Nuclear Softness Promotes the Metastatic Potential of Large-Nucleated Colorectal Cancer Cells via the ErbB4-Akt1-Lamin A/C Signaling Pathway.

Abnormal nuclear enlargement is a diagnostic and physical hallmark of malignant tumors. Large nuclei are positively associated with an increased risk of developing metastasis; however, a large nucleus is inevitably more resistant to cell migration due to its size. The present study demonstrated that the nuclear size of primary colorectal cancer (CRC) cells at an advanced stage was larger than cells at an early stage. In addition, the nuclei of CRC liver metastases were larger than those of the corresponding primary CRC tissues. CRC cells were sorted into large-nucleated cells (LNCs) and small-nucleated cells (SNCs). Purified LNCs exhibited greater constricted migratory and metastatic capacity than SNCs in vitro and in vivo. Mechanistically, ErbB4 was highly expressed in LNCs, which phosphorylated lamin A/C at serine 22 via the ErbB4-Akt1 signaling pathway. Furthermore, the level of phosphorylated lamin A/C was a negative determinant of nuclear stiffness. Taken together, CRC LNCs possessed greater constricted migratory and metastatic potential than SNCs due to ErbB4-Akt1-mediated lamin A/C phosphorylation and nuclear softening. These results may provide a potential treatment strategy for tumor metastasis by targeting nuclear stiffness in patients with cancer, particularly CRC.

Electrochemical oxidation of surfactants as an essential step to enable greywater reuse.

The practical application of electrochemical oxidation technology for the removal of surfactants from greywater was evaluated using sodium dodecyl sulfate (SDS) as a model surfactant. Careful selection of electrocatalysts and optimization of operational parameters demonstrated effective SDS removal in treating a complex greywater matrix with energy consumption below 1 kWh g-1 COD (Chemical Oxygen Demand), paving the way for a more sustainable approach to achieving surfactant removal in greywater treatment when aiming for decentralized water reuse. Chromatographic techniques identified carboxylic acids as key byproducts prior to complete mineralization. These innovative approaches represent a novel pathway for harnessing electrochemical technologies within decentralized compact devices, offering a promising avenue for further advancements in this field.

Enhanced AHL-mediated quorum sensing accelerates the start-up of biofilm reactors by elevating the fitness of fast-growing bacteria in sludge and biofilm communities.

Quorum sensing (QS)-based manipulations emerge as a promising solution for biofilm reactors to overcome challenges from inefficient biofilm formation and lengthy start-ups. However, the ecological mechanisms underlying how QS regulates microbial behaviors and community assembly remain elusive. Herein, by introducing different levels of N-acyl-homoserine lactones, we manipulated the strength of QS during the start-up of moving bed biofilm reactors and compared the dynamics of bacterial communities. We found that enhanced QS elevated the fitness of fast-growing bacteria with high ribosomal RNA operon (rrn) copy numbers in their genomes in both the sludge and biofilm communities. This led to notably increased extracellular substance production, as evidenced by strong positive correlations between community-level rrn copy numbers and extracellular proteins and polysaccharides (Pearson's r = 0.529-0.830, P < 0.001). Network analyses demonstrated that enhanced QS significantly promoted the ecological interactions among taxa, particularly cooperative interactions. Bacterial taxa with higher network degrees were more strongly correlated with extracellular substances, suggesting their crucial roles as public goods in regulating bacterial interactions and shaping network structures. However, the assembly of more cooperative communities in QS-enhanced reactors came at the cost of decreased network stability and modularity. Null model and dissimilarity-overlap curve analysis revealed that enhanced QS strengthened stochastic processes in community assembly and rendered the universal population dynamics more convergent. Additionally, these shaping effects were consistent for both the sludge and biofilm communities, underpinning the planktonic-to-biofilm transition. This work highlights that QS manipulations efficiently drive community assembly and confer specialized functional traits to communities by recruiting taxa with specific life strategies and regulating interspecific interactions. These ecological insights deepen our understanding of the rules governing microbial societies and provide guidance for managing engineering ecosystems.

DNA-PK participates in pre-rRNA biogenesis independent of DNA double-strand break repair.

Although DNA-PK inhibitors (DNA-PK-i) have been applied in clinical trials for cancer treatment, the biomarkers and mechanism of action of DNA-PK-i in tumor cell suppression remain unclear. Here, we observed that a low dose of DNA-PK-i and PARP inhibitor (PARP-i) synthetically suppresses BRCA-deficient tumor cells without inducing DNA double-strand breaks (DSBs). Instead, we found that a fraction of DNA-PK localized inside of nucleoli, where we did not observe obvious DSBs. Moreover, the Ku proteins recognize pre-rRNA that facilitates DNA-PKcs autophosphorylation independent of DNA damage. Ribosomal proteins are also phosphorylated by DNA-PK, which regulates pre-rRNA biogenesis. In addition, DNA-PK-i acts together with PARP-i to suppress pre-rRNA biogenesis and tumor cell growth. Collectively, our studies reveal a DNA damage repair-independent role of DNA-PK-i in tumor suppression.

