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PubMed2026

ATF4-histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation.

BACKGROUND AND PURPOSE: The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation in vivo and in vitro. EXPERIMENTAL APPROACH: Acute sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated macrophages. CUT&Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms. KEY RESULTS: H4K5-hib levels were increased in macrophages during the acute inflammatory phase of sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation. CONCLUSION AND IMPLICATIONS: These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for sepsis.

Animals↗

PubMed2026

XsiAMT1.1a was identified as a novel ammonium uptake functional gene and its overexpression combined with GA4 application significantly increased yield in Arabidopsis thaliana.

Nitrogen (N) is a key limiting factor for plant yield. Ammonium is one of the main N forms absorbed by plants. Overexpression of ammonium uptake functional genes, such as ammonium transporter (AMT), can increase yield. However, the AMTs reported to enhance yield significantly is still limited. No researches have focused on the effect of overexpressing AMT combined with hormone application on yield improvement. In this study, we first investigated the role of XsiAMT1.1a, a potential ammonium uptake functional gene in an ammonium preference plant Xanthium sibiricum, in ammonium uptake by the analysis of bioinformatics, gene expression and subcellular localization, and the determination of ammonium uptake rate in endogenous silencing and heterologous overexpression plants. Subsequently, the effect of XsiAMT1.1a overexpression combined with hormone application on yield increase was further investigated in model plant Arabidopsis thaliana. Our results showed that XsiAMT1.1a shared the same conserved domains with AtAMT1 subfamily members and localized on the plasma membrane. XsiAMT1.1a was induced by N deficiency and highly expressed during the reproductive period. XsiAMT1.1a endogenous silencing and heterologous overexpression significantly decreased and increased ammonium uptake rates in X. sibiricum and A. thaliana, respectively. Overexpression of XsiAMT1.1a significantly improved total N accumulation, biomass and yield in A. thaliana, while XsiAMT1.1a overexpression combined with GA4 application had a stronger promoting effect on the above indicators. Our research identified a novel ammonium uptake functional gene, XsiAMT1.1a, and provided a new yield-increasing strategy which was verified in A. thaliana.

Arabidopsis↗

PubMed2026

Genomic identification and functional characterization of the nuclear receptor gene family in relation to sex determination and gonad development in the Pacific oyster (Crassostrea gigas).

Nuclear receptors (NRs) are a large superfamily of transcription factors that control a wide range of physiological processes by modulating the expression of downstream target genes. Numerous studies have confirmed that NR family members play critical and conserved roles in sex determination and gonadal development across metazoans. However, in mollusks, systematic characterization of NRs and their potential functions in gonadal regulation remain largely unexplored. In this study, 46 NR gene family members in the Pacific oyster (Crassostrea gigas) were identified and assigned to eight subfamilies. All NR family members contain at least one of the two core domains (DNA-binding domain, DBD; ligand-binding domain, LBD), and conserved exon-intron structures were observed within the same subgroup, indicating their evolutionary conservation. Furthermore, expression profiling revealed high expression of CgNR2F, CgNR5A1-1, and CgNR0B1 in undifferentiated gonads, suggesting their potential involvement in sex determination. CgNR1A and CgNR2E5 were specifically expressed in female gonads and exhibited female-biased expression patterns, indicating a putative role in ovarian development. Moreover, CgNR3A and CgNR3B showed high expression levels during the undifferentiated stage and early male development stage, implying their possible participation in male gonadal development and gametogenesis. These results expand the understanding of the NR gene family in C. gigas and help elucidate the potential functions of NR genes in sex determination and gonadal development.

Animals↗

PubMed2025

Parent-Child Communication after Parental Exposure to Potentially Traumatic Events: A Systematic Review.

