Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy.

The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

New frontiers in salivary extracellular vesicles: transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases.

Salivary extracellular vesicles (EVs) have emerged as key tools for non-invasive diagnostics, playing a crucial role in the early detection and monitoring of diseases. These EVs surpass whole saliva in biomarker detection due to their enhanced stability, which minimizes contamination and enzymatic degradation. The review comprehensively discusses methods for isolating, enriching, quantifying, and characterizing salivary EVs. It highlights their importance as biomarkers in oral diseases like periodontitis and oral cancer, and underscores their potential in monitoring systemic conditions. Furthermore, the review explores the therapeutic possibilities of salivary EVs, particularly in personalized medicine through engineered EVs for targeted drug delivery. The discussion also covers the current challenges and future prospects in the field, emphasizing the potential of salivary EVs in advancing clinical practice and disease management.

Alternative pre-mRNA splicing in stem cell function and therapeutic potential: A critical review of current evidence.

Alternative splicing is a crucial regulator in stem cell biology, intricately influencing the functions of various biological macromolecules, particularly pre-mRNAs and the resultant protein isoforms. This regulatory mechanism is vital in determining stem cell pluripotency, differentiation, and proliferation. Alternative splicing's role in allowing single genes to produce multiple protein isoforms facilitates the proteomic diversity that is essential for stem cells' functional complexity. This review delves into the critical impact of alternative splicing on cellular functions, focusing on its interaction with key macromolecules and how this affects cellular behavior. We critically examine how alternative splicing modulates the function and stability of pre-mRNAs, leading to diverse protein expressions that govern stem cell characteristics, including pluripotency, self-renewal, survival, proliferation, differentiation, aging, migration, somatic reprogramming, and genomic stability. Furthermore, the review discusses the therapeutic potential of targeting alternative splicing-related pathways in disease treatment, particularly focusing on the modulation of RNA and protein interactions. We address the challenges and future prospects in this field, underscoring the need for further exploration to unravel the complex interplay between alternative splicing, RNA, proteins, and stem cell behaviors, which is crucial for advancing our understanding and therapeutic approaches in regenerative medicine and disease treatment.

Mixing Insulating Commodity Polymers with Semiconducting n-type Polymers Enables High-Performance Electrochemical Transistors.

Diluting organic semiconductors with a host insulating polymer is used to increase the electronic mobility in organic electronic devices, such as thin film transistors, while considerably reducing material costs. In contrast to organic electronics, bioelectronic devices such as the organic electrochemical transistor (OECT) rely on both electronic and ionic mobility for efficient operation, making it challenging to integrate hydrophobic polymers as the predominant blend component. This work shows that diluting the n-type conjugated polymer p(N-T) with high molecular weight polystyrene (10 KDa) leads to OECTs with over three times better mobility-volumetric capacitance product (µC*) with respect to the pristine p(N-T) (from 4.3 to 13.4 F V-1 cm-1 s-1 ) while drastically decreasing the amount of conjugated polymer (six times less). This improvement in µC* is due to a dramatic increase in electronic mobility by two orders of magnitude, from 0.059 to 1.3 cm2 V-1 s-1 for p(N-T):Polystyrene 10 KDa 1:6. Moreover, devices made with this polymer blend show better stability, retaining 77% of the initial drain current after 60 minutes operation in contrast to 12% for pristine p(N-T). These results open a new generation of low-cost organic mixed ionic-electronic conductors where the bulk of the film is made by a commodity polymer.

Multiply-mesoporous hydrophilic titanium dioxide nanohybrid for the highly-performed enrichment of N-glycopeptides from human serum.

N-glycopeptide is considered as one of significant biomarkers which provide guidance for the diagnosis and drug design of diseases. However, the direct analysis of N-glycopeptides is nearly impracticable mainly owing to their extremely low abundance and grave signal suppression from other interfering substances in the bio-samples. In this research, a multiply-mesoporous hydrophilic TiO2 nanohybrid (mM-TiO2@Cys) was synthesized by immobilizing Cys on a TiO2 substrate with hierarchical mesopores to achieve the highly-performed enrichment of N-glycopeptides. With the advantages of superior hydrophilicity and multiply-mesoporous structure, the obtained material exhibited an excellent selectivity (IgG digests and BSA digests at the molar ratio of 1/500), a high sensitivity (1 fmol µL-1 for IgG digests) and a good size-exclusion ability (IgG digests, IgG and BSA at the molar ratio of 1/500/500) in the enrichment of N-glycopeptides from IgG digests. As a result, 281 N-glycopeptides corresponded with 109 glycoproteins were identified from 2 µL serum digests of the patients with nasopharyngeal carcinoma, and 181 N-glycopeptides corresponded with 78 glycoproteins were identified from 2 µL serum digests of the healthy volunteers, revealing the potential application value of mM-TiO2@Cys in glycoproteomics.

Cleanroom-Free Direct Laser Micropatterning of Polymers for Organic Electrochemical Transistors in Logic Circuits and Glucose Biosensors.

