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PubMed2026

Single-cell transcriptome revealed the aberrant keratinocytes activation in antigen presentation in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD), a common chronic inflammatory skin disease, has been extensively studied using single-cell genomics. However, keratinocytes, as key effector cells in AD, have underlying mechanisms remain incompletely understood and require further investigation. METHODS: We integrated single-cell transcriptomic data from skin tissues of healthy controls, chronic active AD patients, spontaneously healed AD (SHAD) patients, and an ovalbumin-induced AD mouse model. The study particularly emphasized the gene expression and cellular dynamics of keratinocytes across the different groups, as well as their interactions with immune cells. RESULTS: Compared to healthy controls, we observed significant changes in the keratinocyte transcriptome, cellular state, and keratinocyte-immune cell ligand-receptor interactions in AD skin, particularly the marked activation of genes involved in antigen processing and presentation. Interestingly, such gene activation was not observed in keratinocytes from the ovalbumin-induced AD mouse model, despite its phenotype closely resembling human AD. Furthermore, in SHAD, we identified a recovery of both the ligand-receptor interaction patterns and antigen processing and presentation genes, accompanied by a notable shift in the transcriptome. This involved a significant downregulation of genes related to cytoplasmic transcription and oxidative phosphorylation. Notably, this pattern was not observed in the self-healing mouse model following the removal of ovalbumin stimulation. CONCLUSION: Our results suggest that the persistent activation of antigen processing and presentation pathways in keratinocytes may be a key driver of chronic inflammation in AD. Therefore, redirecting anti-allergic therapeutic strategies from solely targeting immune cells to targeting of keratinocyte-mediated antigen presentation may offer a more effective approach. Furthermore, we raise concerns about the use of ovalbumin-induced mouse models to recapitulate human chronic AD, as the underlying mechanisms may differ significantly.

Dermatitis, Atopic↗

PubMed2026

Climate and soil shape Daqu wheat quality and seed microbiome via rhizosphere taxa and microbial assembly.

The grain quality and seed microbiome of Daqu wheat are fundamental determinants of Daqu fermentation performance; however, the mechanisms by which cultivation environments influence these traits via rhizosphere microbial communities remain unclear. Bacterial and fungal communities across the bulk soil-rhizosphere-seed continuum of three wheat cultivars grown in four ecoregions were characterized using absolute quantitative amplicon sequencing. The rhizosphere microbiome was treated as a central intermediary, while the response variables were seed microbial diversity and grain-quality traits, including starch content, protein content, and grain hardness. Twelve physicochemical properties of soil and 11 climatic factors were integrated into a multidimensional association framework. Environmental conditions exerted stronger influences on both seed quality traits and microbial diversity than cultivar identity. Distinct regional signatures were also evident in rhizosphere microbiomes, with environmental gradients explaining community variation more effectively than geographic distance. Bacterial communities exhibited greater sensitivity to environmental fluctuations than fungi. Mantel analyses identified available nitrogen, precipitation, and atmospheric pressure as significant drivers of core rhizosphere taxa (P < 0.05). iCAMP revealed that stochastic processes predominantly governed rhizosphere bacterial assembly, whereas stochastic and deterministic mechanisms jointly shaped fungal assembly. Partial least squares path modeling further uncovered a rhizosphere-mediated environment-seed cascade, wherein sunlight intensity and duration, atmospheric pressure, and soil nitrogen directly or indirectly affected seed wet gluten content, grain hardness, and seed microbial diversity through their influences on rhizosphere microbiota. Rhizosphere bacterial diversity was negatively associated with seed bacterial diversity (path coefficient = -0.118, P < 0.05), indicating that rhizosphere communities may shape seed endophytic bacterial assemblages via environmental filtering and competitive interactions. Collectively, these findings elucidate how environments shape the quality and seed microbiomes of Daqu wheat, providing scientific guidance for optimal site selection and the standardized production of high-quality brewing wheat for industrial Baijiu.

Triticum↗

PubMed2026

Nature-based meaning-focused photography intervention enhances subjective well-being: A three-arm randomized controlled study.

