Although Poly(A)-binding protein cytoplasmic 1 like (PABPC1L) has been studied in specific cancer types, its broader potential as a prognostic biomarker remains uninvestigated, and the systematic pan-cancer analysis is currently lacking. We performed an integrated pan-cancer analysis of PABPC1L expression and function in 33 human malignant tumors. Associations between PABPC1L expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment composition, drug sensitivity, and response to immune checkpoint blockade (ICB) were also evaluated. A gastric cancer (GC) single-cell RNA sequencing dataset was analyzed to examine the correlation between PABPC1L expression and intercellular communication networks. The relationship between PABPC1L and PD-L1 expression was investigated in human colorectal cancer (CRC) tissue. Functional validation experiments were performed in CRC and GC cell lines. PABPC1L expression was consistently upregulated in multiple cancer types and significantly associated with poor patient prognosis. Notably, PABPC1L was identified as an immunomodulatory factor. It influenced the expression of multiple immune-related genes, regulates immune cell infiltration, and correlates with the outcomes following ICB therapy. Single-cell RNA sequencing analysis of GC further indicated that PABPC1L was involved in intercellular communication networks, including immune cells. In CRC, elevated PABPC1L expression was observed in tumor tissues and positively correlated with PD-L1 levels. Functional experiments confirmed that PABPC1L promoted cell proliferation, regulated cell cycle, and impaired the sensitivity of gastric and colorectal cells to 5-FU. In conclusion, PABPC1L is identified as exhibiting oncogenic properties and is proposed to function as a key regulator of tumorigenesis and immunotherapy resistance.

Broadband long-wavelength infrared (LWIR) light sources in the molecular fingerprint spectral region are highly desirable for advanced spectroscopy and remote sensing applications. Intra-pulse difference frequency generation (IPDFG) driven by well-established erbium-doped fiber lasers has recently emerged as an efficient and compact approach for multi-octave LWIR radiation generation. Here, we demonstrate a highly efficient IPDFG with a spectrum spanning from 7.5 to 13 µm in a newly developed ZnGeP2 (ZGP) crystal namely, YS-ZGP, pumped by a few-cycle erbium-doped fiber laser. Benefitted from the high nonlinearity and reduced two-photon absorption in YS-ZGP, an output power of 5.48 mW and a conversion efficiency of 0.67% are obtained, which both represent record values in LWIR IPDFG systems, pumped by 1.55 µm femtosecond lasers. This result overturns the conventional perception that IPDFG in ZGP crystals can only be pumped at wavelengths longer than 2 µm. Furthermore, to extend the spectral coverage into longer wavelengths, IPDFGs in BaGa4Se7 and BaGa2GeSe6 crystals are investigated too, achieving octave-spanning LWIR outputs covering 8-16 µm and 7-16.5 µm, respectively. We anticipate that YS-ZGP-based LWIR sources pumped by 1.55 µm lasers will significantly advance practical applications in molecular spectroscopy and sensing.

Structural remodeling of the dentate gyrus is a hallmark of temporal lobe epilepsy (TLE), yet the underlying molecular mechanisms remain incompletely understood. Nuclear distribution element-like 1 (Ndel1), a cytoskeleton-associated protein involved in neuronal migration and dendritic development, has not been characterized in dentate gyrus remodeling during epileptogenesis. Here, we investigated region- and cell-type-specific alterations in Ndel1 expression in a pilocarpine-induced mouse model of TLE and examined the effects of adeno-associated virus (AAV)-mediated Ndel1 expression on structural remodeling. Immunofluorescence was used to define Ndel1 localization across neural stem cells, granule lineage cells, mature neurons, and astrocytes, and dendritic architecture was assessed using Golgi staining and Sholl analysis. Total hippocampal Ndel1 expression increased after status epilepticus, whereas Ndel1-positive cells decreased selectively in the subgranular zone but increased among granule lineage cells in the hilus. Ndel1 was preferentially expressed in BLBP-positive neural stem cells and mature neurons, but not in neuroblasts. Activated astrocytic processes exhibited increased spatial association with Ndel1-positive cells during early remodeling. Ndel1 overexpression was associated with partial normalization of neuronal marker distribution, increased dendritic spine density, and reduced dendritic branching complexity. These findings suggest that Ndel1 is associated with region- and lineage-specific structural remodeling in the dentate gyrus during epileptogenesis.

