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PubMed2026

Phase IIB, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID-19.

INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS: One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

Adult↗

PubMed2026

Global molecular and serological evidence of dengue and chikungunya infection: a systematic review and meta-analysis of 158,608 tested participants.

INTRODUCTION: Dengue virus (DENV) and chikungunya virus (CHIKV) are Aedes-borne arboviruses with overlapping clinical manifestations, shared vectors, and substantial diagnostic challenges in co-endemic settings. This systematic review and meta-analysis synthesized published evidence on molecular detection, serological positivity, and DENV-CHIKV dual positivity/co-infection in human clinical, surveillance, and community-based study populations. CONTENT: Following PRISMA 2020 guidance, five bibliographic databases (PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, and Google Scholar) and supplementary grey-literature/preprint sources were searched for English-language studies published from 1 January 1980 to 31 December 2024. No prospective PROSPERO or OSF protocol registration was available. Eligible records reported extractable numerators and denominators for DENV and/or CHIKV in humans using recognized molecular or serological assays. A total of 196 studies comprising 158,608 tested or suspected participants were included in the extraction table. The pooled CHIKV estimate was 14.0 % (95 % CI: 12.0-16.4; I2=97.5 %), with molecular and serological estimates of 9.8 and 15.7 %, respectively. The pooled DENV estimate was 13.8 % (95 % CI: 10.9-17.3; I2=99.0 %), with molecular and serological estimates of 13.1 % (95 % CI: 7.9-21.0) and 14.3 % (95 % CI: 10.2-19.8), respectively. DENV-CHIKV dual positivity/co-infection was 52.9 % (95 % CI: 48.7-57.1) among studies that tested and reported both outcomes. Country-level estimates varied widely and should be interpreted as summaries of available studies rather than nationally representative burden estimates. Funnel-plot asymmetry was statistically significant in DENV analyses but not in the overall CHIKV analysis. SUMMARY: Available evidence indicates extensive but highly heterogeneous DENV and CHIKV positivity across selected clinical and surveillance populations. The pooled estimates should be interpreted cautiously because of substantial between-study heterogeneity, diagnostic variability, outbreak-period sampling, and uneven geographic representation. OUTLOOK: The findings support integrated arboviral surveillance, multiplex diagnostics, and vector-control preparedness in co-endemic regions.

Humans↗

PubMed2026

Systematic Review of Pharmacologic Treatment for Migraine Prevention in Adults: Report of the AAN Guidelines Subcommittee and the American Headache Society.

BACKGROUND AND OBJECTIVES: This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS: A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS: A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION: This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Humans↗

PubMed2026

A STORM-based protocol for nanoscale imaging and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber.

Stochastic Optical Reconstruction Microscopy (STORM) enables nanoscale mapping of molecular components beyond the diffraction limit; however, its reproducible implementation in hydrophobic polymer matrices remains challenging because fluorescence-labeling specificity, fluorophore photoswitching, three-dimensional localization, chromatic registration, and quantitative image analysis must be carefully controlled. This protocol presents a standardized experimental workflow for dual-color labeling, astigmatism-based three-dimensional STORM acquisition, and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber (NR). The workflow covers sample pretreatment, Cy5 NHS ester labeling of protein-associated primary amines, DiI labeling of phospholipid-rich domains, STORM imaging-buffer preparation, three-dimensional single-molecule localization, dual-channel registration, generation of standardized xy projections, aggregate-size analysis, and projected lateral spatial correlation assessment. Reproducibility is supported by defined acquisition and localization criteria, three independent sample preparations with at least five fields of view analyzed per condition, and unlabeled, single-color, dye-only matrix, and processing-associated Cy5 controls. Mean lateral localization precisions of 11.8 ± 2.3 nm for Cy5 and 13.5 ± 2.9 nm for DiI were obtained, while two-dimensional Fourier ring correlation analysis of the xy projections yielded effective lateral image resolutions of approximately 25 and 28 nm, respectively. Image-based particle segmentation and localization-coordinate-based density-based spatial clustering of applications with noise (DBSCAN) were applied to standardized xy projections as complementary quantitative approaches. Application of the protocol to untreated, centrifuged, and protease-treated NR samples demonstrated treatment-associated changes in the detected abundance and projected size distributions of protein- and phospholipid-associated aggregates, together with a non-monotonic change in their projected lateral spatial correlation. These observations describe alterations in nanoscale organization but do not, by themselves, establish stable protein-phospholipid complex formation. Unlike previous studies that primarily demonstrated the feasibility of STORM imaging in rubber materials, the principal contribution of this work is an end-to-end, step-by-step protocol incorporating defined controls, three-dimensional localization, image-quality metrics, chromatic-registration procedures, and complementary quantitative-analysis pipelines for non-expert users. The workflow may be adaptable to other hydrophobic polymers and soft-material systems after appropriate optimization and validation.

