Hematopoietic stem cells (HSCs) with mutations that can cause clonal hematopoiesis of indeterminate potential (CHIP) accumulate during aging. Agarwal et al.1 demonstrate in Nature that intestinal barrier permeability increases with age and enables the microbial metabolite ADP-heptose to reach the bone marrow, thus driving the expansion of DNMT3A-mutant HSCs.

Toxicity and immune evasion have hindered the success of CAR T cells in HER2-positive solid tumors. In this issue of Cell Stem Cell, Hosking et al. present an iPSC-derived CAR T cell product engineered for tumor-selective targeting, resistance to the immunosuppressive tumor microenvironment, enhanced persistence and trafficking, and mitigation of antigen escape.

Minocycline (Mino) is an antibiotic with neuroprotective, anti-inflammatory, and antioxidant properties. This study investigated the protective effects of Mino against hydrogen peroxide (H2O2)-induced oxidative damage in dermal fibroblast cells and analyzed these effects using Raman spectroscopy, principal component analysis (PCA), and machine learning (ML). L929 fibroblast cells were evaluated using MTT and scratch wound-healing assays. The production of reactive oxygen species (ROS) and the process of apoptosis were evaluated through the use of 2',7'-dichlorofluorescein diacetate (DCFH-DA) and Annexin V labelling, respectively. The mRNA expression levels of Nrf2, Hmox1, Nqo1, and Col1a were analyzed through quantitative real-time polymerase chain reaction (qRT-PCR). Raman spectroscopy detected molecular alterations, while PCA and ML classified spectral variations. Mino reduced H2O2-induced cellular toxicity, ROS levels, and apoptosis while enhancing fibroblast migration. It significantly upregulated Nrf2 and Hmox1 mRNA under oxidative stress and increased Col1a expression when applied alone. Raman spectroscopy revealed biochemical changes in lipids, proteins, and nucleic acids. PCA distinguished treatment groups, showing Mino-treated cells closely resembled controls. The SVM attained 90.10 % classification accuracy, underscoring the efficacy of Raman-based computational analysis. The findings collectively highlight the potential of Raman spectroscopy, PCA, and ML as a sensitive, label-free approach for monitoring molecular changes, thereby supporting the therapeutic potential of Mino in oxidative stress-related therapies.

Canine periodontal disease, a progressive and irreversible condition, impacts dental health, posing a significant challenge in veterinary medicine. While current treatments focus on managing progression, canine periodontal ligament stem cells (cPDLSCs) offer regenerative potential through their self-renewal capacity, expression of stemness markers and multilineage differentiation. Autologous cPDLSCs have successfully regenerated alveolar bone, cementum, and Sharpey's fibres, while allogeneic cell transplants have demonstrated immunomodulatory benefits without triggering inflammatory reactions. cPDLSCs also show potential for mitigating inflammation and promoting regeneration in experimentally induced canine periodontal disease. Despite promising preclinical results, challenges such as limited clinical studies, disease variability, high costs, and low owner awareness hinder progress in the use of cPDLSCs in veterinary dental clinical settings. Advancing clinical veterinary science requires conducting clinical trials involving dogs with naturally occurring periodontal disease. Interdisciplinary collaboration can lower costs and expand access to these studies. Additionally, educating pet owners about hygiene practices, early disease detection, and the advantages of regenerative therapies will increase their compliance and improve the outcomes. Ultimately, bridging the gap between research and clinical application through real-world studies is essential for advancing accessible and effective periodontal therapies for dogs. Our review aims to explore the potential of cPDLSCs in both in vitro and in vivo contexts, advancing knowledge of the periodontal microenvironment and paving the way for innovative regenerative therapies.

Primordial Germ Cell (PGC) formation and specification is a fundamental conserved process as PGCs are the progenitors of germline stem cells (GSCs). In Drosophila melanogaster, maternally deposited Oskar (Osk) and centrosome dynamics are two independent determinants of PGC fate. Caspar, Drosophila homolog of Fas-associated factor 1 (FAF1), promotes PGC formation/specification and maintains the PGC count by modulating both the Osk levels and centrosome function. Consistently, casplof PGCs display reduction and inefficient release/ transmission of germ plasm. Defective centrosome migration and behavior are evident even prior to PGC formation engineered by Osk and its targets. Taken together with the inability of Osk to regulate nuclear and centrosome migration, our data demonstrate that Casp encodes a novel bi-modal regulator of PGC fate as it controls Osk levels likely by downregulating translational repressor, Smaug (Smg) and also influences nuclear/centrosome migration during early mitotic nuclear division cycles (NCs 6-9) which are Osk-independent. We discuss dual functionality of Casp vis-à-vis germline/soma segregation as it helps acquire both the PGCs and the surrounding soma their individual identities.