Intergenerational traumatization poses a risk for the well-being of children whose parents have been exposed to potentially traumatic events (PTEs). Previous research has implied that parent-child communication may significantly contribute to the transmission of trauma across generations, but findings remain limited and inconclusive, particularly regarding the mechanisms and factors that could underlie this process. Therefore, the present paper performed a mixed methods systematic literature review to methodically map how PTE-exposed parents communicate with their children-both in general and about parental PTEs-and how such communication may contribute to trauma transmission. Five electronic databases were accessed to conduct keyword-led searches, yielding a final inclusion of 31 peer-reviewed, empirical studies that investigated parent-child communication among PTE-exposed parents and/or their nonexposed children. Parental PTE exposure was found to have a negative impact on general parent-child communication, often due to the presence of parental anger, irritability, and withdrawal. Conversations about parental PTEs showed substantial diversity in their frequency, content and style, with strategies of partial/modulated disclosure appearing most common. How parents approached PTE communication frequently stemmed from a desire to keep their children safe and unburdened by their previous experiences. Finally, both general communication and PTE communication were implied to contribute to trauma transmission, revealing a significant impact of parent-child communication on child functioning, identity, and well-being. Based on these key findings, the authors discuss meaningful implications for future research (i.e., prospective directions, addressing methodological concerns) and formulate suggestions for clinicians and policymakers surrounding the treatment of PTE-exposed parents and their offspring.

Humans↗

PubMed2026

Male accessory gland proteins in Grapholita molesta: Identification and reproductive functional validation of four accessory gland-specific lipases.

Accessory gland proteins (Acps), synthesized in the male accessory glands (AGs), are transferred to females via spermatophores during mating and elicit diverse post-mating physiological and behavioral responses. However, Acps have not been comprehensively characterized in Grapholita molesta, a cosmopolitan orchard pest. Here, using data-independent acquisition mass spectrometry, we describe an integrated proteomic approach combining comparative AG analyses (virgin vs. newly mated) with spermatophore profiling to identify Acps in G. molesta. According to the established screening criteria, we identified 83 confirmed Acps, which were classified into nine categories. Tissue-specific expression patterns of 20 randomly selected Acp genes were evaluated, revealing that these genes were specifically or highly expressed in male AGs. Among the 83 confirmed Acps, four Acps harbored the PLN02872 superfamily domain and were classified into the canonical lipase family. Notably, their transcripts were all highly expressed in the AGs during the pre-maturation stage. These four Acps were selected for preliminary validation of their male reproductive functions. RNAi-mediated knockdown of three out of four lipase genes in G. molesta males significantly decreased the fertility of mated females, with phenotypes including a significant reduction in egg production and egg hatching rate. This study provides a comprehensive catalog of high-confidence Acps, lays a foundation for subsequent in-depth functional characterization of these reproductive proteins, and offers promising molecular targets for the development of novel genetic regulation-based integrated pest management strategies.

Animals↗

PubMed2026

Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial.

BACKGROUND: Patients undergoing acoustic neuroma (AN) surgery often experience postoperative negative emotions, including anxiety, depression, and immune function suppression. This trial evaluated whether perioperative sub-anesthetic esketamine improves early postoperative negative emotions and immune function. METHODS: In this single-center, double-blind, randomized trial, 84 patients scheduled for AN surgery were assigned to esketamine (n = 42) or placebo (n = 42). The esketamine cohort received a continuous intravenous infusion of esketamine at 0.2 mg·kg-1·h-1 during anesthesia, followed by 1 mg·kg-1 esketamine as an adjuvant in patient-controlled intravenous analgesia (PCIA). The placebo group received saline. The primary outcome was the incidence of depression on postoperative day (POD1), defined as a Hospital Anxiety and Depression Scale-Depression subscale (HADS-D) score > 7. RESULTS: Seventy-seven patients completed the study (39 in the esketamine group, 38 in the placebo group). Esketamine significantly reduced the incidence of depression at POD1 (7.7% versus 31.6%; relative risk 0.24, 95% CI: 0.08-0.80, p = 0.008) and POD3 (0.0% versus 15.8%, relative risk 0.00, 95% CI: 0.00-0.47, p = 0.031) compared with placebo. The incidences of anxiety on POD1 and 3 and sleep disturbances on POD1 were also significantly reduced (p < 0.05). Notably, no significant differences were observed between the two groups in terms of immune function, postoperative pain scores, or intraoperative morphine equivalent. Adverse events did not differ between the groups. CONCLUSION: Perioperative sub-anesthetic esketamine reduced postoperative depression and anxiety, and improve sleep quality after AN surgery, without significant effects on early immune function or acute postoperative analgesia. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2400084537.