Patients were divided into three groups based on the percentages of CD8+ T cells

Spatial phenotypes of CD8+ T cells

Alternative splicing (AS) is a ubiquitous post-transcriptional regulatory mechanism, that has greatly expanded the transcriptomic and proteomic diversity in vertebrates. While gene regulation of hematopoiesis has been extensively researched in vertebrates, the functions of species- and cell lineage-specific splice variants in vertebrates are largely unknown. Here, we curate transcriptomic data on fetal hematopoietic organ development in six vertebrates and hematopoietic cell differentiation in humans and mice. To identify functional exon-skipping events among thousands of cassette exons in protein-coding genes for a specific differentiation lineage and species, we develop a machine-learning model interrogating 19 features including dynamic expression, protein structure, and evolutionary conservation, and integrate them into a single prediction score, named Functional AS Score (FAScore). Using FAScore, we identify four previously-uncharacterized functional AS events in which deletion of the AS exon leads to defects in erythropoiesis and myelopoiesis. Furthermore, we demonstrate that deletion of exon 15 of TBC1D23 reduces erythropoiesis in mice and zebrafish through elevated binding capacity to RANBP2/RANGAP1 leading to increased SUMOylation level of HDAC1. Collectively, our study presents a valuable tool to identify functional exon skipping (ES) events during hematopoietic lineage commitment, and establishes a research paradigm that can be broadly applied to other biological processes.

Rapid wound healing of oral soft tissue may reduce the opportunity for infection and discomfort of patients. Given that recombinant humanized collagen type III (rhCol III) is considered a nonallergenic biomaterial and can help repair skin wound healing and activate tissue remodeling, the potential effect of rhCol III on palate mucosal wound healing was preliminarily evaluated in vitro and in vivo in this study. A mouse model of an oral palate wound was established, and rhCol III solutions were injected periwound, resulting in a significant acceleration in wound healing compared to the control groups. Histological evaluation showed that rhCol III promoted angiogenesis, collagen deposition, and cell proliferation. Furthermore, the results demonstrated that rhCol III could promote human gingival fibroblast (HGF) and human oral keratinocyte (HOK) proliferation, adhesion, and migration. To further explore the mechanism, RNA-sequencing analysis results showed that rhCol III could regulate the focal adhesion signaling pathway of HGFs. The expression of vinculin and phosphorylation of FAK (Tyr397 and Tyr576) in HGFs was upregulated with rhCol III treatment. In addition, inhibition of FAK phosphorylation could inhibit HGF migration. These results suggested that rhCol III promoted HGF migration by upregulating the focal adhesion signaling pathway. These findings suggest that the topical application of rhCol III is a promising treatment for oral soft tissue wounds with the potential for future clinical use.

Immunoregulatory proteins expressed by SARS-CoV-2 interfere with host antiviral defences in infected cells and play critical roles in the pathogenesis and clinical manifestations of COVID-19. Here, we established a prediction algorithm by integrating a pretrained protein-language model and gene weights in immune-related pathways to quantify perturbations of SARS-CoV-2 proteins in host immunity. The results revealed that the canonical NF-κB pathway was dynamically regulated by SARS-CoV-2 infection and that nonstructural protein 1 (Nsp1) significantly suppressed the activation of the NF-κB pathway by other viral proteins and proinflammatory cytokines, such as IL-1β. Nsp1 binds to TAK1 at the TAB1-binding domain, promoting TRIM21-mediated K48-linked ubiquitination and subsequent proteasomal protein degradation, leading to the inactivation of the NF-κB signalling pathway. This work presents a novel framework to identify viral immunoregulators at the pathway level and provides mechanistic insights into immune evasion by SARS-CoV-2.

