SEARCH · Search PubMed

Results for “target lesion revascularization”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

620 records · Page 11Linked to original sources

PubMed2026

METTL14-mediated m6A modification of CCNE1 accelerates progression of myelodysplastic syndromes via MAPK-ERK and PI3K-AKT signaling pathways.

BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification and plays a key role in the initiation, progression, and relapse of multiple cancers, including hematologic malignancies. However, the role of m6A and m6A regulatory genes in myelodysplastic syndromes (MDS) remains unclear. This study aims to elucidate the function and molecular mechanism of methyltransferase METTL14 in MDS. METHODS: RT-qPCR was used to assess the expression of multiple m6A regulators, focusing on METTL14 in MDS patients and cell lines. METTL14 overexpressing and knockdown cell lines were established, and CCK-8, EdU, and flow cytometry assays were performed to explore the biological functions of METTL14.Dot blot, MeRIP-Seq, MeRIP-qPCR, RT-qPCR, and Western blot were employed to investigate the underlying molecular mechanism. RESULTS: Dysregulation of multiple m6A regulators was observed in MDS, among which METTL14 was upregulated. Elevated METTL14 expression increases MDS risk and adverse prognosis, emerging as a biomarker for poor prognosis. METTL14 promoted proliferation and cell-cycle progression of MDS cells while inhibiting apoptosis; corresponding changes were observed in cell cycle and apoptosis markers. METTL14 regulated cellular m6A levels. Downstream targets of METTL14 were enriched in cell cycle-related pathways, with CCNE1 identified as a critical target. Knockdown of METTL14, actinomycin D, or S-adenosylhomocysteine treatment reduced CCNE1 mRNA and protein levels. Furthermore, METTL14 activated MAPK-ERK and PI3K-AKT signaling via CCNE1 in an m6A-dependent manner, thereby promoting proliferative MDS cells' capacity. CONCLUSIONS: This study delineates a METTL14/m6A/CCNE1 signaling axis in MDS progression and suggests that METTL14-mediated m6A modification may be a potential therapeutic target for MDS.

Humans↗

PubMed2026

Transcranial Alternating Current Stimulation at 40 Hz Improves Social Functioning in Children With Autism Spectrum Disorder: A Randomized Clinical Trial.

BACKGROUND: Autism spectrum disorder (ASD) lacks rapid and effective interventions for its core social difficulties. The right temporoparietal junction (rTPJ), a critical hub for social cognition, together with gamma band abnormalities implicated in ASD, provides a promising neuromodulation target. METHODS: In this randomized, double-blind, sham-controlled trial, 47 children with ASD (39 male; mean [SD] age = 8.79 [2.71] years) were assigned to receive either 21 sessions of 40-Hz high-definition transcranial alternating current stimulation (tACS) targeting the rTPJ (3 sessions/day for 7 days) or sham stimulation, with assessments conducted at baseline, postintervention (week 1), and a 3-week follow-up (week 4). The primary outcome was change in Ohio State University Autism Rating Scale-DSM-5 (OARS-5) total scores. Secondary outcomes included the Aberrant Behavior Checklist-Second Edition, Social Responsiveness Scale-Second Edition, and Short Sensory Profile. Eye-tracking metrics during Frith-Happé animations were exploratory measures of theory of mind (ToM)-related social cognitive processing. RESULTS: The active group demonstrated significant improvements in OARS-5 total scores at week 1 (mean difference = -1.13, 95% CI [-1.78 to -0.47], p < .001) and week 4 (mean difference = -1.47, 95% CI [-2.20 to -0.74], p < .001). Improvements in selected behavioral and sensory domains were observed. Average fixation duration during ToM animations showed a significant group × time interaction. No serious adverse events occurred. CONCLUSIONS: These findings suggest that 40-Hz tACS targeting the rTPJ may be associated with rapid improvements in ASD symptom severity, particularly social functioning, in children with ASD, while being well tolerated. Clinical significance requires further evaluation.

Humans↗

PubMed2026

Insulin, Semaglutide and Dapagliflozin in Adults With Type 1 Diabetes: Design and Methods of Triple Therapy for Type 1 Diabetes (TTT1)-An International Phase 3 Clinical Trial.