Rubber↗

PubMed2026

Multi-omics reveals that burdock seed aglycone alleviates renal fibrosis by restoring mitochondrial oxidative phosphorylation function.

Renal fibrosis (RF), a common pathological process driving chronic kidney disease (CKD) progression to end-stage renal failure, is closely associated with oxidative phosphorylation (OXPHOS). Arctigenin (ATG), the main active component of burdock seed, exhibits anti-inflammatory and anti-fibrotic activities, but its mechanisms in RF treatment remain unclear. Here, we performed integrated transcriptomic and proteomic analyses to identify key targets and pathways of ATG in a unilateral ureteral obstruction-induced rat RF model. Multi-omics enrichment analysis revealed that NDUFS8 and NDUFS2 were the core targets of ATG, with the OXPHOS pathway as the central intersecting pathway. Our results suggest that ATG exerts anti-renal fibrosis effects by targeting the OXPHOS pathway to inhibit excessive reactive oxygen species production and oxidative stress. SIGNIFICANCE: Chronic kidney disease (CKD) continues to impose an escalating global health and socioeconomic burden, while renal fibrosis (RF), as the convergent pathological endpoint of virtually all progressive nephropathies, remains the principal determinant of irreversible renal failure and adverse clinical outcomes. Despite extensive efforts to develop antifibrotic therapies, effective clinical interventions remain elusive, largely due to the complex and multifactorial nature of RF pathogenesis. In this study, we employed an integrated multi-omics framework encompassing transcriptomics, proteomics, and metabolomics to systematically decipher the antifibrotic mechanism of arctigenin (ATG), a bioactive natural compound derived from traditional Chinese medicine. Our findings identify mitochondrial oxidative phosphorylation as the pivotal regulatory axis underlying the renoprotective effects of ATG and further establish key catalytic subunits of mitochondrial complex I as its direct molecular targets. Mechanistically, ATG not only restores complex I activity and reprograms mitochondrial energy metabolism but also preserves the intracellular stability and localization of these subunits, thereby preventing their aberrant release-mediated inflammatory activation and disrupting the self-perpetuating cycle linking metabolic dysfunction, inflammation, and fibrosis progression. Beyond revealing a previously unrecognized dual mechanism integrating metabolic and inflammatory regulation, this study provides compelling evidence that mitochondrial dysfunction is not merely a secondary consequence of tissue injury but a fundamental driver of fibrotic remodeling. Importantly, our work highlights the translational potential of natural product-based mitochondrial interventions for CKD treatment and supports a broader conceptual shift toward metabolism-centered therapeutic strategies for chronic fibrotic diseases. Given the central role of mitochondrial dysfunction across multiple organs, these findings may also have far-reaching implications for the treatment of systemic fibrosis-related disorders beyond the kidney.

Animals↗

PubMed2026

Machine learning-assisted Mn-N-C nanozyme colorimetric sensor array for trace-level detection of biogenic amines in meat.

Accurate detection of biogenic amines (BAs) in meat remains challenging due to their high structural similarity and co-occurrence. Herein, an Mn-N-C nanozyme was synthesized via a metal-organic framework confined pyrolysis strategy, possessing excellent oxidase (OXD)- and peroxidase (POD)-like activities. The dual enzyme-like activity showed Km values of 0.1584 mM (OXD) and 0.1498 mM (POD), respectively, in detection system. Leveraging these properties, a colorimetric sensor array was constructed, enabling the detection of four representative BAs within a concentration range of 2-10 ppm with 100% classification accuracy. In addition, a concentration independent recognition model based on an artificial neural network was developed to address signal nonlinearity interference in meat. The integrated system achieved accurate trace-level identification of BAs in perishable fish, pork, and chicken, demonstrating its applicability for early-stage BAs monitoring and quality deterioration warning during storage and transportation.