Humans↗

PubMed2026

Distinct cell morphotypes of Aureobasidium melanogenum ZN exhibit differential functional profiles in promoting maize growth.

Black yeast-like fungi of the genus Aureobasidium exhibit morphological plasticity, but whether distinct cellular states within the same genetic background are associated with different plant growth-promoting functions remains unclear. Here, yeast-like cells (YL), swollen cells (SC), and chlamydospores (CH) of Aureobasidium melanogenum ZN were characterized. YL was associated mainly with siderophore production and laccase activity, SC with extracellular polysaccharide accumulation, and CH with phosphate mobilization and higher ammonia and IAA production. Whole-genome and comparative genomic analyses revealed a shared repertoire related to nutrient acquisition, auxin-associated metabolism, extracellular oxidation, and carbohydrate remodeling, with expansions in nutrient- and cell-surface-related gene families. Transcriptomic and metabolomic analyses showed distinct deployment of these capacities, with CH exhibiting broad reprogramming of tryptophan-associated, nitrogen, phosphate, central-carbon, and amino-acid metabolism. In maize, CH at the optimal inoculation concentration of 105 CFU·mL-1 produced the strongest growth promotion, increasing plant height, dry biomass, root length, root surface area, and root volume by 58.6%, 365.1%, 191.0%, 194.3%, and 222.4%, respectively. Consistent with this pronounced growth phenotype, maize root transcriptomics showed coordinated CH-induced responses involving root development, nutrient transport, redox regulation, and root-interface remodeling. Root-zone tracking showed greater short-term stability and persistence of CH. These findings identify cellular state as an important functional dimension of Aureobasidium-plant interactions and provide a basis for developing fungal inoculants with defined beneficial cellular states.

Zea mays↗

PubMed2026

Functional characterization of the MdFLZ2 gene in drought and salt stress tolerance in apple.

Drought and salt stress are significant environmental limitations that severely constrain plant growth and productivity, therefore, enhancing stress tolerance is a key goal in crop improvement. The plant-specific FCS-like zinc finger (FLZ) proteins have been identified as important regulators of stress adaptation. In this study, we conducted a genome-wide characterization of the FLZ gene family in apple and functionally characterized MdFLZ2. qRT-PCR analysis revealed that MdFLZ2 was differentially expressed across various tissues and transcriptionally induced by both drought and salt stress. Subcellular localization assays demonstrated that the MdFLZ2 protein is localized to both the nucleus and the cytoplasm. The overexpression of MdFLZ2 in apple calli, Arabidopsis and tomato conferred increased resistance to drought and salt stress. In addition, yeast two-hybrid (Y2H) assays confirmed that MdFLZ2 interacted with MdSnRK1.1, and similar interactions were also detected between other MdFLZ family members and MdSnRK1.1. Collectively, our findings suggest MdFLZ2 as a positive regulator of drought and salt tolerance and highlight its potential to serve as a genetic resource for abiotic stress improvement.

Malus↗

PubMed2026

Effect of photobiomodulation on pain relief and functional improvement in fractures: a systematic review and meta-analysis.

INTRODUCTION: Fractures, the most common type of trauma, can cause considerable distress to patients. Pain can not only affect the comfort of fracture patients but also delay their participation in rehabilitation training. Photobiomodulation (PBM) has been associated with pain reduction and the promotion of tissue healing. This systematic review and meta-analysis aimed to evaluate the efficacy of PBM in reducing pain and promoting rehabilitation in patients with fractures. METHODS: This study was registered on PROSPERO (CRD42024591373). We systematically searched PubMed, EMBASE, the Cochrane Library and Web of Science for RCTs that investigated PBM in fractures as of August 2025. The primary outcome was the pain score. The secondary outcomes included functional and healing. RESULT: Finally, 12 and 9 studies were ultimately included in the systematic review and meta-analysis, respectively. The pooled analysis showed that the one-week pain score was lower in the PBM group than in the placebo group (MD -0.74, 95% CI -1.00, -0.47, p < 0.0001, I2 = 0%). Subgroup analysis showed that the difference between the two groups was statistically significant regardless of fracture site or acupoint irradiation. Changes in pain scores were statistically significant in both groups at different wavelength combinations. The improvement in grip strength at 4 weeks was significantly greater in PBM than in placebo (MD 5.03, 95% CI 4.29, 5.78; p < 0.0001; I2 = 0%). There were no significant differences in pain and functional scores at 4-26 weeks. Bone healing did not show differences between the two groups. No side effects reported. CONCLUSION: PBM appears to relieve short-term pain in fractures and improve grip strength in patients with upper limb fractures, but does not show significant long-term benefits. Evidence for mandibular functional recovery and bone healing remains inconsistent. Future studies should determine therapeutic parameters and their impact on bone healing and long-term functional outcomes across fracture types.