Bone is an incredibly robust tissue thanks to its high blood supply, rapid cell turnover, and continuous remodeling. A significant body of research investigates strategies to improve osteogenesis, angiogenesis, and immunomodulation for bone regeneration, facilitated by numerous various therapeutic approaches (e.g. pharmacologics, biomaterials, stem cell therapy, and more). However, a critically understudied but recently emerging area of research lies in the inflammatory cascade and the cleanup of apoptotic cells during repair, aging, and disease. Termed "efferocytosis," this natural and efficient cleaning up of cells at the end of their lifespan is a crucial step in resolving injury, controlling disease, maintaining homeostasis, and tissue repair. Currently, the primary mechanism(s) driving efferocytosis in most tissue but especially bone, is unknown. Despite this knowledge gap, mounting evidence suggests that impaired efferocytosis plays a significant role in many chronic illnesses and impairs tissue regeneration. Biomaterials-based interventions are well-positioned to interrogate mechanisms of efferocytosis due to their ability to provide local support and guide cellular activity not only in combination with but also without additional pharmaceutical aid. This review will highlight the current understanding of efferocytosis in bone and discuss cutting-edge biomaterials-based strategies to engineer efferocytosis for improved outcomes in bone regeneration.

Metazoan nucleosomes harboring H3K79 methylation (H3K79me) deposited by the methyltransferase DOT1L (disruptor of telomeric silencing 1-like) decorate actively transcribed genes. While DOT1L regulates transcription and the pathogenesis of leukemia and neurological disorders, the role of H3K79me remains elusive. Here, we reveal a functional synergism between H3K79me and H3K36 trimethylation (H3K36me3) in regulating gene expression and cellular differentiation. Simultaneous catalytic inactivation of DOT1L and the H3K36 methyltransferase SETD2 (SET domain containing 2) leads to hyperactive transcription and failures in neural differentiation. H3K79me/H3K36me3 loss causes increased transcription elongation, gained chromatin accessibility at a group of enhancers, and increased recruitment of TEAD4 (TEA domain transcription factor 4) and its coactivator YAP1 (Yes-associated protein 1) to these enhancers. Furthermore, YAP-TEAD inhibition restores the expression levels of genes hyperactivated by H3K79me/H3K36me3 loss. Together, we demonstrate a synergism of H3K79me and H3K36me3 in regulating transcription and cell fate transition, unveil the underlying mechanisms, and provide insight into targeting diseases driven by misregulation/mutations of DOT1L and/or SETD2.

Long-lived perennial plants accumulate numerous somatic mutations with age. Mutations originating in stem cells at the shoot apex often become fixed in large sectors of the plant body due to cell lineage drift during repeated branching. Understanding the somatic evolution of such mutations requires knowledge of the effective stem cell population size, the cellular bottleneck strength during branch initiation, and the mutation rate. Here we show that these parameters can be estimated directly from cell-layer-enriched DNA sequencing data, thus filling a gap where no other in vivo method exists.

This study assessed the biological and antimicrobial properties of a calcium silicate-based material and calcium hydroxide (CH) when used as intracanal medications. MTT assay, osteogenic differentiation of human periodontal stem cells (hPDLSCs), cell mineralization-assay, and determination of ALP activity were assessed to investigate the biological properties. While the agar well diffusion, crystal violet (CRV) assay and LIVE/DEAD staining of dentin slices infected with a mature E. faecalis biofilm were used to assess the antimicrobial properties. Normally distributed data were analyzed using one and two-way ANOVA and post hoc Tukey test, while for non-normally distributed data Kruskal Wallis and Dunn's tests were used. The results showed that both materials were cytocompatible, but BioC-Temp showed statistically higher hPDLSCs viability (P < 0.05). hPDLSCs cultured with BioC-Temp extract demonstrated a significantly higher mineralization and more mineralized nodules than CH extract (P < 0.05). Both BioC-Temp and CH had similar antibacterial potential against E. faecalis in radicular dentin. BioC-Temp has higher mineralization potentials than CH. For the antimicrobial properties, BioC-Temp caused significantly higher inhibition zones than CH (P = 0.0001). The biofilm biomass reduction of BioC-Temp was significantly higher than for CH (P < 0.05). Regarding the percentage of live E. faecalis in biofilm, both BioC-Temp and CH caused significant reductions with no significant difference between them (P > 0.05).