Gaining meaning from nature contact can promote subjective well-being. However, few studies have validated the effectiveness of nature-based meaning interventions in enhancing subjective well-being. This study consisted of a 7-day online intervention to examine the effects of nature-based meaning-focused photography on well-being by comparing a photo-only group, a photo + writing group, and a waiting list control group and how meaning in life mediates the relationship between nature contact and well-being. A pre-registered three-arm randomized controlled trial (groups: photo + writing group vs. photo-only group vs. control group) * (time: pre-test vs. post-test vs. 1-month follow-up) was conducted with 219 college students. In the photo + writing group, participants captured nature scenes and wrote 100-word reflections. The photo-only group only took nature photos. The primary outcomes were meaning in life and well-being, and the secondary outcome was life satisfaction. A conservative Bayesian causal forest analysis based on machine learning was used to detect both treatment and heterogeneous intervention effects. Compared with the control group, the photo + writing group showed positive effects on meaning in life, subjective well-being, and life satisfaction, with average treatment effects of 0.36, 0.27, and 0.66 standard deviations (SD), respectively. The photo-only group also showed generally positive effects on these outcomes, with average treatment effects of 0.27, 0.24, and 0.54 SD, respectively. However, these effects were not sustained after 1 month. The intervention was especially beneficial for participants from lower subjective socioeconomic status, with limited prior nature exposure, or lower baseline psychological well-being. Importantly, enhanced meaning in life helped explain how the intervention improved well-being and life satisfaction. This study also demonstrated that combining nature-based photography and reflective writing can improve well-being.

Humans↗

PubMed2026

Premature closure underlies bias in medical diagnosis in students: A randomised controlled experiment.

OBJECTIVE: The purpose of the study reported in this article was to shed light on the cognitive mechanism mediating between biasing information and diagnostic error. The literature suggests at least two different hypotheses: premature closure leading biased participants to spend less time on diagnosis or increased competition between diagnostic hypotheses. The latter hypothesis predicts that biased participants would spend more time reaching a diagnosis. METHOD: Using the salient distracting findings (SDF) experimental paradigm, we biased 58 fourth-year medical students while diagnosing 12 clinical vignettes in a within-group incomplete block design under three conditions: cases presented without SDF, with SDF at the beginning and with SDF at the end. For each of these conditions, diagnostic accuracy, the number of SDF-related mistakes and time per word needed to process the case were recorded. The data were analysed using linear mixed modelling. Estimated marginal mean scores were reported. RESULTS: Participants confronted with salient distracting features (SDFs) at the beginning of a clinical case demonstrated significantly lower diagnostic accuracy (mean 0.11) compared with the No-SDF condition (0.27), representing a 61% reduction (F2,693 = 11.995, p < 0.001), and made more SDF-related mistakes (F2, 693 = 16.395, p < 0.001). When SDFs were presented at the end of the case, diagnostic accuracy was also reduced (mean 0.17; 36% reduction), but processing time did not differ from the No-SDF condition. Only early presentation of SDFs was associated with reduced processing time per word (F2,636 = 4.799, p < 0.01), consistent with premature closure. CONCLUSION: These findings demonstrate that biasing information increases diagnostic error in medical students and that only early bias is associated with reduced information processing. The data do not support the competition hypothesis for early bias, as processing time did not increase under biasing conditions. Premature closure can therefore be directly observed rather than inferred, inviting further research.

Humans↗

PubMed2026

In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.

Hyperoxaluria, Primary↗

PubMed2026

Deimplementation of inappropriate feeding practices in early care and education: a Hybrid Type 3 cluster-randomized trial.

BACKGROUND: The science of deimplementation-reducing harmful or ineffective practices-has focused almost exclusively on clinical prescribing, with no studies conducted in community or educational settings. Early care and education (ECE) settings offer a strategic venue for shaping eating behaviors, with children consuming up to 500 meals annually in these environments. However, ECE educators routinely use feeding practices that undermine self-regulation, including pressuring children to eat, rushing mealtimes, and offering food as reward. These practices contribute to food aversions, diminished self-regulation, and obesity risk. METHODS: We will conduct a Hybrid Type 3 cluster-randomized trial evaluating a co-designed deimplementation strategy package (WISE Words) across 88 ECE sites in Arkansas and Louisiana. Sites will be randomized 1:1 to WISE Words or usual practice, with usual practice sites receiving the intervention after two years (waitlist design). WISE Words includes six strategies: dynamic training using improvisation methods, peer learning collaboratives with goal setting, external facilitation, audit and feedback, environmental reminders, and tailored educational materials. The primary outcome is de-adoption of inappropriate feeding practices measured via direct mealtime observation (Table Talk). Secondary outcomes include adoption of evidence-based practices, acceptability, appropriateness, and sustainability at 12- and 24-months post-intervention. Child outcomes include Body Mass Index, skin carotenoid levels (Veggie Meter) willingness to try new foods (observed) and food neophobia (teacher and caregiver report). An explanatory sequential mixed methods design will test mechanisms of change derived from the Implementation Trust Building Theory of Change examining whether trust mediates strategy effects on outcomes. DISCUSSION: This trial extends deimplementation science into community settings by targeting culturally embedded behavioral practices rather than clinical prescribing behaviors. Results will inform approaches to shifting entrenched practices in ECE and similar settings while testing trust as a deimplementation mechanism. Sustainability assessments will address a notable gap, as few studies have examined whether deimplementation effects persist. TRIAL REGISTRATION: NCT07101321, July 20, 2025.