Humans↗

PubMed2026

Lactylation-related immune-metabolic dysregulation defines prognostic and therapeutic stratification in lung adenocarcinoma.

BACKGROUND: Lactylation links lactate metabolism with inflammatory signaling and immune regulation in tumors. However, its cellular distribution and translational value in lung adenocarcinoma (LUAD) remain unclear. METHODS: Single-cell RNA-sequencing datasets GSE189357 and GSE171145 were integrated to characterize lactylation-related activity, intercellular communication, and malignant epithelial cell states in LUAD. Single-cell-derived lactylation-related differentially expressed genes were mapped to TCGA-LUAD and multiple GEO cohorts. Univariate Cox regression and machine learning algorithms were used to construct a lactylation-related prognostic signature (LRPS). The associations of LRPS with prognosis, immunotherapy response, drug sensitivity, genomic alterations, immune infiltration, and inflammation- and metabolism-related pathways were evaluated. KRT7 was further validated using virtual knockout analysis, spatial transcriptomics, and in vitro and in vivo experiments. RESULTS: lactylation-related transcriptional activity showed heterogeneous distribution across LUAD cell populations and was associated with altered cell-cell communication. In malignant epithelial cells, LRTS-high and LRTS-low states exhibited distinct metabolic, inflammatory, and tumor-related pathway activities. LRPS showed stable prognostic performance in TCGA-LUAD and multiple GEO cohorts and remained an independent prognostic factor. Low LRPS was associated with greater potential benefit from immunotherapy, whereas different LRPS groups displayed distinct drug sensitivity, genomic alteration, and immune microenvironment patterns. KRT7 was highly expressed in LUAD and associated with poor prognosis. KRT7 knockdown suppressed LUAD cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. CONCLUSIONS: This study identifies lactylation-related immune-metabolic dysregulation as a clinically relevant feature of LUAD and develops a single-cell-guided LRPS for prognosis and therapeutic stratification. KRT7 emerged as an LRPS-related functional candidate with experimentally supported roles in malignant LUAD phenotypes.

Immunotherapy↗

PubMed2026

Functional Reading Activities to Motivate and Empower: Maintenance of Reading Outcomes for Young Adults With Intellectual and Developmental Disabilities Following a Randomized Controlled Trial.

PURPOSE: This study examined whether the effects of Functional Reading Activities to Motivate and Empower (FRAME), a functional, strategy-based reading comprehension intervention for young adults with intellectual and developmental disabilities (IDDs), were maintained 6 months following the completion of the intervention and explored participants' perceptions of the intervention's feasibility, relevance, and perceived impact. METHOD: Participants were 44 young adults with IDDs (ages 18-26 years) who participated in a previously reported randomized controlled trial (FRAME participants: n = 23; controls: n = 21). Trial outcomes were assessed via telepractice at pretest, posttest, and 6-month follow-up. Six-month maintenance analyses focused on outcomes that demonstrated significant posttest group differences: use of (a) reading comprehension strategies (proximal) and (b) reading comprehension questions (distal). Participant perceptions (social validity) were collected post-intervention from FRAME participants using a structured interview protocol with closed- and open-ended items. RESULTS: At the 6-month follow-up, FRAME participants demonstrated sustained but reduced improvements in strategy use relative to controls (p = .040). Between-groups differences were not maintained for reading comprehension questions (p = .091). Participants reported high acceptability and perceived relevance of FRAME, with qualitative themes reflecting perceived improvements in comprehension, self-improvement, and increased independence. CONCLUSION: Findings suggest that FRAME supports sustainable gains in reading comprehension strategy use and is perceived as meaningful and feasible for young adults with IDDs, although additional supports may be needed to promote sustained improvements in distal comprehension outcomes. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.33307218.