Human umbilical cord mesenchymal stromal cells (hucMSCs) have emerged as a promising therapeutic option for acute liver failure (ALF). However, the detailed mechanism by which hucMSCs modulate hepatocyte pyroptosis in ALF remains unclear. In this study, we induced ALF in mice using acetaminophen (APAP). Mice were intravenously injected with 1 × 106 hucMSCs/ hucMSCs-Exo via the tail vein 6 h after APAP administration. Liver pathological changes were assessed by hematoxylin and eosin (H&E) staining. Subsequently, an in vitro model of liver cell failure and pyroptosis model was established using LO2 cells treated with lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). The levels of cell pyroptosis marker caspase-1 were detected by flow cytometry analysis, RT-qPCR assay, and western blot assay. The study employed a comprehensive approach, including flow cytometry analysis, RT-qPCR assay, miRNA sequencing, and luciferase reporter gene experiments. hucMSCs and hucMSCs- exosomes (MSCs-Exo) inhibited cell inflammation to improve ALF in vivo model of ALF and inhibited hepatocyte pyroptosis in LO2 cells induced by ATP and LPS. MiR-423-5p emerged as a potential mediator of the anti-pyroptotic effects of hucMSCs-Exo, with ZBP1 identified as one of its downstream targets. Subsequent validation confirmed that miR-423-5p targets ZBP1 to regulate pyroptosis. These findings highlight the role of hucMSCs-derived exosomal miR-423-5p in inhibiting hepatocyte pyroptosis in LO2 cells induced by ATP and LPS. miR-423-5p serves as a crucial mediator in this process, targeting ZBP1, a protein significantly involved in the pyroptotic pathway. Our findings may provide basics for further research on mechanism of hucMSCs and present a promising cell-free strategy treating ALF.

Glioma, a prevalent primary brain tumor, arises from the supporting cells of the central nervous system (CNS) and is categorized into grades I-IV. Despite advancements in therapeutic strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, glioma remains associated with high mortality and recurrence rates, often leading to poor patient outcomes. The pathogenesis of glioma is influenced by a combination of environmental factors, genetic mutations, and lifestyle choices. Transforming growth factor-beta (TGF-β) signaling plays a pivotal role in glioma progression by regulating cell proliferation, survival, and differentiation. TGF-β activates Small mothers against decapentaplegic 2/3 (Smad2/3) proteins through specific receptors, forming a complex with Smad4 that translocate to the nucleus to modulate gene expression. In addition, TGF-β-activated kinase 1 (TAK1) initiates mitogen-activated protein kinase (MAPK) cascades, further contributing to tumorigenesis. The TGF-β/Smad pathway can be negatively regulated by inhibitory Smad6/7. Elevated expression of TGF-β isoforms (Ι-Ш) is correlated with increased glioma risk. TGF-β promotes tumor growth by sustaining glioma stem cell self-renewal and suppressing antitumor immune responses. Preclinical studies demonstrate that TGF-β signaling inhibitors reduce glioma viability and invasion in animal models, highlighting their potential as promising therapeutic agents for glioma treatment.

Acute kidney injury (AKI), characterized by a sudden and sustained decline in renal function, is linked to significant morbidity and mortality. The regeneration of the kidney following AKI is a complex process in which the activation of stem and progenitor cells plays a crucial role. Numerous studies have demonstrated that endogenous Sox9+ cells contribute to this regeneration. Traditionally, the status of kidney regeneration after AKI has been evaluated through histopathological examination and renal function indices, which are limited in providing real-time and dynamic insights. To address these limitations, we propose a novel approach using two-photon live imaging to track lineage-labeled endogenous Sox9+ cells in AKI mouse models, allowing long-term monitoring and visualization of the kidney regeneration process.