AIMS: Attaining target glycaemia can be a challenge in Type 1 Diabetes (T1D) due to insulin-induced weight gain. Adjunct therapy with modern glucose-lowering agents developed for type 2 diabetes (T2D) has great potential but may be insufficiently efficacious and carries risks of hypoglycaemia and ketosis. We designed the first Phase 3 clinical trial to assess the efficacy and safety of adding a Glucagon-Like Peptide 1 receptor agonist (GLP-1RA) and a Sodium-Glucose Co-transporter (SGLT2) Inhibitor to insulin therapy in overweight and obese adults with T1D and glycaemia above target (HbA1c 7.5%-11.0% inclusive) (NCT03899402). MATERIALS AND METHODS: In Period 1, participants are randomized 2:1 (open label) for 26 weeks to semaglutide and insulin (uptitrated to 1.0 mg weekly) or standard insulin therapy. In Period 2, those randomized to semaglutide and insulin in Period 1 are further randomized (double-blind) for 26 weeks to dapagliflozin (10 mg daily) or placebo, in addition to semaglutide. The primary objective is to compare change in HbA1c on 'triple therapy' (dapagliflozin, semaglutide and insulin) with 'dual therapy' (placebo, semaglutide and insulin). Secondary objectives include comparisons of triple therapy with standard insulin therapy and dual therapy (semaglutide and insulin) with standard insulin therapy. Safety outcomes include hypoglycaemia and ketosis. A sample size recalculation during the trial based on analysis of masked data revised the original recruitment target from 114 to 82 participants. CONCLUSION: The TTT1 trial will provide clinically useful information on combination adjunct therapy in the treatment of T1D.

Humans↗

PubMed2026

Characterizing Submental Neuromuscular Activity of Swallowing Rehabilitation: An Electromyographic Evaluation of Rehabilitative Maneuvers in Healthy Adults.

PURPOSE: The effortful swallow (ES), the Mendelsohn maneuver (MM), and isometric tongue presses (TPs) are widely used swallowing maneuvers/exercises to improve elements of swallowing, such as muscle strength and biomechanics. However, the underlying neuromuscular mechanisms of these exercises remain unclear, potentially limiting our ability to specify treatment targets and improve treatment efficacy. This study aimed to compare submental neuromuscular activation patterns during the ES, MM, TPs, and typical swallows in healthy young and older adults. METHOD: As part of a larger randomized crossover validation study, 60 healthy adults (30 young and 30 older) completed typical swallows and three maneuvers using a wearable submental surface electromyographic (sEMG) system (i-Phagia). Outcome variables included (a) normalized mean sEMG amplitude and (b) time to peak sEMG amplitude. Linear mixed models were used to examine effects of task, age, and sex on both outcomes. RESULTS: Normalized mean amplitude was significantly different across tasks. Post hoc pairwise comparisons confirmed that all three maneuvers produced higher normalized mean sEMG amplitude than typical swallows, with the ES eliciting the highest amplitude across age groups. Time to peak amplitude differed significantly across tasks, with typical swallows requiring the shortest time to reach peak amplitude, followed by the ES, MM, and TP. CONCLUSIONS: The ES required the highest neuromuscular effort with the shortest time to reach peak amplitude, suggesting its potential for targeting submental muscle power. Typical swallows required the least neuromuscular effort with the shortest time to reach peak amplitude, suggesting their potential for training submental muscle speed. The MM and TP may also improve submental muscle strength; however, given their temporal requirements (longer durations), they may be more beneficial for targeting coordination and endurance, though more research in this area is warranted. These findings underscore the importance of task-specific neuromuscular profiling to inform mechanism-based swallowing rehabilitation. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32948549.

Humans↗

PubMed2026

A Meta-learning-driven strategy for adulteration detection in sweet potato starch and vermicelli using Raman spectroscopy.