Humans↗

PubMed2026

Virtual reality physical education and adolescents' exercise interest and physical fitness: An explanatory sequential mixed-methods randomized trial with exploratory pathway analysis.

Traditional physical education (PE) faces declining student interest and limited fitness gains. Virtual reality (VR) offers immersive, gamified experiences, but evidence regarding its effectiveness and explanatory pathways remains limited. This explanatory sequential mixed-methods randomized trial assigned 360 adolescents (aged 13-16) from three middle schools to either VR-supported PE (n = 180) or conventional PE (n = 180) for 12 weeks, with a 4-week follow-up. Outcomes included exercise interest (validated scale), physical fitness (coordination via MABC-2, cardiorespiratory endurance via the 20-m shuttle run, explosive power via the standing long jump, and speed via the 10-m sprint), and accelerometer-measured physical activity. The qualitative component involved 38 unique students: 32 completed individual semi-structured interviews, and six additional students participated only in focus groups. Three-level linear mixed-effects models and exploratory structural equation modeling were used. The VR group showed significantly greater improvements in exercise interest (d = 0.78), coordination (d = 0.62), cardiorespiratory endurance (d = 0.55), and speed (d = 0.48) than the control group (all p < 0.001), but not in explosive power (d = 0.12, p = 0.148). Effects were partially retained at follow-up (interest d = 0.65, coordination d = 0.48, endurance d = 0.42, and speed d = 0.30), a pattern not fully consistent with a purely novelty-driven explanation. Exploratory mediation identified exercise interest as a statistically compatible explanatory pathway (indirect effect = 0.34, 95% CI [0.22, 0.46]), although the timing of measurement precludes causal interpretation. Qualitative findings contextualized these results by highlighting immersion, feedback, self-efficacy, and perceived transfer. VR-supported PE may enhance adolescents' exercise interest and selected fitness dimensions, but its limited effect on explosive power and possible novelty contribution indicate that it should complement, rather than replace, conventional PE. Longer-term studies are needed.

Humans↗

PubMed2026

Secretory Phospholipase A2 in Patients With Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain Episodes.

BACKGROUND: Secretory phospholipase A2 (sPLA2) is an inflammatory mediator linked to acute chest syndrome (ACS) in sickle cell disease (SCD), a serious complication that can develop during an acute vaso-occlusive pain episode (VOE). Plasma sPLA2 levels have been proposed as a potential biomarker for predicting ACS onset. OBJECTIVE: To assess serial plasma sPLA2 levels in 105 pediatric patients hospitalized for SCD-VOE and determine the effects of arginine therapy compared to placebo. PROCEDURES: This is a pharmacokinetics/pharmacodynamics and randomized controlled trial of intravenous arginine therapy. Statistical methods included t-tests, chi-square, and correlation analyses. RESULTS: Mean age was 12.7 ± 3.7 years, 48% were male, 67% had Hb-SS, and 70% were prescribed hydroxyurea. Using a previously established SCD-specific cutoff of 48 ng/mL, presenting sPLA2 levels were elevated in 33% of patients (mean sPLA2 level 85.7 ± 32.9 ng/mL). SPLA2 elevation in the emergency department was more common in patients with ACS compared to those without ACS (64% vs. 30%; p = 0.02; negative predictive value of 94%). Peak sPLA2 levels were significantly higher in febrile (n = 34) versus afebrile patients (n = 71;101.0 ± 45.3 vs. 48.7 ± 35.4 ng/mL; p < 0.0001). Among subjects with elevated baseline sPLA2, arginine therapy resulted in a significant reduction in sPLA2 levels by discharge compared to placebo (-27.8 ± 38.1 ng/mL; p = 0.002; n = 23 vs. -15.0 ± 41.2 ng/mL; p = 0.23; n = 12). CONCLUSIONS: SPLA2 is an underutilized biomarker of ACS given accumulating evidence of its role. In particular, low levels may identify patients at low risk for ACS. Arginine therapy may modulate inflammation in patients with SCD during VOE and/or ACS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02447874; NCT02536170.