Humans↗

PubMed2026

Identification and functional analysis of MeJA-responsive bHLH family genes in Taraxacum kok-saghyz.

Taraxacum kok-saghyz (T. kok-saghyz) is considered a highly promising alternative source of natural rubber (NR), as its roots synthesize high-molecular-weight NR comparable to that produced by Hevea brasiliensis. The basic helix-loop-helix (bHLH) family of transcription factors (TFs) plays crucial roles in plant organogenesis, hormonal signal transduction, and the regulation of secondary metabolism. This study aimed to systematically identify TkbHLH family members and to elucidate their potential functions in responding to methyl jasmonate (MeJA) and regulating root development. Based on the T. kok-saghyz genome, 172 TkbHLH members were identified and phylogenetically classified into 16 subfamilies. Among these, 37 genes were selected due to their significant induction by MeJA. Sequence analysis confirmed all encoded proteins contain the conserved bHLH domain. Subcellular localization verified nuclear localization of five core TkbHLH proteins. Interactions were shown by yeast two-hybrid and bimolecular fluorescence complementation, revealing these proteins form homodimers and heterodimers. Notably, a specific interaction was detected between TkbHLH162 and TkHMGS1, a key enzyme in the mevalonate (MVA) pathway, suggesting a potential molecular link between JA signaling and the rubber biosynthesis precursor pathway. Functional characterization via overexpression assays showed that selected TkbHLH genes significantly either promoted or inhibited root elongation. In summary, this study presents the first systematic characterization of the bHLH TF family in T. kok-saghyz, elucidating its involvement in JA signal response, protein interaction networks, and root development regulation. These findings provide a crucial foundation for further investigation into the molecular mechanisms by which TkbHLH TFs influence root morphogenesis and NR biosynthesis in T. kok-saghyz.

Taraxacum kok-saghyz (T. kok-saghyz)↗

PubMed2026

Engineering bubble structures as Cas12a activators for highly sensitive monitoring of WRN helicase function.

The Werner syndrome helicase (WRN) is a critical synthetic lethal target in microsatellite instability cancers, essential for resolving complex genomic structures like replication bubbles and R-loops. However, strategies to simultaneously discriminate WRN activity on DNA versus DNA-RNA substrates in living cells are lacking. Here, we developed a structure-specific CRISPR/Cas12a biosensing strategy to visualize WRN functional activity by engineering bubble-structure probes. These probes were rationally designed to structurally mimic DNA replication bubbles and R-loop associated DNA-RNA hybrids. Upon specific unwinding by WRN, the probes release a sequestered activator strand that triggers Cas12a trans-cleavage, effectively converting the unwinding event into an amplified fluorescent signal. This assay achieves low picomolar sensitivity (LODs: 5.6-6.0 pM) and exceptional selectivity against homologous RecQ helicases. Uniquely, this strategy enables the parallel quantification of WRN activity on both substrate types, providing insights into distinct WRN-mediated pathways for resolving genomic stress. We further demonstrated the strategy's utility by visualizing endogenous WRN dynamics in living cells and profiling the efficacy of small-molecule inhibitors. This work offers a powerful molecular toolkit for dissecting WRN biology and facilitating high-throughput drug screening in targeted cancer therapy.

Werner Syndrome Helicase↗

PubMed2026

Clinical efficacy and brain mechanism characteristics of guide chi and regulate spirit tuina therapy in the treatment of post-stroke walking dysfunction: A randomized controlled trial based on fNIRS.