To address the widespread adulteration of sweet potato starch and its vermicelli with cheaper starches and overcome conventional supervised learning's dependency on large labeled datasets, this study developed a few-shot discrimination method integrating Raman spectroscopy with meta-learning. We constructed a meta-learning framework using cassava- and wheat-adulterated sweet potato starch as the source domain for training, with potato-adulterated sweet potato starch and cassava-adulterated sweet potato vermicelli as two target domains for testing. Raman spectra showed high consistency between sweet potato vermicelli and its raw starch, laying the foundation for cross-domain detection. Testing yielded comprehensive classification accuracies of 95.33% and 98.00% for the two target domains, significantly outperforming SVM, RF, and CNN (max. 85.24%). This approach effectively identifies subtle starch variety differences in complex adulteration, providing novel food quality inspection solutions and verifying the feasibility of raw material-to-finished product cross-domain detection.

Ipomoea batatas↗

PubMed2026

Adaptive Sports Exposure Across Physical Medicine and Rehabilitation Residency and Sports Medicine Fellowship Programs: A National Cross-Sectional Website Analysis.

Adaptive sports improve health and quality of life for people with disabilities, yet the extent of adaptive sports exposure in physical medicine and rehabilitation (PM&R) training is unclear. This cross-sectional study reviewed the public websites of 115 accredited physical medicine and rehabilitation residency programs and 26 sports medicine fellowship programs for any mention of adaptive sports, characterizing exposure type, target populations, and associated program characteristics. Adaptive sports were mentioned by 32 residency programs (27.8%) and 8 fellowship programs (30.8%). Mention varied significantly by geographic region in both cohorts (residency, West 64% vs. South 19%, P=.017; fellowship, Midwest 80% vs. South 0%, P=.035) and, among residencies, was associated with larger program size and a greater number of associated subspecialty fellowships. Residency exposure was predominantly volunteer-based, whereas fellowship exposure was exclusively clinical or undisclosed; target populations served were frequently unspecified. Programs have an opportunity to expand structured adaptive sports training and to clearly convey these opportunities to applicants and patients.

Adaptive sports↗

PubMed2026

A Conserved 3'UTR Stem-loop Directs UPF1/eIF4AIII-Dependent Regulation of GABARAPL1 mRNA.

RNA-binding proteins (RBP) interact with mRNA untranslated regions containing cis-regulatory elements to govern mRNA localization, stability, and translational efficiency. Among these trans-regulatory factors, RNA helicase UPF1 is a central factor which play a role in multiple mRNA decay pathways, including nonsense-mediated mRNA decay (NMD). NMD is triggered when an exon-junction complex (EJC) is located downstream of a premature termination codon. However, in some cases, NMD can be activated in an EJC-independent manner through mechanisms involving the 3'UTR. In the present study, we focused on the GABARAPL1 3'UTR, as previous studies had shown that this region plays a key role in NMD targeting, although the underlying molecular mechanism had not yet been elucidated. Unlike canonical NMD targets such as SC35, we found that the chemical inhibition of eIF4AIII helicase activity did not affect GABARAPL1 transcript levels, indicating that this transcript is regulated through its 3'UTR via an EJC-independent mechanism. We therefore investigated the potential presence of cis-regulatory element within the 3'UTR of GABARAPL1 which can regulate mRNA and protein levels in a UPF1-dependent manner. Furthermore, we identified a conserved RNA region spanning nucleotides 364-421 involved in GABARAPL1 targeting and used biochemical analysis to demonstrate the direct binding of UPF1 and eIF4AIII to this RNA region, to analyse its secondary structure in solution, and to map the protein-binding sites. By complementing these approaches with molecular modelling, we showed that this stem-loop adopts a stable global fold but a local flexibility and dynamic behaviour properties. Together, our results support the role of UPF1 and eIF4AIII as specific regulators of GABARAPL1 transcript and reveal a novel RNA regulatory element within its 3'UTR, which provides a completely unexpected binding site for these factors.

3' Untranslated Regions↗

PubMed2026

Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97Ufd1-Npl4 complex.

The AAA ATPase VCP/p97 has emerged as a critical regulator of ubiquitin and chromatin-associated processes but progress in understanding has been hampered by the complexity of p97 functions and the various p97 cofactors involved. Here, we combined ubiquitin profiling with acutely induced degradation of the Ufd1 subunit of the p97 ubiquitin adapter, Ufd1-Npl4, in human cells. We identified a set of chromatin regulators, HUS1, XRCC1, MORF4L1, and the cohesin subunit RAD21 as targets of p97Ufd1-Npl4 We find that RAD21 is ubiquitylated and targeted by p97Ufd1-Npl4 specifically in S phase to remove a subpopulation of cohesin from chromatin. Acute degradation of Ufd1 in S phase, after replication licensing is completed, impedes replication and leads to replication-associated DNA damage. Our findings suggest that a fraction of cohesin rings need to be removed by p97Ufd1-Npl4 from DNA to allow unhindered replication and reveal a critical function of p97 that ensures genome stability.