ABSTRACT Pulmonary manifestation in malaria can be life-threatening. Using a rodent malaria model and comprehensive transcriptomics analyses to illustrate the immune landscape of malaria-associated lung pathology, we identified that IFN-γ signaling in T cells plays an important role in malaria-associated lung pathology. Disruption of IFN-γ signaling in T cells leads to reduced parasite load in the lungs and attenuated lung pathology by enhancing T cell-monocyte interaction. Surprisingly, the stronger interaction leads to an increase in a proinflammatory monocyte subset characterized by CD8 and Ly6C expression, which exhibits prominently elevated phagocytic capacity compared to the CD8− counterpart. Our study illustrates the importance of IFN-γ signaling in T cell-monocyte interaction in malaria-associated lung pathology, highlighting the complex and intricate immune network induced by the Plasmodium infection.IMPORTANCEMalaria-associated lung pathology is a common complication of malaria in adults and often occurs during or even after antimalarial treatment, and current evidence suggests that it is associated with cytokine imbalance and dysregulation of immune responses in the lungs. In this study, we conducted detailed flow cytometry analyses, time-series bulk transcriptomics, and spatial transcriptomics to profile the immune landscape of malaria-associated lung pathology in a mouse malaria model and revealed that IFN-γ signaling in T cells plays a key role in the lung pathology. In addition, we identified a subgroup of CD8-expressing proinflammatory monocytes that exhibit heightened parasite phagocytotic capability.

Chaos LiDAR enables unambiguous ranging with superior anti-jamming properties, though its applications have been primarily demonstrated in the near-infrared region. Leveraging the excellent atmospheric transparency, strong resistance to scattering and turbulence, and the molecular fingerprint characteristics of the mid-infrared (MIR) wavelengths, MIR chaos LiDAR could be particularly advantageous for achieving unambiguous ranging and remote sensing. However, the lack of broadband chaotic light and fast photodetectors in the MIR region hinders the realization of high-performance MIR chaos LiDAR. Here, we demonstrate, for the first time to the best of our knowledge, a frequency conversion-based MIR chaos LiDAR that employs a novel MIR chaos laser generated via frequency down-conversion of near-infrared random fiber laser and the up-conversion chaos detection. The approach facilitates the generation of a wavelength-tunable MIR laser with a large chaos bandwidth, enabling MIR hyperspectral chaos LiDAR operating in the spectral range of 3330-3390 nm within the 3-5 & micro;m atmospheric window that integrates centimeter-level high-resolution ranging and spectroscopy, highlighting its potential for remote sensing applications. This work provides a new paradigm for high-resolution ranging and hyperspectral imaging in arbitrary spectral regions where broadband chaos light generation and detection are challenging.

Tau aggregation and hyperphosphorylation are key pathological hallmarks and early diagnostic biomarkers of Alzheimer's disease (AD). However, the simultaneous profiling and quantitative analysis of Tau and its phosphorylated isoforms remain technically challenging. Here, by introducing an acidic aspartate residue at the G6 site of FraCG13F, we engineered a high-resolution FraCG6DG13F nanopore with enhanced temporal resolution for protonated polypeptide detection. Integrated with machine-learning algorithms, our nanopore-based workflow enabled the real-time identification of 12 tryptic peptides from native Tau (2N4R) protein with over 91.1% accuracy. Furthermore, positional phosphorylation isomers at either S400 or S402 of Tau (2N4R) were precisely resolved and quantified in mixed digestion samples, achieving classification accuracy exceeding 93% and sensitivity comparable to that of microgram-level mass spectrometry. This study demonstrates a promising advancement of global analysis of phosphorylated Tau in nanopore-based methods, highlighting its potential for high-resolution characterization and accurate quantification of proteins with PTMs.