Acute myeloid leukemia (AML) is a blood cancer caused by genetic mutations in hematopoietic precursor cells, leading to abnormal cell production in the bone marrow (BM) and results in complications like anemia, leukopenia, and thrombocytopenia. Treatments, such as chemotherapy and hematopoietic stem cell transplantation carry risks like graft-versus-host disease (GVHD) and infections due to immune suppression. Recently, treatment with natural killer (NK) cells has emerged as a novel approach for treating AML. NK cells can identify and destroy leukemic cells, and methods like NK cell transfer and cytokine activation show promise as effective treatments. This article evaluates the feasibility and safety of NK cell-based therapies for AML patients. This article is a systematic review that registered its protocol in PROSPERO. A strategic search was conducted in the PubMed, Scopus, Google Scholar, and Web of Science databases using the keywords "Natural killer cell, " "Acute myeloid leukemia" and "Immunotherapy". After removing duplicates and applying inclusion/exclusion criteria, 1623 articles were selected. Two reviewers screened titles and abstracts, followed by a full-text review. Disagreements were resolved by a third reviewer, resulting in 17 articles for inclusion. Data were organized in Excel, and study quality was assessed using the Cochrane risk-of-bias tool. Data analysis was performed using R software. Out of 1623 initially identified records, 17 clinical studies comprising 402 AML patients aged between 1 and 82 years were included. Most studies used allogeneic or homologous NK cells, sometimes combined with chemotherapy or interleukin-2. The pooled complete remission (CR) rate was 48.22% (95% CI 31.75-65.09%), with significant heterogeneity (I2 = 76%). Immune response prevalence across 14 studies was 69.34% (95% CI 49.18-84.09%). Adverse events were generally mild and manageable, with no consistent reports of severe toxicity. Although study quality varied, eight studies demonstrated low risk of bias. Publication bias was detected for CR outcomes, adjusting the CR rate to 36.94% after correction. We conducted a systematic review that demonstrates that NK cell therapy shows promising efficacy and acceptable safety in treating AML patients, with a pooled complete remission rate of 48.22% and encouraging immune response rates. Despite heterogeneity across studies and varying methodological quality, the consistent observation of anti-leukemic effects and manageable adverse events supports the potential role of NK cell therapy as a complementary treatment. Further high-quality, large-scale trials are warranted to validate these findings and optimize clinical protocols.

Anorectal malignant melanoma (ARMM) is a refractory malignancy that not only responds poorly to radiotherapy but also to immunotherapy. Tumor microenvironment (TME) components play an essential role in tumor progression and therapeutic response. However, TME characteristics of ARMM are not well understood.

Nanopesticides (NPs) provide a sustainable approach to reducing the use of chemical pesticides and mitigating their environmental risks in agriculture. In the present study, a pH and cellulase dual-stimulating system with the loaded pesticide penthiopyrad (PEN) was developed by incorporating hydroxypropyl cellulose (HPC) on the surfaces of mesoporous nanoselenium (MSe). In the measurement of antifungal efficacy of PEN against Colletorichum orbiculare Arx, compared to the neutral environment, i.e., pH = 7 without cellulase, the cumulative release of PEN from HPC@PEN@MSe NPs increased 5.7 and 4.8 times of the amount released at pH 3 and 5, respectively; at pH 7, the presence of cellulase solution substantially enhanced PEN release by 6.1 times more than that without cellulase. The HPC@PEN@MSe NPs demonstrated 3.2-fold of antifungal efficacy greater than the commercial 20% PEN suspension concentrate (20% PEN SC). This dual-stimulating NPs can induce oxidative stress responses and cell structural damage in pathogens, demonstrating a broad spectrum of antifungal activity. Mechanistic investigations illustrated that HPC@PEN@MSe NPs specifically promote the accumulation of reactive oxygen species, including hydroxyl radicals (•OH), superoxide radicals (•O2-), and singlet oxygen (1O2) in pathogenic cells by regulating gene expressions relevant to oxidative phosphorylation and lipid metabolism pathways, ultimately leading to eradication of pathogens. In vivo, HPC@PEN@MSe NPs sprayed could be transported in plants and specifically activated at the infected leafy, stem, and root tissues of cucumber plants, with the maximum PEN concentration at 0.93 mg/kg detected in the infected leaves at 12 h. The PEN residual concentration still had 0.09 mg/kg after 14 days, which suggests long-lasting activity. Moreover, the results of detached cucumber leaves and pot experiments indicated that HPC@PEN@MSe NPs significantly increased antioxidant enzyme levels, enhanced resistance to anthracnose, and manifested no apparent effects on plant growth. This eco-friendly plant protection strategy developed in this study exhibits apparent potential in practical applications while maintaining ecological sustainability and providing a potential path to address plant health management in modern agriculture.

The Rev response element (RRE) forms an oligomeric complex with the viral protein Rev to facilitate the nuclear export of intron-retaining viral RNAs during the late phase of HIV-1 (human immunodeficiency virus type 1) infection. However, the structures and mechanisms underlying this process remain largely unknown. Here, we determined the crystal structure of the HIV-1 RRE stem-loop II (SLII), revealing a unique three-way junction architecture in which the base stem (IIa) bifurcates into the stem-loops (IIb and IIc) to compose Rev binding sites. The crystal structures of various SLII mutants demonstrated that while some mutants retain the same "compact" fold as the wild type, other single-nucleotide mutants induce drastic conformational changes, forming an "extended" SLII structure. Through in vitro Rev binding assays and Rev activity measurements in HIV-1-infected cells using structure-guided SLII mutants designed to favor specific conformers, we showed that while the compact fold represents a functional SLII, the alternative extended conformation inhibits Rev binding and oligomerization and consequently stimulates HIV-1 RNA nuclear export dysfunction. The propensity of SLII to adopt multiple conformations as captured in crystal structures and their influence on Rev oligomerization illuminate emerging perspectives on RRE structural plasticity-based regulation of HIV-1 nuclear export and provide opportunities for developing anti-HIV drugs targeting specific RRE conformations.