Cell Cycle Proteins↗

PubMed2026

Suppression of AAV-Delivered Transgene Expression Using Artificial MicroRNAs Delivered by an Alternative AAV Serotype.

Adeno-associated virus (AAV) gene transfer vectors mediate long-term expression in nondividing cells, an advantage for treating chronic disorders. However, current platforms lack a way to selectively shut down transgene expression if adverse effects arise. To create an "off switch," we hypothesized that incorporating unique artificial microRNA (amiRNA) target sequences into an AAV expression cassette would allow subsequent suppression of transgene expression using a second AAV vector encoding the cognate amiRNA. We introduced 22-nt sequences absent from human and mouse transcriptomes into the 3' untranslated region (UTR) of a therapeutic AAV cassette. To identify optimal amiRNAs, two tandem copies of each amiRNA were cloned into the 3'UTR of an mCherry reporter gene. In vitro assessment of six amiRNA/target pairs using a dual luciferase assay identified four amiRNAs that efficiently suppressed reporter expression. Cells cotransfected with target site 3 (TS3) and amiRNA-T3B showed the greatest reduction in luciferase activity (80%, p < 0.0001) and were selected for further study. The "off-switch" system was then evaluated using an AAV5 therapeutic vector expressing a recombinant humanized anti-IgE monoclonal antibody (AAV5-TBG-anti-IgE-TS3), designed for long-term suppression of allergen-induced reactions. Co-transfection of HEK293T cells with anti-IgE-TS3 and amiRNA-T3B significantly reduced anti-IgE mRNA and protein levels relative to a control amiRNA (p < 0.0001). In vivo testing in Balb/c mice (n = 5) involved intravenous administration of AAV5-anti-IgE-TS3 (3.2 × 1010 gc), followed 4 weeks later by an AAVrh.10 amiRNA vector (AAVrh.10-TBG-amiRNA-T3B; 1 × 1011 gc). Control mice receiving only the therapeutic vector expressed 18.4 ± 13.8 µg/mL serum anti-IgE at 10 weeks. In contrast, mice receiving the amiRNA "off" vector showed marked suppression of anti-IgE (0.3 ± 0.15 µg/mL, p < 0.0001). These findings provide proof-of-concept that AAV-delivered amiRNAs can selectively switch off transgene expression, offering a strategy to improve the safety of AAV-mediated gene therapies.

Dependovirus↗

PubMed2026

Microglial modulation in general anesthesia: molecular.

General anesthetics profoundly alter brain function and consciousness, yet the mechanisms underlying these effects remain incompletely understood. Although traditional studies have primarily focused on neuronal targets, accumulating evidence suggests that microglia dynamically respond to anesthetic exposure and may participate in anesthesia-associated neurophysiological changes. Beyond their established immune functions, microglia are increasingly implicated in synaptic remodeling, metabolic regulation, neuronal activity surveillance, and neuron-glia communication. Recent studies indicate that different classes of anesthetic agents modulate microglial activity through diverse and context-dependent mechanisms involving inflammatory signaling, purinergic pathways, calcium dynamics, mitochondrial metabolism, and neural circuit interactions. These responses are associated with postoperative neurocognitive disorders, altered synaptic plasticity, and anesthesia-related changes in brain states. In this review, we summarize current evidence regarding the effects of volatile anesthetics, intravenous anesthetics, and analgesics on microglial function and discuss the molecular, functional, and circuit-level mechanisms underlying anesthesia-associated neuron-microglia interactions. We further highlight the dynamic and heterogeneous nature of microglial responses during anesthesia and discuss current limitations in the field, including the lack of temporally resolved and cell-specific approaches. Understanding these processes may provide insights into anesthesia-associated neurocognitive dysfunction and support the development of neuroimmune-targeted strategies in anesthesiology.