The generation of transcript variants via alternative utilisation of transcription start sites (TSSs) is a pivotal regulatory mechanism in physiological and pathological states. Recent advancements in 5' single-cell RNA sequencing (scRNA-seq) have enabled TSS analysis at the single-cell level. However, RNA degradation leads to non-uniform read coverage, posing a critical challenge that significantly compromises accurate TSS quantification of scRNA-seq data. To address RNA degradation and improve TSS quantification, we develop scATS (single-cell alternative transcription start site) to estimate RNA degradation at both isoform and sample levels, and provide TSS quantification with or without degradation correction. Application of scATS reveals dynamic and context-dependent regulation of TSSs in haematopoiesis and disease, providing additional information on TSS isoforms that aids cell clustering at a finer resolution. Furthermore, we establish a machine-learning pipeline, lung cancer relevance score (LRS), to identify TSSs associated with lung cancer. We analyse TSS isoforms of CCR6, CCR2 and RTKN2 in lung cancer cell lines and confirm that isoforms highly transcribed in lung cancer promote cell proliferation and migration. Combined, we present a robust tool to accurately quantify TSS by accounting for RNA degradation, a common issue that confounds transcript quantification, and experimentally demonstrate the important roles of TSS-mediated gene regulation in tumourigenesis.

Abstract: BackgroundUlcerative colitis (UC) is a chronic relapsing inflammatory bowel disease affecting over 5 million people globally, with a steadily rising incidence. Current frontline UC therapies are severely limited by low durable remission rates, frequent adverse events, high costs, and emerging drug resistance, as conventional single-target interventions fail to address the multifactorial, network-driven pathogenesis of UC. The rhizome of Atractylodes chinensis (RAC), a classic traditional Chinese medicine, has long been used for UC management, yet its in vivo bioactive constituents and molecular mechanisms remain incompletely characterized. Purpose This study aimed to explore the pharmacodynamic material basis of RAC against UC and investigate its potential multi-component synergistic therapeutic mechanisms via an integrated multi-omics strategy. Methods Serum pharmacochemistry was performed to characterize absorbed prototype components of RAC in mice, followed by network pharmacology to predict UC-related targets, in vivo efficacy validation in a dextran sulfate sodium (DSS)-induced UC mouse model, colonic transcriptomic profiling, and molecular docking to assess the predicted binding affinities between components and targets. Results Twenty-eight prototype components of RAC that are systemically absorbed into the circulation were systematically identified in mice. RAC dose-dependently ameliorated UC-like phenotypes in DSS-induced mice, downregulated pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), and restored colonic architecture. The potential core mechanisms underlying its anti-UC activity may be centered on metabolic reprogramming. These included shifting arachidonic acid metabolism toward an inflammation-resolving phenotype, activating folate-driven one-carbon metabolism to support epithelial regeneration, and inhibiting ferroptosis. Core RAC constituents exhibited favorable predicted binding affinities to key targets. Conclusion RAC ameliorates DSS-induced UC in mice, potentially via modulating metabolic reprogramming and ferroptosis. These findings provide a scientific basis for its clinical application and a validated paradigm for pharmacological research of traditional Chinese medicine.

BACKGROUND:Recurrence of colorectal cancer (CRC) after curative-intent treatment is largely driven by minimal residual disease (MRD). Circulating tumor DNA (ctDNA) offers a noninvasive approach to detect MRD and tailor adjuvant therapy and surveillance. METHODS:This scoping review synthesized prospective cohorts, interventional/randomized trials, and real-world registries on ctDNA-based MRD testing in resected CRC, comparing tumor-informed vs plasma-only (mutation- and/or methylation-based) assays. RESULTS:Postoperative ctDNA positivity strongly predicts recurrence and often precedes radiologic relapse by 3 to 10 months. Tumor-informed assays provide high specificity and analytical sensitivity, whereas plasma-only assays enable tissue-free, faster testing but often require serial sampling. In stage II colon cancer, ctDNA-guided management reduced the use of chemotherapy without compromising recurrence-free survival. ctDNA dynamics add prognostic resolution. Clearance after adjuvant therapy is associated with excellent outcomes, whereas persistent positivity signals a very high relapse risk. Escalation approaches tested to date (eg, intensified chemotherapy or trifluridine/tipiracil) have not shown definitive disease-free survival gains in patients with a positive ctDNA. Implementation data indicate that ctDNA can influence treatment and surveillance decisions. However, barriers include assay variability, optimal timing, counseling, and reimbursement. CONCLUSION:ctDNA-based MRD testing is a robust prognostic tool and a practical framework for biology-guided postoperative CRC care. Ongoing phase III trials should establish standardized algorithms and effective MRD-directed therapies.