Humans↗

PubMed2026

Major cardiovascular event risk of advanced therapies in inflammatory bowel diseases: systematic review and meta-analysis.

BACKGROUND: Patients with chronic immune-mediated disorders (IMIDs), including inflammatory bowel disease (IBD), are at increased risk of cardiovascular disease. While advanced therapies show cardioprotective effects in other IMIDs, their impact on major adverse cardiovascular events (MACE) in IBD remains unclear. We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating MACE risk with advanced therapies in IBD. METHODS: Systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials identified 43 studies (36 RCTs, including 9 long-term follow-up (LTF) studies, and 7 observational studies) published between 2002 and 2024. Primary analyses estimated odds ratios (OR) for MACE comparing advanced therapy to placebo, with secondary analyses stratifying studies by drug class and length of follow-up. Sensitivity analyses were conducted using alternative methods to account for zero-event data. RESULTS: Placebo-controlled RCTs showed a nonsignificant trend toward reduced MACE risk (OR 0.60; 95% CI 0.24-1.51), with similar findings across sensitivity analyses accounting for sparse and zero-event data. Class-specific trends suggested lower MACE risk with IL-12/IL-23 inhibitors (OR 0.35; 95% CI 0.05-2.21), JAK inhibitors (OR 0.57; 95% CI 0.16-2.06), and a potential increase with Anti-TNF agents (OR: 3.04; 95% CI 0.31-29.47), though none reached statistical significance. LTF studies showed consistent findings. Observational studies suggested lower MACE risk with Anti-TNF therapies (OR 0.29; 95% CI 0.21-0.40), but not with IL-12/IL-23 (OR 4.41; 95% CI 0.49-39.28) or JAK inhibitors (OR 1.57; 95% CI 0.86-2.84). CONCLUSION: Advanced therapies did not demonstrate a clear increase or decrease in cardiovascular risk in IBD. The discrepancies between RCTs and observational studies underscore the urgent need for rigorous-designed observational research with long-term follow-up to evaluate the real-world impact of advanced therapies on MACE risk.

Humans↗

PubMed2026

Safety and immunogenicity of an mRNA COVID-19 vaccine administered to adults: A phase 2, randomized, active-controlled trial.

We conducted a phase 2, randomized, active-controlled, observer-blind study (NCT05960097) among healthy adults ≥18 y of age who completed a primary COVID-19 mRNA vaccination series, with or without a booster, ≥3 months earlier. Participants were randomized (1:1:1:1:1) to either receive an investigational bivalent mRNA COVID-19 vaccine encoding ancestral D614G and Omicron BA.4-5 spike proteins (CV0701 mRNA vaccine) at one of three dose levels, an investigational monovalent mRNA COVID-19 vaccine encoding the Omicron BA.4-5 spike protein (CV0601 mRNA vaccine), or a licensed Original Wuhan/Omicron BA.4-5 bivalent mRNA COVID-19 vaccine. The primary objectives were to evaluate reactogenicity, safety and immunogenicity post-vaccination. Secondary and tertiary objectives were to further evaluate humoral and cell-mediated immunity post-vaccination. In total, 425 participants were vaccinated and 381 were included in the Day 29 per-protocol immunogenicity analysis. Most solicited events were mild to moderate. No vaccine-related serious adverse events or myocarditis/pericarditis cases were reported. For the CV0701 mRNA vaccine, a dose-dependent increase in Day 29 neutralizing titers against ancestral D614G and Omicron BA.4-5 was observed. Neutralizing titers against ancestral D614G and Omicron BA.4-5 declined by Days 91 and 181, but remained above baseline. Similar immune responses were observed for the CV0601 mRNA vaccine. At Day 8, CD4+ T cells (Th1 profile) increased in all study groups and CD8+ T cells increased in all study groups, except the lowest CV0701 dose group. The CV0701 and CV0601 mRNA vaccines elicited robust humoral and cellular immunity with an acceptable safety profile, comparable to a licensed, bivalent mRNA vaccine. Clinical Trial Registration EU CT number: 2023-504596-25-00 ClinicalTrials.gov: NCT05960097.