Cellulose nanocrystals (CNC) have garnered significant attention in pharmaceutical and medical applications due to their biocompatibility, biodegradability, renewability, and strong surface reactivity. In this study, we designed 3D-printed bioactive composite scaffolds via fused deposition modeling (FDM), incorporating polycaprolactone (PCL), CNC derived from Ficus thonningii bark, and silver nanoparticles (AgNps) synthesized through in situ reduction of silver nitrate AgNO3. Energy-dispersive X-ray spectroscopy (EDX) confirmed AgNps incorporation, while scanning electron microscopy (SEM) revealed a highly porous, interconnected structure. The inclusion of CNC and AgNps enhanced PCL's biodegradability, hydrophilicity, and hydroxyapatite nucleation, all crucial for osteoconductivity. The scaffolds demonstrated mechanical properties suitable for bone regeneration, effective antibacterial activity against Escherichia coli, and cytocompatibility with Mesenchymal Stem Cells (MSCs). These findings highlight the potential of PCL/CNCx/AgNps scaffolds as advanced biomaterials for bone tissue engineering, since they offer enhanced resorbability, antibacterial protection, and structural adaptability.

Inflammatory bowel disease (IBD) is a complex disorder characterized by chronic gastrointestinal inflammation. This paper examines the use of Drosophila melanogaster as a model organism to investigate interactions among the gut microbiota, intestinal stem cells (ISCs), and signaling pathways involved in IBD pathogenesis. Key findings indicate that dysbiosis of the gut microbiota significantly contributes to IBD by altering immune responses and inflammatory signaling, leading to increased intestinal damage. Additionally, ISCs are crucial for intestinal regeneration; their dysregulation exacerbates injury, highlighting their role in maintaining gut homeostasis. Natural compounds, particularly those derived from traditional herbal medicines, show promise in alleviating IBD symptoms by targeting oxidative stress, regulating inflammation, and modulating autophagy, thus promoting ISC homeostasis and restoring microbial balance. This review underscores the intricate relationships among the gut microbiota, ISCs, and inflammatory pathways in IBD, as elucidated through Drosophila studies. The studies summarized here emphasize the need to address microbial imbalances, ISC dysregulation, and inflammatory mechanisms to develop effective therapeutic strategies. Further research is essential to fully elucidate these interactions and inform innovative treatments that improve patient outcomes in IBD management.

The ossification of the posterior longitudinal ligament (OPLL) is a progressive spinal disorder predominantly observed in Asian populations. Unfortunately, there is a limited availability of conservative therapies to impede the progression of OPLL. This study investigates the effects of cobalt chloride (CoCl2), which simulates an in vitro hypoxic microenvironment, on OPLL and explores its potential mechanisms, aiming to enhance our understanding of the pathogenesis of OPLL.

Inflammatory bowel disease (IBD), which encompasses ulcerative colitis and Crohn's disease, poses significant treatment difficulties because of its persistent course and underlying inflammatory mechanisms. Existing treatments primarily focus on alleviating symptoms, while novel biological drugs that target specific molecular pathways could address the root causes of the disease. One such pathway involves the farnesoid X receptor (FXR), a nuclear receptor essential for bile acid metabolism, intestinal homeostasis and modulation of inflammation. Activating FXR can reduce intestinal inflammation and improve gut barrier function, highlighting its potential as a treatment target for IBD. However, using synthetic agonists to directly activate FXR has drawbacks, including off‑target effects and limited effectiveness. Exosomes, tiny nanoscale vesicles involved in cell‑to‑cell communication, have emerged as promising therapeutic tools for regulating FXR signaling in IBD. Exosomes, particularly those derived from mesenchymal stem cells, can deliver bioactive molecules that promote FXR activation, reduce inflammation, and enhance tissue regeneration. The present review examines how exosomes regulate FXR signaling and their potential therapeutic use in IBD. It covers exosome biogenesis, therapeutic benefits and their molecular mechanisms in IBD.