iScience最新文献

To compare the effects of nonpharmacological interventions on frailty, sarcopenia, and related physical-function outcomes in older adults with gastrointestinal cancers, we conducted a Bayesian random-effects network meta-analysis of 21 randomized controlled trials from 10 countries. Most interventions did not show clear benefits for frailty, sarcopenia, gait speed, Timed Up and Go performance, sit-to-stand performance, skeletal muscle index, or 6-min walk distance. Prehabilitation exercise showed a low-certainty benefit for handgrip strength, whereas enhanced nutritional support and intensive physiotherapy showed limited benefits for patient-reported physical function. However, these findings were based on small, sparsely connected networks, and the certainty of evidence was generally low or very low. No single intervention was consistently effective across outcomes. These results highlight the need for larger, cancer-specific trials using standardized outcome definitions and clearer reporting of intervention intensity, adherence, safety, and feasibility.

Soil contamination threatens ecosystem functioning, while conventional ecological risk assessment (ERA) based on single-species toxicity may not capture system-level responses. We developed a probabilistic soil health sensitivity distribution (SHSD) framework integrating microcosm-derived soil health indicators with joint probability modeling and applied it to Pb, Cu, and Cd risks in Tianjin soils, northern China. SHSD-derived risks were lower than species sensitivity distribution (SSD)-based estimates by 61.90%, 59.55%, and 84.38% for Pb, Cu, and Cd, respectively. Normalizing SSD toxicity data to microcosm soil conditions reduced part of the SSD-SHSD discrepancy, highlighting the influence of soil physicochemical heterogeneity. Observed SHSDs were also shifted rightward relative to additive, non-interactive predictions, indicating lower apparent sensitivity of the integrated microcosm. These findings support SHSD as a higher tier, function-oriented complement to conventional SSDs, while emphasizing the need for independent field validation before regulatory application.

While the kinesin MKLP1 is a well-established regulator of cytokinesis, whether its individual domains possess autonomous functions has remained unexplored. Here, using the holocentric Bombyx mori BmN4 system, we show that isolated head, stalk, and tail domains of MKLP1 exhibit distinct subcellular localization patterns and exert divergent control over mitosis. These domains differentially regulate cell-cycle progression, with the head and stalk inducing G2/M arrest, whereas the tail, and to a lesser extent the head, promotes polyploidization. Despite these divergent outcomes, all three domains converge on a shared pathological activity, aberrantly recruiting γ-tubulin, disrupting spindle organization, and compromising chromosome segregation. The domains also exert opposing effects on EdU incorporation, with the head suppressing EdU labeling and the stalk and tail enhancing it. Together, our findings redefine MKLP1 as a composite platform of regulatory modules, whose uncoupling reveals a principle of kinesin organization with broad implications for mitotic robustness and genomic stability.

Staphylococcus aureus is a common pathogen in children with cystic fibrosis (CF), frequently preceding or coexisting with Pseudomonas aeruginosa. The impact of transient P. aeruginosa infection and therapeutic intervention on S. aureus phenotypic shaping remains poorly understood. We characterized 546 isolates from a longitudinal cohort of sixteen pediatric patients in CF follow-up, either monoinfected or coinfected, over eighteen months. Isolates were grouped into three phenotypic clusters. Monoinfected patients were enriched in a cluster with high pigment and biofilm, whereas transient P. aeruginosa detection was associated with a shift toward reduced pigment and biofilm, while coinfected patients maintained stable phenotypes. Phenotypes were determined by the airway microenvironment rather than by clonal background. In two monoinfected patients, this shift coincided with transient infection and ciprofloxacin treatment with increased MRSA; in vitro, MRSA predominated over MSSA when both P. aeruginosa and ciprofloxacin were present, underscoring the need to monitor S. aureus phenotypic transitions.

Hirschsprung disease (HSCR) is characterized by distal intestinal aganglionosis and persistent dysfunction of the enteric nervous system after surgical treatment. Here, we integrated single-cell transcriptomics, network-based virtual perturbation analysis, proteomics, human tissue validation, enteric glial cell assays, neuron-glia co-culture systems, and an Ednrb conditional knockout (cKO) mouse model to investigate TXNRD1-dependent enteric glial remodeling in HSCR. We found that thioredoxin reductase 1 (TXNRD1) enrichment was associated with expansion of an SPP1-high/CXCL9-low enteric glial state and selective ERK/MAPK activation. TXNRD1 overexpression increased oxidative stress, impaired enteric glial migration and neurotrophic support, and induced neuronal dysfunction through suppression of GDNF/GFRα1/RET signaling. TXNRD1 inhibition alleviated HSCR-like phenotypes in Ednrb cKO mice. These findings identify TXNRD1-driven redox-dependent enteric glial remodeling as a mechanism contributing to neuronal dysfunction and HSCR progression.