Humans↗

PubMed2026

Amino acid reprogramming and biofilm-specific tricarboxylate transporters in PET-degrading Piscinibacter sakaiensis.

Plastic-degrading bacteria predominantly colonize polymer surfaces as biofilms, yet it remains unclear whether the biofilm phenotype contributes to metabolism beyond retaining extracellular enzymes. Here, we combine population-level RNA-sequencing across three conditions-biofilm cells on polyethylene terephthalate (PET), planktonic cells incubated with PET, and planktonic cells on maltose-with single-cell Raman spectroscopy to characterize the PET response of Piscinibacter sakaiensis (formerly Ideonella sakaiensis). This integrated approach reveals two metabolically distinct response layers. A carbon-source-driven response shared by all PET-exposed cells is dominated by a broad amino acid reprogramming, led by upregulation of branched-chain amino acid transport genes, enhanced serine biosynthesis, and reduced chemotaxis. A biofilm-specific layer selectively induces tripartite tricarboxylate transporter genes from three distinct genomic loci. This transcriptional feature is accompanied by a single-cell phenotype consistent with a protein-rich and saturated membrane. These results suggest that biofilm formation is not limited to enzyme retention but is associated with selective activation of transport systems, consistent with a putative role in capturing PET-derived intermediates at the polymer interface. This two-layer model separates general metabolic adaptation to PET from biofilm-specific functions and provides a framework for understanding how surface-associated bacterial physiology contributes to plastic degradation.IMPORTANCEPolyethylene terephthalate (PET) degradation in natural and engineered environments is largely mediated by surface-attached microbial communities, yet the physiological role of biofilm state during plastic degradation remains poorly understood. Using the model PET degrader Piscinibacter sakaiensis, we show that biofilm-associated cells are not simply retained near the polymer surface but exhibit a distinct metabolic program characterized by selective induction of tripartite tricarboxylate transporters. In contrast, extensive amino acid reprogramming occurs in both biofilm and planktonic PET-exposed cells, indicating that it is driven by carbon source rather than surface attachment. These findings reveal that PET degradation involves two separable physiological layers: a general metabolic response to PET-derived carbon shared across cell phenotypes, and a biofilm-specific transport response potentially linked to substrate capture at the plastic interface. This work advances our understanding of how microbial physiology is organized during plastic biodegradation and identifies transport processes as previously unrecognized components of PET-degrading biofilms.

PET biodegradation↗

PubMed2026

Ameliorating Effects and Autonomic Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation on Abdominal Pain in Patients With Functional Dyspepsia and Irritable Bowel Syndrome.

BACKGROUND: Patients with functional dyspepsia (FD) and irritable bowel syndrome (IBS) often experience abdominal pain and reduced quality of life and need effective treatments. This exploratory study aimed to evaluate whether transcutaneous auricular vagus nerve stimulation (taVNS) could improve abdominal pain and quality of life in patients with FD and IBS, and whether the effects were mediated via the autonomic mechanisms. METHODS: A total of 64 patients with abdominal pain (43 FD and 21 IBS) with a pain score of 3 out of 10 or higher were randomized to receive 2 weeks of taVNS or sham-taVNS treatment. The primary outcome was numeric rating scale (NRS) for abdominal pain. The dyspeptic symptom scales (DSS), IBS symptom severity scale score (IBS-SSS), anxiety and depression scores, and the SF36 quality of life scale were assessed before and after the treatment. The electrocardiogram was also recorded for the assessment of autonomic function at baseline and after the treatment. KEY RESULTS: (1) taVNS reduced the abdominal pain score (p < 0.001 for both FD and IBS), the frequency of abdominal pain (p < 0.001 for both FD and IBS), and overall symptom scores in both FD patients and IBS patients (p < 0.001 for FD and IBS). There was no significant difference in the effect of taVNS on abdominal pain between FD and IBS patients. (2) taVNS improved quality of life compared with baseline in both FD and IBS patients. (3) taVNS decreased anxiety (p < 0.001) and depression (p < 0.001). (4) taVNS increased vagal activity. At the end of the taVNS treatment, the vagal activity was negatively correlated with the pain score (r = -0.491, p = 0.004). CONCLUSIONS: Non-invasive taVNS improves abdominal pain, quality of life, and anxiety and depression in patients with FD and patients with IBS, possibly attributed to the enhancement of vagal activity. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2400085697.