General anesthesia↗

PubMed2026

Closed-loop vasopressor systems for hemodynamic control in perioperative and critical care settings: a systematic review and meta-analysis.

Maintaining mean arterial pressure (MAP) within a predefined target is central to haemodynamic management in surgical and critically ill adults receiving vasopressors. Closed-loop vasopressor (CLV) systems automate titration to optimise blood pressure control, but their clinical effectiveness remains uncertain. We performed a systematic review and meta-analysis comparing CLV with manual titration. This PRISMA 2020-compliant review was prospectively registered in PROSPERO (CRD420250655697). MEDLINE, Embase, Scopus, Web of Science, CENTRAL, and the Cochrane Library were searched (January 2000-June 2025). Randomised controlled trials enrolling adults receiving vasopressors in perioperative or intensive care settings were included. Primary outcomes were time within the MAP target range and time spent in hypotension or hypertension. Risk of bias was assessed using RoB 2.0 and certainty of evidence using GRADE. Random- or fixed-effects models were selected according to heterogeneity. Six randomized controlled trials (215 patients) were included in the systematic review, whereas five perioperative trials contributed to the meta-analysis of haemodynamic control outcomes, and one ICU-based study was summarized narratively because it did not report comparable MAP control endpoints. CLV increased time within the MAP target range (mean difference [MD] 33.94%, 95% CI 20.41-47.46; I2 = 77%) and reduced time in hypotension (MD - 18.24%, 95% CI - 28.95 to - 7.53; I2 = 73%). There was no significant difference in time in hypertension, cumulative norepinephrine dose, or major/minor adverse events. ICU length of stay was not pooled because of clinical and methodological heterogeneity. Certainty of evidence ranged from low to high (moderate for haemodynamic control outcomes). CLV systems improved haemodynamic control, primarily in perioperative settings, but heterogeneity and small samples limit confidence in effect size and generalisability. Evidence in critically ill populations remains limited, and larger trials are needed to determine whether improvements in these physiological surrogate endpoints translate into meaningful patient-centred outcomes.

Humans↗

PubMed2026

Physician-Modified Fenestrated Stent-Grafts Planned Using Three-Dimensional Techniques for Complex Aortic Pathology: A Systematic Review and Meta-Analysis.

BACKGROUND: Complex aortic pathology involving the visceral arteries remains a significant therapeutic challenge. Open repair is associated with considerable perioperative risk, particularly in patients with multiple comorbidities, while standard endovascular aneurysm repair (EVAR) is often not feasible because of inadequate proximal sealing zones. Fenestrated and branched endovascular repair (F/BEVAR) represents an established treatment strategy; however, the use of custom-made devices is limited by manufacturing time and availability. Physician-modified stent grafts (PMSGs) have therefore emerged as a pragmatic alternative. Three-dimensional planning techniques have been increasingly used to facilitate accurate graft modification. The aim of this systematic review and meta-analysis was to evaluate the effectiveness and safety of PMSG procedures planned with three-dimensional techniques. Technical success, target vessel patency, early mortality, endoleak occurrence, and reintervention rates were analyzed. METHODS: A systematic search was conducted in the PubMed/MEDLINE and Embase databases. Studies describing the use of physician-modified fenestrated stent grafts planned with three-dimensional tools were included. Meta-analyses were performed using a random-effects model with restricted maximum likelihood estimation. A logit transformation was used for the analysis of proportions. RESULTS: The analysis included five studies involving 172 patients. The estimated weighted mean follow-up duration was 14.9 months. The overall technical success rate was 92.9% (95% confidence interval [CI]: 84.5-96.9%), with low-to-moderate heterogeneity. Target vessel patency was 96.9% (95% CI: 93.6-98.5%). Early mortality was 5.5% (95% CI: 2.1-13.3%). The incidence of endoleaks was 13.3% (95% CI: 5.8-27.4%), with significant heterogeneity among studies. Reinterventions were reported in 6.6% of patients (95% CI: 2.3-17.5%). CONCLUSION: The results indicate that PMSG procedures planned with three-dimensional techniques are associated with a high rate of technical success and preserved patency of target vessels in patients with complex aortic pathology. The observed variability in endoleak and reintervention rates likely reflects differences in anatomical complexity and patient selection among studies. Further prospective studies are needed to confirm long-term outcomes.