Tumor Microenvironment-Activatable Nanosystem Capable of Overcoming Multiple Therapeutic Obstacles for Augmenting Immuno/Metal-Ion Therapy.

Abnormal tumor microenvironment (TME) imposes barriers to nanomedicine penetration into tumors and evolves tumor-supportive nature to provide tumor cell protection, seriously weakening the action of antitumor nanomedicines and posing significant challenges to their development. Here, we engineer a TME-activatable size-switchable core-satellite nanosystem (Mn-TI-Ag@HA) capable of increasing the effective dose of therapeutic agents in deep-seated tumors while reversing tumor-supportive microenvironment for augmenting immuno/metal-ion therapy. When activated by TME, the nanosystem disintegrates, allowing ultrasmall-sized Ag nanoparticles to become unbound and penetrate deep into solid tumors. Simultaneously, the nanosystem produces O2 and releases TGF-ß inhibitors in situ to drive macrophage M2-to-M1 polarization, increasing intratumoral H2O2 concentration, and ultimately augmenting metal-ion therapy by accelerating hypertoxic Ag+ production. The nanosystem can overcome multiple obstacles that aid in tumor resistance to nanomedicine, demonstrating effective tumor penetration, TME regulation, and tumor inhibition effects. It can provoke long-term immunological memory effects against tumor rechallenge when combined with immune checkpoint inhibitor anti-PD-1. This work provides a paradigm for designing efficient antitumor nanomedicines.

Environmental exposure to polycyclic aromatic hydrocarbons: An underestimated risk factor for systemic lupus erythematosus onset and progression.

OBJECTIVE: To investigate the link between systemic lupus erythematosus (SLE) incidence and exposure to environmental polycyclic aromatic hydrocarbons (PAH). METHODS: A case-control study (ChiCTR2000038187) involving 316 SLE patients and 851 healthy controls (HCs) was executed. Environmental exposure was assessed via a questionnaire, stratified by gender and age (females <35 and ≥35 years, males). Blood samples collected from 89 HCs, 85 inactive, and 95 active SLE patients were used to measure serum benzo[a]pyrene diol epoxide -albumin (BPDE-Alb) adducts and PAH concentrations, indicating long-term and short-term exposure respectively. Intergroup comparisons and statistical analyses were conducted using R version 4.3.1. RESULTS: Diverse patterns were found in how environmental factors affect SLE onset across different demographics. Lifestyle exposure factors were found to be a stronger determinant of SLE onset than occupational exposure factors in women under 35. Indoor air pollution had a significant impact on SLE incidence, potentially comparable to outdoor air pollution. Lifestyle-related PAH exposure had a greater impact on SLE than occupational PAH exposure. PAH exposure levels progressively increase from HCs to inactive and active SLE patients. Active SLE patients show markedly higher BPDE-Alb levels than HCs. CONCLUSIONS: Environmental PAH, particularly lifestyle-related, are significant, yet under-recognized, risk factors for SLE. STATEMENT OF ENVIRONMENTAL IMPLICATION: We examined the relationship between exposure to environmental polycyclic aromatic hydrocarbons (PAH) and the incidence of systemic lupus erythematosus (SLE). PAH, prevalent in sources such as cigarette smoke, air pollution, and charred food, pose significant health hazards. This study is the first to investigate specific PAH exposure levels in SLE patients. We determined actual PAH exposure levels in both SLE patients and healthy individuals and indicated that long-term PAH exposure biomarker is more reliable for evaluating exposure in non-occupationally exposed groups like SLE, compared to short-term markers. These findings provide valuable insights for future research on similar non-occupationally exposed populations.

Tuning Local Atomic Structures in MoS2 Based Catalysts for Electrochemical Nitrate Reduction.