Humans↗

PubMed2026

Associations Between Short Video Exposure, Empathy and Attitudes Toward End-Of-Life Care Among Nursing Students: A Cross-Sectional Study.

AIM: This cross-sectional study examined the associations between short video exposure, nursing students' empathy, and attitudes toward end-of-life (EOL) care, and tested whether perceived impact is statistically consistent with an indirect pathway in these relationships. DESIGN: A descriptive cross-sectional study. METHODS: In total, 534 undergraduate nursing students were included. Data were collected using a self-designed questionnaire, including the Attitudes Toward Care of the Dying Scale and the Jefferson Scale of Empathy-Health Professions Student version for empathy assessment. Statistical analysis for correlation and mediation analysis (PROCESS macro) was performed. RESULTS: 85.96% of students watch short videos for more than 30 min daily, with more than 60% of them viewing EOL-related content. Students with prior caregiving experience or formal palliative care education showed significantly higher empathy and more positive attitudes (p < 0.05). Exposure to medical and EOL-related short videos was positively correlated with perceived impact, empathy, and positive EOL attitudes, with effect sizes ranging from very weak to modest (r = 0.10 to 0.27). The data were consistent with an indirect pathway between short video exposure and empathy via perceived impact (indirect effect = 0.04; 95% bootstrap CI [0.01, 0.08]). However, for EOL attitudes, short video exposure showed a direct association rather than an indirect pathway via perceived impact (direct effect = 0.09, p < 0.01). CONCLUSION: In this cross-sectional study, short video exposure was modestly associated with nursing students' empathy, with data consistent with an indirect pathway via perceived impact; the observed associations explained only approximately 1% to 7% of the variance in the outcome variables. However, reshaping EOL attitudes may require more systematic education beyond brief video exposure. These findings are hypothesis-generating and await validation through longitudinal and experimental research using standardized video content. IMPLICATIONS FOR NURSING PRACTICE: Nursing educators should consider integrating curated short video content into palliative care curricula to enhance students' empathy and perceived impact of end-of-life education. However, brief video exposure alone may be insufficient to reshape deeper end-of-life attitudes, suggesting the need for comprehensive, multi-modal educational strategies.

Humans↗

PubMed2026

Genome-resolved analysis reveals disruption of gut microbial vitamin B and K2 biosynthesis during Toxoplasma gondii infection in mice.

UNLABELLED: Toxoplasma gondii infection remodels the gut microbiome, yet its impact on microbial vitamin biosynthetic potential and host redox metabolism remains unclear. Here, we integrated mouse gut metagenomes with publicly available metagenome-assembled genomes (MAGs) to construct a genome-resolved atlas of B-vitamin and vitamin K2 biosynthesis. From 45,697 MAGs, we curated 4,771 representative genomes, of which 2,682 met high-quality criteria (completeness ≥90%, contamination <5%). Functional annotation identified 229,717 vitamin-related genes corresponding to 177 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs across de novo pathways for eight B vitamins, thiamine (B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), biotin (B7), folate (B9), cobalamin (B12), and vitamin K2. Among the high-quality genomes, 1,665 encoded complete de novo pathways for at least one vitamin, highlighting functional specialization and community-level complementarity. Transcripts per million-normalized metagenomic read counts revealed significant differences in KEGG ortholog abundances across six of the nine vitamin pathways. Reanalysis of metagenomic data from infected mice (acute, chronic, and control; n = 10 per group) revealed a stage-dependent reduction in α-diversity of vitamin biosynthesis pathways during acute infection, and a clear β-diversity separation from chronic and control groups. Core niacin biosynthesis genes (nadB, nadA, nadC) displayed phylum-specific redistribution, indicating selective remodeling of microbial NAD+ precursor production under infection-induced metabolic stress. These results suggest that T. gondii infection disrupts cooperative vitamin biosynthetic networks while specifically modulating niacin pathways linked to host NAD+ metabolism. IMPORTANCE: Gut microbes can synthesize essential vitamins, but how infection alters this function is poorly understood. By integrating mouse gut metagenomes with genome-resolved microbial data, we show that Toxoplasma gondii infection reshapes the vitamin biosynthetic potential of the gut microbiome in a stage-dependent manner. Acute infection reduces the diversity of vitamin biosynthesis pathways and shifts the taxonomic distribution of key niacin biosynthesis genes involved in microbial NAD+ precursor production. These findings identify vitamin metabolism, especially niacin-related pathways, as a sensitive functional axis of microbiome remodeling during infection. Our work links microbial taxonomic changes to functional metabolic consequences and suggests that microbiome-mediated regulation of NAD+-related metabolism may contribute to host redox adaptation during T. gondii infection.