Galleria mellonella is an emerging experimental model, but its current genome annotation lacks transcription start site (TSS) information. Because TSS annotation is essential for understanding transcriptional regulation, we used low quantity single strand CAGE (LQ-ssCAGE) to map cap analysis of gene expression (CAGE)-defined TSSs from 72 G. mellonella larval samples. Among these, 36 larvae were infected with the fungal pathogen Madurella mycetomatis and 36 served as healthy controls, allowing identification of TSSs under both infected and healthy conditions. Infected and healthy larvae were treated with itraconazole or ravuconazole. To assess key characteristics of the CAGE data, TSS peaks and putative enhancers were intersected with the existing genome annotation for annotation and characterization. This analysis identified two sets of TSS peaks, permissive and robust, representing the first draft TSS atlas for G. mellonella. The atlas-derived annotations showed a markedly stronger core promoter sequence signature than the NCBI reference annotation, supporting improved resolution and accuracy of TSS annotation in the atlas.

Early fault detection is important for the safe and stable operation of large hydro turbine units under complex and variable operating conditions. This study develops an early fault warning framework for high dimensional multisource monitoring data by integrating Kendall rank correlation-based parameter grouping, systematic data governance, sparse principal component analysis, and a CNN LSTM prediction model. Fifty two operating parameters are organized into six groups and transformed into six sparse state features. The CNN LSTM model captures local correlations and temporal evolution, achieving R² values of 0.947, 0.955, 0.848, 0.701, 0.687, and 0.853 for SPCA1 to SPCA6. Prediction residuals combined with 2σ and 3σ thresholds identify early degradation before the recorded fault, with warning lead times of up to 33 time steps. The framework provides a practical approach for condition monitoring and hierarchical early warning of large hydro turbine units.

The first 1,000 days of brain development are sensitive to nutrient availability, and large longitudinal early-life cohorts provide an opportunity to study early nutritional influences on neurodevelopment in generally healthy populations. We aimed to identify international pregnancy and birth cohorts with at least 1,000 children collecting early-life nutrition data, including maternal nutrition during pregnancy or lactation, breastfeeding, and solid-food feeding, along with later child neurodevelopmental outcomes. In total, 104 pregnancy and birth cohorts were identified, representing over 1.17 million children across 41 countries. Cohorts spanned six continents, with the largest participant representation from high- and upper middle-income settings. Maternal diet during pregnancy and breastfeeding status were the most frequently captured nutrition domains, while neurodevelopmental assessments varied across developmental periods, using over 200 assessment tools. These cohorts support future harmonized analyses of early nutrition and neurodevelopment, and further work will benefit from international collaboration, shared data standards, and pooled or federated infrastructures.

Most of glioma patients still experience relapse after radiotherapy owing to the formation of tumor immunosuppressive microenvironment. However, the comprehensive landscape of immune cell infiltration and the molecular mechanisms mediating glioma recurrence remains unclear. Bulk RNA sequencing (RNA-seq) analysis revealed the significant changes in the immune system including increased total tumor-associated macrophages (TAMs) and elevated M2-TAMs in recurrent glioma accepting radiotherapy. Meanwhile, C-C motif chemokine 18 (CCL-18) was the highest elevated molecule after radiotherapy. Consistently, the aforementioned results were confirmed in tissue microarray containing 23 paired gliomas. In vitro, radiation promoted TAM polarization into M2-TAMs, accompanying CCL-18 secretion. However, CCL-18 promoted non-irradiated glioma proliferation but did not mediate glioma recurrence after radiotherapy. Mechanistically, the pro-tumor effect of CCL-18 was weakened by the down-regulation of CCL-18 receptors on glioma accepting radiotherapy. Our study indicates CCL-18 does not mediate glioma recurrence but has the potential to serve as a biomarker for recurrent gliomas.

This study developed T cell receptor (TCR)-like antibodies targeting the intracellular neoantigen derived from the common NPM1 type A mutation (NPM1^mutA) in acute myeloid leukemia (AML), presented by HLA-A∗02:01. Hybridoma technology was employed to generate a murine monoclonal antibody (m2E2) specifically recognizing the NPM1^mutA _283-291-HLA-A∗02:01 complex. The lead antibody was humanized (hu2E2) and engineered into bispecific formats engaging CD3 or CD16, alongside an Fc-enhanced variant (hu2E2-GAALIE). In vitro, these antibodies mediated potent antibody-dependent cellular cytotoxicity (ADCC) against NPM1^mutA-positive AML cell lines, inducing apoptosis and cytokine release. In vivo, a single dose of hu2E2 variants significantly suppressed tumor growth in NCG mice engrafted with OCI-AML3-LUC cells. Fc silencing abolished antitumor efficacy, confirming FcγR-dependent mechanisms. Critically, m2E2 specifically bound to primary CD33⁺ blasts from HLA-A∗02:01-positive, NPM1-mutated AML patients. These findings demonstrate a potent immunotherapeutic strategy for targeting intracellular oncogenic peptides in AML and support further clinical development of TCR-like antibodies.