Humans↗

PubMed2026

Messaging Strategies for Tobacco Prevention and Cessation Among People with Depression: A Scoping Review.

INTRODUCTION: Depression is strongly associated with higher tobacco use and lower quit rate; few communication campaigns have been designed with these mental health factors in mind. This scoping review compiles existing research on tobacco prevention and cessation messaging involving people with depression to identify gaps and opportunities for future message development. METHODS: Sources included PubMed, PsycINFO, Scopus, Academic Search Premier, and ProQuest Central (November - December 2024). The 55 studies included examined tobacco prevention or cessation messages and measured depression, depressive symptoms, or mental health as a primary outcome or analytic covariate. Study characteristics, target population, delivery format, message content, theoretical frameworks, outcomes, and gaps were extracted. RESULTS: RCTs made up half (51%) of the included studies, and most (78%) were conducted in the U.S. Nearly half (46%) required participants to have a mental health condition. Interventions most often used interactive (65.5%) or text-based (47.3%) communication and focused on tobacco cessation (89%) rather than vaping (9%). Common outcomes included feasibility or acceptability (37.7%) and point prevalence abstinence (37.7%). Mental health-specific messages showed mixed effectiveness. CONCLUSIONS: Despite progress in integrating mental health into tobacco messaging, targeted interventions for people with depression remain limited. Few studies tested long-term outcomes or used biochemical verification; many relied on untargeted generalized messaging.

Journal Article↗

PubMed2026

Intravenous lidocaine reduces the propofol EC50 for loss of consciousness and intraoperative anesthetic consumption in gynecological laparoscopy: A randomized controlled trial.

BACKGROUND: Intravenous lidocaine reduces propofol requirements and procedure-related adverse events. OBJECTIVES: The study aimed to test whether intravenous lidocaine would reduce the effect-site concentration of propofol required to achieve loss of consciousness and decrease propofol consumption during total intravenous anesthesia in gynecological laparoscopy. METHODS: This was a prospective, randomized, double-blind, placebo-controlled trial. Sixty patients were randomly allocated to receive either intravenous lidocaine (1.5 mg·kg-¹ bolus) followed by continuous infusion or an equal volume of saline. Propofol was administered via target-controlled infusion starting at an effect-site concentration of 3.5 μg/mL. The concentration was then adjusted in steps of 0.5 μg/mLaccording to Dixon's up-and-down sequential method: decreased if loss of consciousness was achieved, or increased if not. Loss of consciousness was defined as loss of response to verbal commands. The median effective concentration (EC50) of propofol for inducing loss of consciousness was calculated using the Dixon's up-and-down method. General anesthesia was maintained with propofol and remifentanil, guided by state entropy (target 40-60) and surgical pleth index (target 20-50). Drug consumption was normalized to anesthesia duration and body weight. RESULTS: The estimated EC50 of propofol for inducing loss of consciousness was significantly lower in the lidocaine group than in the saline group (3.32 μg/mL, 95% Confidence Interval (CI): 3.04-3.59 vs. 3.89 μg/mL, 95% CI: 3.50-4.28). Under the study protocol, the lidocaine group also required less propofol (8.62 mg·kg-1·h-1, 95% CI: 8.10-9.15 vs. 9.89 mg·kg-1·h-1, 95% CI: 9.05-10.73) and less remifentanil (0.23 μg·kg-1·min-1, 95% CI: 0.21-0.24 vs. 0.27 μg·kg-1·min-1, 95% CI: 0.24-0.30) compared with the saline group. CONCLUSION: Intravenous lidocaine reduced the propofol EC50 for Loss of Consciousness (LOC) and decreased intraoperative propofol and remifentanil consumptions in patients undergoing gynecological laparoscopy. These findings suggest a propofol- and opioid-sparing effect of intravenous lidocaine in this setting, although confirmation in larger multicenter trials is needed.

Humans↗

PubMed2026

A transcription factor-focused CRISPR screen identifies SKI as a BCL11A-independent repressor of ζ-globin.