B vitamins↗

PubMed2026

MET-Aberrant non-small cell lung cancer: from kinase dependence to cell-surface targetability-mechanistic basis and biomarker framework for bispecific antibodies and antibody-drug conjugates.

MET-aberrant non-small cell lung cancer (NSCLC) is not a uniform therapeutic entity. Its biology, diagnostic pathways, and treatment sensitivity differ across MET exon 14 skipping alteration (METex14), MET amplification, and MET overexpression. This heterogeneity cannot be fully explained by conventional event-based classification and is reflected in the distinct clinical activity of MET tyrosine kinase inhibitors (MET-TKIs), bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). With the emergence of antibody-based therapies, MET has evolved from a signaling driver to a cell-surface target for receptor modulation and payload delivery. We therefore propose a clinically anchored two-dimensional framework for interpreting therapeutic relevance in MET-aberrant NSCLC: kinase dependence and cell-surface targetability. Neither dimension should be regarded as a directly measurable binary variable. Kinase dependence is inferred from genomic and treatment-contextual proxies, most strongly METex14 and, more conditionally, high-level focal MET amplification. Cell-surface targetability is approximated by drug-specific IHC assessment of assay-defined c-MET protein expression; however, receptor internalization, intracellular trafficking, and payload delivery capacity remain incompletely measurable in routine clinical practice. Within this framework, MET-TKIs have the most evidence-supported established role in tumors with evidence of MET-driven kinase dependence. EGFR × MET BsAbs have demonstrated clinical activity in broad post-osimertinib EGFR-mutant NSCLC, while EGFR/MET co-dependence or MET-mediated bypass activation provides a mechanistic rationale for their use; MET-defined preferential benefit remains to be prospectively established. MET-directed antibody-drug conjugates (MET-ADCs) are supported in drug- and assay-defined populations with high c-MET protein overexpression, although the predictive relevance of delivery-related factors remains hypothesis-generating. Accordingly, MET testing should shift from single-event detection to platform-oriented stratification: next-generation sequencing (NGS) for driver alterations and resistance profiles, fluorescence in situ hybridization (FISH) for high-level focal amplification, and immunohistochemistry (IHC) for surface expression relevant to antibody-based therapies. This framework is intended to organize current biological and clinical evidence rather than to replace drug-specific companion diagnostics, regulatory indications, or prospectively validated treatment-selection algorithms. Precision treatment of MET-aberrant NSCLC is thus moving from event-based drug selection toward mechanism-based therapeutic matching. Future priorities include standardizing biomarkers, defining optimal target populations, and aligning biological subtypes, diagnostic strategies, and therapeutic platforms.

Antibody-drug conjugate↗

PubMed2026

A dual-dimensional CRISPR toolkit enables one-step high-efficiency multiplex genome editing in Komagataella phaffii.