BACKGROUND: This study aims to preliminarily evaluate the role of Guide Chi and Regulate Spirit(GCRS) Tuina in enhancing walking function in post-stroke patients with walking dysfunction; secondly, by using functional near-infrared spectroscopy (fNIRS), it investigates the effect of GCRS Tuina on the restoration of brain function in this patient population. METHODS: Participants in the control group received 4-week rehabilitation treatment, while those in the Combined Tuina Group (CTG) additionally received GCRS Tuina therapy for another 4 weeks on this basis. Functional Ambulation Category (FAC), Fugl - Meyer Assessment Scale for Lower Extremity Motor Function (FMA - LE), and Modified Barthel Index (MBI) were evaluated at the baseline and after 4 treatment weeks. A gait and motion analysis system was used to measure step length, stride, walking speed, and step frequency. FNIRS was used to measure the resting-state functional connectivity(FC) strength, as well as the β - value and HbO2 concentration mean during the walking task. RESULTS: A total of 60 participants completed the randomized, and 53 completed the trial and entered the statistical analysis. Compared with the Single Rehabilitation Group(SRG), the CTG group had higher FAC, FMA-LE, and MBI scores after 4 weeks. After the treatment course, the standardized step length, stride, walking speed, and step frequency of the CTG were higher than SRG. At the Region of Interest(ROI) level, the CTG exhibited 13 inter-ROI FC strengths that were higher than SRG, and the differences could survive the FDR correction (PFDR<0.05). Under the walking task, the CTG group had higher β values in 18 channels and higher Oxyhemoglobin(HbO2) concentrations in 19 channels than the SRG (PFDR <0.05). CONCLUSION: GCRS Tuina therapy can significantly improve patients' walking function, enhance lower limb motor ability and daily living ability. It can improve walking efficiency. Tuina can significantly increase the FC and enhance the activation levels and HbO2 concentrations. The stimulation of Tuina may help reconstruct the brain's motor control network, restore impaired motor function, promote the occurrence of neural plasticity, strengthen the neural circuits in the cognitive-motor-sensory cortex to improve walking function. TRIAL REGISTRATION: This study has been registered with the International Traditional Medicine Clinical Trial Registry (ITMCTR2024000654).

Humans↗

PubMed2026

Integrated widely targeted metabolomics and GC-IMS reveal dynamic flavor, nutritional, functional, and metabolic profiles in macadamia kernels during processing.

Different processing stages influence the color, flavor, and antioxidant activities of macadamia kernels. However, the biochemical mechanisms that occur during processing are not well known. This study integrated widely targeted metabolomics (UPLC-MS/MS) with GC-IMS to systematically characterize non-volatile and volatile compounds in macadamia kernels across key three sample groups: fresh kernels (FMN), low-temperature-dried kernels (DMN), and roasted kernels (BMN). A total of 622 non-volatile metabolites and 52 volatile compounds were identified. Low-temperature drying promoted the accumulation of phenolic acids and flavonoids, enhancing antioxidant capacity. Roasting degraded heat-sensitive nutrients but generated flavor compounds via Maillard reaction and lipid oxidation, shifting aroma from green to nutty notes. Nutritional assessment confirmed that roasting significantly reduced antioxidant activities and bile acid binding capacity. Pearson correlation analysis verified the key metabolite-antioxidant relationships. These findings provide critical insights into metabolic dynamics during nut processing and establish a scientific basis for optimizing thermal processing strategies.

Metabolomics↗

PubMed2026

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs)-arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin)-led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Actin dysfunction also displayed a more "aged" transcriptome using previously validated transcriptomics clocks, and broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting some links between aging and actin across organisms. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how changes in actin integrity correlate with diverse aging phenotypes across tissues. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics can potentially influence aging.

actin↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2026

The interplay between circadian misalignment or sleep disturbances and cognition and brain function in individuals with different degrees of insulin resistance - a systematic review.

Disruption of sleep increases the risk of type 2 diabetes and worsens cognitive outcomes, yet few studies have evaluated the interaction between insulin resistance and sleep parameters in relation to cognitive outcomes or the risk of dementia. This systematic review examines how circadian misalignment and sleep disturbances affect cognition and neuroimaging findings in individuals with varying degrees of insulin resistance. Across 27 studies, disrupted circadian rhythmicity and sleep disturbances were negatively associated with brain health, possibly through its effects on insulin sensitivity, whereas the impact of sleep duration and quality were inconclusive. Methodological heterogeneity, reliance on cross-sectional designs, and limited control for confounders restricted definitive conclusions and highlighted the need for longitudinal and interventional studies with objective measurements. Nonetheless, the findings support circadian rhythmicity as a potentially modifiable risk factor for preserving cognition in insulin-resistant populations. Future research should prioritise prospective and interventional studies and focus on biological markers rather than self-reported outcomes.

Humans↗