The regulation of α-like globin genes, particularly the embryonic ζ-globin gene (HBZ), remains incompletely understood. To identify transcriptional regulators of HBZ, we establish a GFP reporter system based on the HBZ-P2A-GFP allele in erythroid cell lines and conduct a CRISPR/Cas9 screen targeting 1639 transcription factors. This screen identifies SKI as a potent HBZ repressor. Functional validation shows that SKI loss increases HBZ expression without impairing erythropoiesis, whereas SKI overexpression suppresses HBZ. Tet-on-inducible SKI overexpression and auxin-inducible SKI degradation indicate that SKI rapidly represses HBZ transcription. Transcriptome profiling further reveals that SKI deletion activates HBZ while minimally affecting other erythroid genes. Mechanistically, genome-wide occupancy analyses show that SKI binds the distal enhancers HS-10 and HS-40, with partial co-occupancy by BCL11A. Despite this overlap, dual knockout of SKI and BCL11A synergistically increases HBZ expression, as does base editing of the SKI-binding site within HS-10. We also identify a naturally occurring variant (chr16:193207G>A) within this enhancer in α-thalassemia patients with elevated ζ-globin levels. Together, these findings establish SKI as a direct, BCL11A-independent transcriptional repressor of ζ-globin. This work advances our understanding of globin gene regulation and suggests targeted ζ-globin reactivation as a potential therapeutic strategy for α-thalassemia.

Enhancer↗

PubMed2026

Bergamottin, a bioactive component of bergamot: dual inhibition of Japanese encephalitis virus internalization and genome replication.

Japanese encephalitis virus (JEV) is associated with high mortality and severe neurological sequelae, and existing prevention and control strategies remain insufficient. Therefore, the development of novel antiviral agents is of critical public health importance. This study systematically evaluated the antiviral activity and underlying mechanism of bergamottin, a natural product. Bergamottin exhibited significant dose-dependent inhibitory effects against JEV in multiple cell lines, including BHK-21, HuH-7, and Vero cells, demonstrating potent antiviral efficacy. Mechanistic investigations revealed that bergamottin primarily targeted the internalization and replication stages of the JEV life cycle, thereby effectively suppressing viral proliferation. Additionally, adaptive mutation screening indicated that the D389G mutation in envelope protein E confers drug resistance by potentially changing E protein conformation or reducing endocytic efficiency. In vivo experiment, bergamottin significantly reduced viral loads in mouse brain tissue and effectively improved the survival rate of infected mice. Our findings indicated that bergamottin exerted antiviral activity by dual targeting of key steps in the viral life cycle, making it a highly promising candidate for anti-JEV therapy. Further exploration of the antiviral properties of bergamottin is expected to facilitate its clinical development as a treatment for JEV infection.

Animals↗

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

Chalcone-indole hybrid scaffolds as promising anticancer drug candidates: a mini-review.

Cancer treatment is hampered by severe systemic side effects, poor tumor selectivity, and multidrug resistance (MDR). Molecular hybridization integrates chalcone and indole, two privileged antitumor pharmacophores, into one scaffold to generate chalcone-indole hybrids that synergistically enhance antitumor potency, improve tumor targeting, and reverse MDR. This mini-review analyzes literature from 2020 to 2026 on chalcone-indole anticancer hybrids. Based on structural modification patterns, the reported hybrids are categorized into four subgroups: simple substituted, α/β-position modified, N-1 fatty acid-substituted, and multi-pharmacophore fused hybrids. For each category, we summarize structure-activity relationships (SARs), antiproliferative activity, selective toxicity, molecular mechanisms, and in vivo xenograft performance. Most lead compounds exert tumor-suppressive effects via tubulin polymerization inhibition, G2/M cell cycle arrest, ROS overaccumulation, and mitochondrial-dependent apoptosis. Representative hybrids 10a, 12a, 21a, and 25a exhibit remarkable efficacy against drug-resistant colorectal, lung, and breast tumors with favorable in vivo safety. We highlight the application potential of different subtypes for specific malignancies, including α/β-modified analogues for resistant colorectal cancer, N-1 fatty acid-platinum conjugates for platinum-resistant lung cancer, NLRP3 inhibitor 7a for oral cancer, and multi-pharmacophore fused derivatives for broad-spectrum activity. Current bottlenecks limiting clinical transformation are discussed. This review provides structural design rules for developing novel chalcone-indole targeted anticancer agents.

Humans↗