Against the backdrop of green biomanufacturing, engineering methanol-utilizing Komagataella phaffii (K. phaffii) represents an effective strategy to expand the one carbon (C1) product profile and speed up the industrialization of C1-based bioeconomy. To address the technical challenges of low efficiency and cumbersome experimental procedures for multiplex gene editing and precise large-fragment integration during the reconstruction of complex metabolic pathways in K. phaffii, this study established a CRISPR toolkit - Efficient Multi-Gene Editing System 3.0 (EMGES 3.0) - which enabled one-step large-fragment integration coupled with multiplex gene knockout. EMGES 3.0 was constructed through the synergistic optimization of a repair-engineered chassis and an episomal CRISPR vector. For chassis engineering, five DNA repair modules: Δlig4 (DNA Ligase IV, non-homologous end joining end ligation), ppMRE11(The endogenous MRE11 gene from Pichia pastoris) overexpression (The Meiotic Recombination 11, DNA double-strand break end resection), Δrad9 (Radiation-Sensitive 9, DNA damage checkpoint regulation), Δmph1 (Mutator Phenotype Helicase 1, improvement of homologous recombinant strand extension), and PapRecT-PaSSB co-expression (stabilization of recombination intermediates) were integrated to generate the highly recombinogenic strain Y09. For vector engineering, cenARS was replaced by panARS and the endogenous promoter PGAP was employed to drive the double hammerhead ribozyme-single guide RNA-hepatitis delta virus ribozyme (double HH-sgRNA-HDV: dHgH)-mediated sgRNA expression, yielding the optimized vector Nov_pGAP_panARS_pLAT1_Cas9. These two features on K. phaffii together enhanced the EMGES 3.0 to a higher standard of transformation rate and editing efficiency. According to our results, EMGES 3.0 achieved dual-functional gene knockout efficiencies between 76.6% and 100%. For insertion of medium-long fragments (>4.5 kb), the efficiency achieved 93.3%. In addition, the one-step integration of ultra-long fragments (>16 kb) achieved 14.8%, which was reported for the first time. Furthermore, the efficiency of simultaneous long-fragment integration at three neutral loci reached 38.4% (>15 kb). We applied the system for one-step production of free fatty acids (FFAs, yield: 5.82 ∼ 7.30 mg/L/OD600) and resveratrol (yield: 1.14 ∼ 1.28 mg/L) using methanol as the sole carbon source. EMGES 3.0 provides a robust technical foundation for complex compounds biosynthesis and high-yield industrial strains, while also advancing K. phaffii as an industrial synthetic biology chassis for efficient C1 utilization.

CRISPR-Cas Systems↗

PubMed2026

Optimized AAV5-RPGR ORF15 Gene Therapy Rescues Photoreceptor Structure and Function in X-Linked Retinitis Pigmentosa Mouse Model.

PURPOSE: To develop and evaluate an rAAV5-based gene therapy vector expressing an optimized human RPGR ORF15 transgene (rAAV5-RPGR) for the treatment of X-linked retinitis pigmentosa caused by RPGR mutations, addressing the challenges of cloning the unstable wild-type ORF15 sequence. DESIGN: This was a prospective experimental study. SUBJECTS: This was an animal study. METHODS: An optimized RPGR ORF15 sequence was designed to eliminate problematic secondary structures and cryptic splice sites. In vitro expression was validated in HEK 293T and photoreceptor-like 661 W cells. A complete Rpgr knockout mouse model (Rpgr-knockout [KO]) was generated and characterized phenotypically. Therapeutic efficacy was assessed in Rpgr-KO mice via subretinal injection of rAAV5-RPGR at low (1 × 10⁹ vg/eye), medium (3 × 10⁹ vg/eye), or high (1 × 10¹⁰ vg/eye) doses. Structural and functional outcomes were evaluated at 12- and 14-month postinjection. Short-term safety was assessed in rabbits 1 month after subretinal injection. MAIN OUTCOME MEASURES: Level of RPGR protein expression and Protein isoform profile (elimination of truncated isoforms), Cellular localization of transgene expression and Dose-dependence of expression, outer nuclear layer thickness, and electroretinography parameters. RESULTS: (1) The optimized vector increased RPGR protein expression 3.3-fold in vitro compared to wild-type and eliminated truncated isoforms. (2) Subretinal delivery of rAAV5-RPGR in mice demonstrated dose-dependent transgene expression localized correctly to photoreceptor inner segments. (3) In Rpgr-KO mice, high-dose treatment significantly preserved outer nuclear layer thickness at the injection site (42% greater than controls at 14 months, P < .01) and central retina (P < .05), reduced aberrant rhodopsin mislocalization (P < .01), and partially restored retinal function. ERG showed significantly improved scotopic a-wave (≥100 vs <90 µV in controls at 10 cd·s/m²) and photopic b-wave amplitudes (49-66 vs 31-46 µV at 30 cd·s/m²) in treated mice. (4) No vector-related toxicity was observed in rabbits. CONCLUSIONS: rAAV5-RPGR mediated efficiently, targeted expression of optimized RPGR-ORF15, significantly preserved photoreceptor structure and function in a severe X-linked retinitis pigmentosa mouse model, and demonstrated a favorable safety profile. This study provides preclinical proof-of-concept for RPGR-targeted gene replacement therapy.

Animals↗

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↗