ABSTRACT Approximately 10%–30% of elderly patients experience cognitive decline after general anesthesia and surgery. However, how specific brain regions coordinate cellular and molecular networks to mediate cognitive decline remains unknown. Here, we revealed that the hippocampus, but not other cognitive‐related brain regions, exhibits increased blood–brain barrier (BBB) permeability, leading to neuroinflammation activation and cognitive decline after general anesthesia and surgery in aged mice. Mechanistically, anesthesia and surgery induce expression of the mechanosensitive channel Piezo1 in hippocampal endothelial cells (ECs) of aged mice. Inducible EC‐specific deletion of Piezo1 restores hippocampal BBB integrity, inhibits neuroinflammation activation, and improves cognitive decline in aged mice following anesthesia and surgery. Conversely, injection of the Piezo1 agonist Yoda1 promotes hippocampal BBB breakdown. Moreover, activation of Piezo1 induces Nox4, which mediates hippocampal BBB breakdown and neuroinflammation activation after anesthesia and surgery in aged mice. Therapeutically, AAV‐BR1 transduction to brain microvascular ECs for the knockdown of endothelial Nox4 blocks Piezo1‐mediated hippocampal BBB breakdown and neuroinflammation activation. Overall, inhibiting the endothelial Piezo1‐Nox4 axis restores hippocampal BBB integrity to improve anesthesia‐ and surgery‐induced cognitive decline in aged mice, highlighting potential therapeutic strategies.

Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinct histologic features, characterized by accumulated mucins in the cytoplasm which compress nuclei. Gastric SRCC is the most common SRCC whose incidence is increasing in recent years. The molecular mechanisms underlying the histopathology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1 A (ARID1A), one of the most frequently mutated genes in gastric SRCC, functions as a bona fide tumor suppressor. Its loss, together with Trp53 and Pten loss, drives SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins through the competing BRD9-containing ncBAF complex. And mucin secretion is impaired by the downregulation of Scin, a direct target of Arid1a in SRCC. Inhibition of Brd9 ameliorates the malignancy of SRCC. Thus, our study reveals dual roles of ARID1A in both mucin production and secretion, providing new mechanistic insights and potential therapeutic vulnerabilities in SRCC.

Neutrophils, an essential innate immune cell type with a short lifespan, rely on continuous replenishment from bone marrow (BM) precursors. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the molecular regulators involved in the differentiation process remain poorly understood. Here we developed a random forest-based machine-learning pipeline, NeuRGI (Neutrophil Regulatory Gene Identifier), which utilized Positive-Unlabeled Learning (PU-learning) and neural network-based in silico gene knockout to identify neutrophil regulators. We interrogated features including gene expression dynamics, physiological characteristics, pathological relatedness, and gene conservation for the model training. Our identified pipeline leads to identifying Mitogen-Activated Protein Kinase-4 (MAP4K4) as a novel neutrophil differentiation regulator. The loss of MAP4K4 in hematopoietic stem cells and progenitors in mice induced neutropenia and impeded the differentiation of neutrophils in the bone marrow. By modulating the phosphorylation level of proteins involved in cell apoptosis, such as STAT5A, MAP4K4 delicately regulates cell apoptosis during the process of neutrophil differentiation. Our work presents a novel regulatory mechanism in neutrophil differentiation and provides a robust prediction model that can be applied to other cellular differentiation processes.