for HIV elimination is the long-term viral reservoir in lymphoid tissues (LT) that can cause rebound viremia if therapy is stopped. Cytotoxic CD8+ T cells are critical for control of HIV and SIV viremia; however, CD8+ T cells that migrate to LT are primarily non-cytotoxic, calling into question whether these cells could reduce the viral reservoir on ART or control viral replication when therapy is halted. To determine if CD8+ T cells can inhibit viral replication when retained in lymphoid tissues, we inhibited lymphocyte egress from LTs in antiretroviral therapy (ART)-treated SIV-infected rhesus macaques (RM) during analytic treatment interruption (ATI) using the S1PR modulator FTY720 alone or in combination with anti-PD1 and the IL-15 receptor superagonist N-803 to increase cytolytic function. FTY720 retained migrating CD4+ and CD8+ T cells in LT, whereas cytotoxic CD8+ T cells remained in the vasculature. After ATI and viral rebound, activated SIV-specific CD8+ T cells increased in frequency in LT of FTY720-treated RM but failed to become cytotoxic or control plasma viremia compared to controls, even when combined with anti-PD1 and N-803. These findings indicate that LT-localized CD8+ T cells alone are insufficient to delay or prevent plasma viral rebound during ATI. Significance StatementHIV therapeutic and cure strategies have all operated under the assumption that CD8+ T cells can become cytotoxic in lymph nodes to eliminate infected cells from reservoir repositories. Using FTY720 to prevent lymphocyte egress from lymph nodes, we demonstrated that lymphoid tissue-restricted CD8+ T cells are insufficient to prevent SIV rebound during antiretroviral treatment interruption, even in the presence of immunomodulators such as IL-15 receptor superagonist and PD-1 blockade. These findings call into question the ability of lymph node CD8+ T cells to control or eliminate SIV/HIV infection from lymphoid tissues without substantial immunomodulation, a notion contrary to current efforts to engage CD8+ T cells for therapeutic elimination of HIV viral reservoirs during ART.

immunology↗

Advancing Cardiac Graft Assessment Methods During Normothermic Machine Perfusion to Achieve Improved Transplantation Outcomes

Heart failure, a leading global health challenge, affects over 23 million people worldwide, with heart transplantation being the gold standard for end-stage disease. However, the scarcity of viable donor hearts presents a significant barrier, with only one-third of available grafts used due to stringent selection criteria. Machine perfusion technologies, particularly normothermic machine perfusion (NMP), offer promise in improving graft preservation and assessment, yet their full potential for predicting transplantability remains underexplored. This study investigates three assessment methods to enhance human heart evaluation during NMP, focusing on mitochondrial function, left ventricular (LV) performance, and inflammatory markers. First, resonance Raman spectroscopy (RRS) is employed to assess mitochondrial redox state as a proxy for metabolic competency, offering a non-invasive and dynamic evaluation of mitochondrial function during ex vivo preservation. Second, LV function is quantified using intraventricular balloons, providing critical insights into graft viability and performance. Third, inflammatory markers and endothelial activation are assessed from perfusate to predict post-transplant outcomes. These methods were tested on human donor hearts declined for transplantation, preserved via static cold storage (SCS) and subsequently assessed with NMP in Langendorff mode. The results demonstrate that these parameters can be easily integrated into existing clinical perfusion workflows and hold potential for improving heart transplantation outcomes by enhancing graft selection and optimizing donor heart use. Future studies will further validate these biomarkers across different preservation techniques and evaluate their clinical applicability.

bioengineering↗

Multi-lineage transcriptional and cell communication signatures define pathways in individuals at-risk for developing rheumatoid arthritis that initiate and perpetuate disease

Rheumatoid arthritis (RA) is a systemic autoimmune disease arising from loss of tolerance and autoantibody development in at-risk individuals. Targeted therapies yield variable responses and current preventive strategies delay but do not stop disease onset. We propose that a set of transcription factors (TFs) and their downstream pathways regulate inflammatory cell communication networks in at-risk populations and RA. These networks enable multiple pathogenic cell types and mediators and could account for variable responses to targeted agents. To test this hypothesis, we identified anti-citrullinated protein antibody (ACPA)-positive at-risk individuals, patients with early and established RA and healthy controls. Single cell chromatin accessibility and transcriptomic profiles from blood mononuclear r cells were integrated and identified share pathogenic mechanisms, especially SUMOylation, RUNX2, YAP1, NOTCH3, and {beta}-Catenin Pathways. Surprisingly, this signature was found in multiple cell types. Individualized gene expression patterns were then confirmed in RA synovium. Cell communication analysis revealed that multiple lineages can deliver a core set of pro-inflammatory mediators to receiver cells. Longitudinal analysis showed that the signature cell types evolve in individual at-risk participants. Cell-type-specific signature pathways could contribute to the differing clinical responses to targeted therapies. This study describes how a common clinical phenotype could arise from multiple pathogenic mechanisms.

systems biology↗

Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers

Telomerase reverse transcriptase (hTERT) overexpression, a hallmark of most cancers, drives tumorigenesis by enabling limitless replicative potential. Direct targeting of hTERT is challenging, necessitating alternative strategies. Through genome-wide synthetic dosage lethality (SDL) screening in cancer models, including patient-derived organoids, we identify FTSJ3, an RNA 2-O-methyltransferase, as a critical vulnerability in hTERT-overexpressing cells. FTSJ3 methylates telomeric repeat-containing RNA (TERRA), a modification essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts this cascade, impairing H3K9 trimethylation, HP1-alpha recruitment, and telomeric heterochromatin maintenance. Notably, this reveals an unexpected dependency on TERRA methylation for telomeric heterochromatin stability in hTERT-driven cancers. Non-malignant cells, lacking telomerase activity and de novo telomere repeat synthesis, are unaffected by FTSJ3 suppression. Our findings establish the FTSJ3/TERRA/SUV39H1 axis as a critical mechanism supporting telomeric heterochromatin stability in hTERT-driven cancers. This telomere-directed epigenetic strategy provides a robust framework for translational therapeutic innovation.

cancer biology↗

Systemic inflammation and lymphocyte activation precede rheumatoid arthritis

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical at-risk state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset. One Sentence SummaryACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA

immunology↗