Biogenic Amines↗

PubMed2026

LitCTL1: A novel C-type lectin involved in the mucosal and cellular immunity of the common periwinkle Littorinalittorea.

C-type lectins (CTLs) are vital pattern-recognition receptors (PRRs) that mediate innate immune responses in mollusks, yet their characterization in Caenogastropoda, the largest gastropod group, remains limited. This study characterizes LitCTL1, a novel secreted single-domain C-type lectin from the common periwinkle, Littorina littorea. The 199-amino acid polypeptide contains a conserved carbohydrate recognition domain with canonical QPD and WND motifs and is predicted to form a homodimer. Uniquely, LitCTL1 was localized in both circulating hemocytes and mucus-secreting epithelial cells of the foot, mantle, and hypobranchial gland - the first report of such dual localization for a molluscan lectin, linking systemic and mucosal defense. Expression analysis revealed that LitCTL1 is constitutively expressed in hemocytes. Functional assays with recombinant LitCTL1 demonstrated its role as a potent opsonin with hemagglutinating activity, significantly enhancing hemocyte spreading and the phagocytosis of zymosan. Genomic analysis reveals that LitCTL1 belongs to a rapidly diversifying, genus-specific expansion distinct from conserved perlucin-like lineages. These results identify LitCTL1 as a key effector molecule in both systemic and mucosal innate immunity, likely reflecting an evolutionary adaptation to the microbial challenges of the intertidal environment.

Animals↗

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

Cre-loaded integrase-defective lentiviral vectors for targeted cassette exchange in CHO cells.

Genome-modifying enzymes, such as recombinases and CRISPR-associated nucleases, enable targeted gene insertion when delivered transiently to minimize off-target effects. Precise genome engineering requires controlled enzyme activity, as well as efficient donor DNA transfer. Integrase-defective lentiviral vectors (IDLVs) provide a promising platform for transient episomal DNA transfer; however, their integration efficiency depends on complementary genome-targeting strategies. Here, we engineered Cre-loaded IDLVs (Cre-IDLVs) that co-package lentiviral vector genomes together with bioactive Cre recombinase. Cre was inserted into the Gag region of an integrase-defective gag-pol construct, allowing for efficient encapsidation and protease-mediated release during virion maturation without compromising the viral titer. The resulting particles carried donor cassettes flanked by heterospecific loxP sites. When applied to CHO founder cells harboring compatible genomic loxP landing pads, Cre-IDLVs efficiently mediated recombination-mediated cassette exchange, producing the highest number of G418-resistant colonies among the plasmid ratios tested. Genomic PCR and sequencing confirmed precise locus-specific insertion without detectable random integration in the analyzed clones. These findings establish Cre-IDLVs as a streamlined dual-delivery platform that couples transient recombinase activity with episomal donor DNA transfer. This hybrid lentiviral strategy provides a programmable approach for controlled and site-specific genome modification in mammalian cells.

Integrases↗

PubMed2026

Maize ZmMYB59 inhibits post-germinative shoot and root elongation through ZmGA2ox3/10-mediated gibberellin catabolism.

Gibberellin (GA) promotes seed germination, but sustained or excessive GA signaling after germination can lead to aberrant root and shoot elongation. How GA homeostasis is transcriptionally restrained during post-germinative seedling development remains unclear. Using overexpression and gene-edited maize materials, we demonstrate that ZmMYB59 inhibits root and shoot elongation during post-germinative growth. Integrated RNA-Seq and CUT&Tag analyses identified the GA catabolism genes ZmGA2ox3 and ZmGA2ox10 as candidate direct targets of ZmMYB59. Hormone profiling analysis showed elevated bioactive GA1 and GA4 levels in the scutellum and aleurone layer cells of zmmyb59 mutants. Dual-luciferase assays, electrophoretic mobility shift assays, and ChIP-qPCR further confirmed that ZmMYB59 directly binds AC8 cis-elements in the ZmGA2ox3/10 promoters and activates their transcription. The zmga2ox3/10 double mutant, but neither single mutant, exhibited enhanced root and shoot elongation, accompanied by GA4 accumulation. This phenotype was suppressed by exogenous application of the GA biosynthesis inhibitor uniconazole. Transcriptomic and biochemical analyses further revealed enhanced starch degradation, reduced starch content, and increased soluble sugar accumulation in the double mutant. Taken together, these findings reveal that the ZmMYB59-ZmGA2ox3/10 module restrains GA accumulation and starch mobilization after germination, thereby coordinating reserve utilization with post-germinative root and shoot growth in maize.