Organic electrochemical transistors (OECTs) are promising devices for bioelectronics, such as biosensors. However, current cleanroom-based microfabrication of OECTs hinders fast prototyping and widespread adoption of this technology for low-volume, low-cost applications. To address this limitation, a versatile and scalable approach for ultrafast laser microfabrication of OECTs is herein reported, where a femtosecond laser to pattern insulating polymers (such as parylene C or polyimide) is first used, exposing the underlying metal electrodes serving as transistor terminals (source, drain, or gate). After the first patterning step, conducting polymers, such as poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), or semiconducting polymers, are spin-coated on the device surface. Another femtosecond laser patterning step subsequently defines the active polymer area contributing to the OECT performance by disconnecting the channel and gate from the surrounding spin-coated film. The effective OECT width can be defined with high resolution (down to 2 µm) in less than a second of exposure. Micropatterning the OECT channel area significantly improved the transistor switching performance in the case of PEDOT:PSS-based transistors, speeding up the devices by two orders of magnitude. The utility of this OECT manufacturing approach is demonstrated by fabricating complementary logic (inverters) and glucose biosensors, thereby showing its potential to accelerate OECT research.

Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond.

RNA modifications, known as the "epitranscriptome", represent a key layer of regulation that influences a wide array of biological processes in mesenchymal stem cells (MSCs). These modifications, catalyzed by specific enzymes, often termed "writers", "readers", and "erasers", can dynamically alter the MSCs' transcriptomic landscape, thereby modulating cell differentiation, proliferation, and responses to environmental cues. These enzymes include members of the classes METTL, IGF2BP, WTAP, YTHD, FTO, NAT, and others. Many of these RNA-modifying agents are active during MSC lineage differentiation. This review provides a comprehensive overview of the current understanding of different RNA modifications in MSCs, their roles in regulating stem cell behavior, and their implications in MSC-based therapies. It delves into how RNA modifications impact MSC biology, the functional significance of individual modifications, and the complex interplay among these modifications. We further discuss how these intricate regulatory mechanisms contribute to the functional diversity of MSCs, and how they might be harnessed for therapeutic applications. The review also highlights current challenges and potential future directions in the study of RNA modifications in MSCs, emphasizing the need for innovative tools to precisely map these modifications and decipher their context-specific effects. Collectively, this work paves the way for a deeper understanding of the role of the epitranscriptome in MSC biology, potentially advancing therapeutic strategies in regenerative medicine and MSC-based therapies.

Constructing a T-Cell Receptor-Related Gene Signature for Prognostic Stratification and Therapeutic Guidance in Head and Neck Squamous Cell Carcinoma.

BACKGROUD: The stratification of head and neck squamous cell carcinoma (HNSCC) patients based on prognostic differences is critical for therapeutic guidance. This study was designed to construct a predictive signature derived from T-cell receptor-related genes (TCRRGs) to forecast the clinical outcomes in HNSCC. METHODS: We sourced gene expression profiles from The Cancer Genome Atlas (TCGA) HNSCC dataset, GSE41613, and GSE65858 datasets. Utilizing consensus clustering analysis, we identified two distinct HNSCC clusters according to TCRRG expression. A TCRRG-based signature was subsequently developed and validated across diverse independent HNSCC cohorts. Moreover, we established a nomogram model based on TCRRGs. We further explored differences in immune landscapes between high- and low-risk groups. RESULTS: The TCGA HNSCC dataset was stratified into two clusters, displaying marked variations in both overall survival (OS) and immune cell infiltration. Furthermore, we developed a robust prognostic signature based on TCRRG utilizing the TCGA HNSCC train cohort, and its prognostic efficacy was validated in the TCGA HNSCC test cohort, GSE41613, and GSE65858. Importantly, the high-risk group was characterized by a suppressive immune microenvironment, in contrast to the low-risk group. Our study successfully developed a robust TCRRG-based signature that accurately predicts clinical outcomes in HNSCC, offering valuable strategies for improved treatments.

Facile fabrication of hydrophilic covalent organic framework composites for highly selective enrichment of N-glycopeptides.

The development of facilely synthetic materials acts an essential role in glycoproteome analysis, especially for the highly efficient enrichment of N-linked glycopeptides. In this work, a facile and timesaving route was introduced in which COFTP-TAPT served as a carrier and poly (ethylenimine) (PEI) and carrageenan (Carr) were successively coated on the surface via electrostatic interaction. The resultant COFTP-TAPT@PEI@Carr showed remarkable performance in glycopeptide enrichment with high sensitivity (2 fmol µL-1), high selectivity (1:800, molar ratio of human serum IgG to BSA digests), large loading capacity (300 mg g-1), satisfactory recovery (102.4 ± 6.0%) and reusability (at least eight times). Due to the brilliant hydrophilicity and electrostatic interactions between COFTP-TAPT@PEI@Carr and positively charged glycopeptides, the prepared materials could be applied in the identification and analysis in the human plasma of healthy subjects and patients with nasopharyngeal carcinoma. As a result, 113 N-glycopeptides with 141 glycosylation sites corresponding to 59 proteins and 144 N-glycopeptides with 177 glycosylation sites corresponding to 67 proteins were enriched from 2 µL plasma trypsin digests of the control groups and patients with nasopharyngeal carcinoma, respectively. 22 glycopeptides were identified only from the normal controls and 53 glycopeptides were detected only from the other set. The results demonstrated that this hydrophilic material was promising on a large scale and further N-glycoproteome research.

Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension.

Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.