Gibberellins↗

PubMed2026

Glycaemic burden disrupts innate immunity in TB by modulating CD206 expression and macrophage antimicrobial responses.

Tuberculosis (TB) and diabetes mellitus (DM) represent a growing dual global health burden, with chronic hyperglycaemia recognized as a major modifier of host immunity against Mycobacterium tuberculosis (Mtb). Macrophages, central to pathogen recognition, phagocytosis, antigen presentation, and intracellular killing, may be particularly vulnerable to diabetic metabolic dysregulation. This study evaluated phenotypic and functional macrophage alterations in individuals with pulmonary TB, type 2 DM, TB-DM comorbidity, and healthy controls. Surface receptor expression was analysed by multicolour flow cytometry, while phagocytosis and intracellular bacterial clearance were assessed using FITC-labelled Mtb assays and colony-forming unit enumeration. Hyperglycaemia was associated with reduced CD11b, MARCO, and TLR2 expression alongside upregulation of the mannose receptor CD206, which correlated positively with HbA1c levels, indicating a shift toward a permissive M2-like phenotype. Phagocytic uptake of Mtb was significantly impaired and inversely correlated with HbA1c. Antigen-presenting capacity was selectively compromised, with reduced CD80 and CD86 expression in DM and TB-DM groups, while HLA-DR remained unchanged. Intracellular Mtb killing was markedly diminished in diabetic macrophages. These findings demonstrate that chronic hyperglycaemia profoundly disrupts macrophage innate immunity, contributing to increased TB susceptibility and poor infection control in diabetic populations.

Humans↗

PubMed2026

Genome-wide identification and functional validation of asparagine synthetase genes (NtASNs) in Nicotiana tabacum.

Asparagine (Asn) is pivotal for plant nitrogen (N) metabolism and plays indispensable roles in plant growth, development, and stress tolerance. However, the systematic characteristics and core functions of asparagine synthetase genes (NtASNs) in tobacco remain unclear. Through a comprehensive genome-wide investigation, nine members of the NtASN gene family were identified. Subsequent CRISPR/Cas9-mediated knockout and overexpression assays of these NtASN genes revealed that NtASN1e, NtASN2a, and NtASN2b are the core genes responsible for Asn biosynthesis in tobacco. Their knockout reduced asparagine synthetase activity and Asn content, delayed seed germination by 2-3 days, and displayed elevated oxidative injury when exposed to salinity conditions. In contrast, overexpression of these genes elevated Asn accumulation. Subcellular localization analysis indicated that NtASN1e was localized to both the cytoplasm and chloroplasts, whereas NtASN2a exhibited dual localization in the cytoplasm and endoplasmic reticulum, and NtASN2b was mainly localized in the cytoplasm. This study systematically clarifies the evolutionary characteristics and core functions of the NtASN gene family and provides candidate genes for optimizing nitrogen metabolism and improving salt-stress adaptation in tobacco. These findings hold important practical significance for molecular breeding and product quality improvement in industrial crops.

Nicotiana↗

PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗

PubMed2026

HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.

Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly12 (G12X) or Gly13 (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln61 (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.

Humans↗

PubMed2026

Reprogrammed Komagataella phaffii for enhanced secretory expression of human lactoferrin.

Human lactoferrin (hLF) is a multifunctional glycoprotein of the transferrin family derived from milk and mucosal secretions, which exhibits antibacterial, anti-tumor, and immunomodulatory functions, and is an important component of infant formula. Conventional methods for lactoferrin expression are often inefficient, primarily due to inadequate protein synthesis capabilities and poor stability within microbial hosts. Herein, a Komagataella phaffii yeast strain capable of high-level secretory expression of hLF was constructed by reprogramming the endoplasmic reticulum (ER) and vacuole using CRISPR/Cas9 technology. A dual-expression cassette containing the AOX1 promoter, an α-secretion signal peptide, the hLF gene, and a terminator was integrated into three different sites of the K. phaffii genome. The stepwise strategy combining expansion of the ER membrane involved in protein synthesis with knockout of vacuolar proteases further enhanced hLF production. Subsequently, 0.1 g/L FeCl₃ was added to the medium to reduce the toxicity of hLF and improve its stability. After high-density cultivation of K. phaffii through optimization of cultivation conditions in shake flasks and a 5 L bioreactor, the secretory intact hLF titer reached 2214 mg/L, representing a 76.3-fold increase achieved through these engineering strategies. In addition, antibacterial experiments demonstrated that this secretory hLF had a significant inhibitory effect on Escherichia coli, Staphylococcus aureus, and yeast. Overall, the developed K. phaffii protein expression platform enabled efficient production of lactoferrin, demonstrating its potential for expressing other lactoproteins.

Lactoferrin↗

PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed2026

Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.

Natural killer (NK) cells are innate lymphocytes that directly eliminate tumor and virus-infected cells by integrating signals from activating and inhibitory receptors, and their effector functions are tightly coupled to cellular metabolism. Given that the inhibitory receptor PD-1 reprograms T cell metabolism to shape functional fate, the bioenergetic consequences of inhibitory receptor engagement on human NK cells remain largely unexplored, particularly for sialic acid-binding immunoglobulin-like lectin (Siglec-7), a glyco-immune checkpoint receptor. Here, we investigated metabolic programs and effector functions associated with Siglec-7 expression and antibody-mediated Siglec-7 ligation in primary NK cells and NK-92MI cells. Siglec-7POS NK cells exhibited selectively impaired CD107a degranulation under glycolytic and oxidative phosphorylation inhibition, whereas Siglec-7NEG cells remained relatively resistant, indicating distinct energetic wiring between these subsets. Engagement of Siglec-7 by an agonistic antibody induced mitochondrial fission with altered Drp1 phosphorylation, transient mitochondrial depolarization, and broadly suppressed mitochondrial respiration, while concurrently enhancing glycolytic capacity, consistent with a dual metabolic shift upon Siglec-7 ligation. In contrast, sustained Siglec-7 expression in NK-92MI-S cells was associated with globally enhanced mitochondrial respiratory capacity, indicating that sustained Siglec-7 expression and short-term treatment with an agonistic anti-Siglec-7 antibody were associated with distinct metabolic profiles in NK cells. Furthermore, Siglec-7POS NK cells showed increased accumulation of autophagic vacuole, reduced proliferation, and heightened apoptotic susceptibility compared with Siglec-7NEG counterparts. Collectively, these findings support an association between Siglec-7 status, mitochondrial homeostasis, and metabolic fitness in NK cells, with Siglec-7NEG cells retaining a metabolically robust, cytotoxic phenotype.

Journal Article↗

PubMed2026

Measuring economic efficiency in adult intensive care units: A systematic review of methods, metrics, and evidence.

OBJECTIVES: Intensive care units (ICUs) consume substantial hospital resources, yet "efficiency" is inconsistently defined and measured. This study systematically reviewed how economic efficiency has been conceptualised and quantified in adult ICUs and appraised the quality of evidence. METHODS: Following PRISMA 2020 and a PROSPERO-registered protocol (CRD420251107866), we searched MEDLINE, Embase, CINAHL, Cochrane Library and Web of Science (2000-August 2025), plus global grey sources. Eligible studies explicitly defined efficiency and reported an efficiency metric/model linking ICU inputs (e.g., staff, beds/capacity, time, consumables, or costs) to outputs/outcomes (e.g., throughput/discharges, length of stay/resource use, risk-adjusted mortality). Dual independent screening and extraction were performed. Study quality was appraised using MMAT, and findings were synthesised narratively (SWiM), given heterogeneity. RESULTS: 39 studies (2001-2025) from 17 countries were included, all from high-income or upper-middle-income settings. Four methodological families were identified: (1) frontier modelling (predominantly DEA; occasional SFA/RFDH), (2) benchmarking indicators (risk-adjusted mortality and LOS/resource-use ratios; "efficiency matrix" quadrant classification), (3) cost-outcome evaluations, and (4) operational/process metrics. Across families, variation in decision-making units, input/output selection, and risk adjustment limited comparability; long-term and patient-reported outcomes were absent, and equity considerations were uncommon. CONCLUSIONS: ICU efficiency research is feasible but fragmented and often methodologically limited. Standardised definitions, validated risk adjustment, uncertainty quantification, and inclusion of patient-centred and equity-relevant outcomes are needed before efficiency metrics can reliably inform value-based decision making.

Intensive Care Units↗

Results for “dual&#x2010;antiplatelet therapy”

Results for “dual‐antiplatelet therapy”