In recent years, there has been a substantial surge in the investigation of transition-metal dichalcogenides such as MoS2 as a promising electrochemical catalyst. Inspired by denitrification enzymes such as nitrate reductase and nitrite reductase, the electrochemical nitrate reduction catalyzed by MoS2 with varying local atomic structures is reported. It is demonstrated that the hydrothermally synthesized MoS2 containing sulfur vacancies behaves as promising catalysts for electrochemical denitrification. With copper doping at less than 9% atomic ratio, the selectivity of denitrification to dinitrogen in the products can be effectively improved. X-ray absorption characterizations suggest that two sulfur vacancies are associated with one copper dopant in the MoS2 skeleton. DFT calculation confirms that copper dopants replace three adjacent Mo atoms to form a trigonal defect-enriched region, introducing an exposed Mo reaction center that coordinates with Cu atom to increase N2 selectivity. Apart from the higher activity and selectivity, the Cu-doped MoS2 also demonstrates remarkably improved tolerance toward oxygen poisoning at high oxygen concentration. Finally, Cu-doped MoS2 based catalysts exhibit very low specific energy consumption during the electrochemical denitrification process, paving the way for potential scale-up operations.

A Graphene Composite Film Based Wearable Far-Infrared Therapy Apparatus (GRAFT) for Effective Prevention of Postoperative Peritoneal Adhesion.

Postoperative peritoneal adhesion (PPA) is the most frequent complication after abdominal surgery. Current anti-adhesion strategies largely rely on the use of physical separating barriers creating an interface blocking peritoneal adhesion, which cannot reduce inflammation and suffers from limited anti-adhesion efficacy with unwanted side effects. Here, by exploiting the alternative activated macrophages to alleviate inflammation in adhesion development, a flexible graphene-composite-film (F-GCF) generating far-infrared (FIR) irradiation that effectively modulates the macrophage phenotype toward the anti-inflammatory M2 type, resulting in reduced PPA formation, is designed. The anti-adhesion effect of the FIR generated by F-GCF is determined in the rat abdominal wall abrasion-cecum defect models, which exhibit reduced incidence and area of PPA by 67.0% and 92.1% after FIR treatment without skin damage, significantly superior to the clinically used chitosan hydrogel. Notably, within peritoneal macrophages, FIR reduces inflammation reaction and promotes tissue plasminogen activator (t-PA) level via the polarization of peritoneal macrophages through upregulating Nr4a2 expression. To facilitate clinical use, a wirelessly controlled, wearable, F-GCF-based FIR therapy apparatus (GRAFT) is further developed and its remarkable anti-adhesion ability in the porcine PPA model is revealed. Collectively, the physical, biochemical, and in vivo preclinical data provide compelling evidence demonstrating the clinical-translational value of FIR in PPA prevention.

Effects and mechanisms of polycyclic aromatic hydrocarbons in inflammatory skin diseases.

Polycyclic aromatic hydrocarbons (PAHs) are hydrocarbons characterized by the presence of multiple benzene rings. They are ubiquitously found in the natural environment, especially in environmental pollutants, including atmospheric particulate matter, cigarette smoke, barbecue smoke, among others. PAHs can influence human health through several mechanisms, including the aryl hydrocarbon receptor (AhR) pathway, oxidative stress pathway, and epigenetic pathway. In recent years, the impact of PAHs on inflammatory skin diseases has garnered significant attention, yet many of their underlying mechanisms remain poorly understood. We conducted a comprehensive review of articles focusing on the link between PAHs and several inflammatory skin diseases, including psoriasis, atopic dermatitis, lupus erythematosus, and acne. This review summarizes the effects and mechanisms of PAHs in these diseases and discusses the prospects and potential therapeutic implications of PAHs for inflammatory skin diseases.

Proanthocyanidins Ameliorate LPS-Inhibited Osteogenesis of PDLSCs by Restoring Lysine Lactylation.

Periodontitis is a bacteria-induced inflammatory disease characterized by the progressive destruction of periodontal supporting tissues. Periodontal ligament stem cells (PDLSCs) are capable of differentiating into osteoblasts, which is an important stem cell source for endogenous periodontal tissue regeneration. Lysine lactylation (Kla) is a novel post-translational modification of proteins that is recently thought to be associated with osteogenic differentiation. Here, we found that lactylation levels are reduced both in the periodontal tissue of rats with periodontitis and lipopolysaccharide (LPS)-stimulated human PDLSCs. Proanthocyanidins were able to promote the osteogenesis of inflamed PDLSCs by restoring lactylation levels. Mechanistically, proanthocyanidins increased lactate production and restored the lactylation levels of PDLSCs, which recovered osteogenesis of inflamed PDLSCs via the Wnt/ß-catenin pathway. These results provide evidence on how epigenetic regulation by pharmacological agents influence the osteogenic phenotype of stem cells and the process of periodontal tissue repair. Our current study highlights the valuable potential of natural product proanthocyanidins in the regenerative engineering of periodontal tissues.

Development and Application of an Advanced Biomedical Material-Silk Sericin.

Sericin, a protein derived from silkworm cocoons, is considered a waste product derived from the silk industry for thousands of years due to a lack of understanding of its properties. However, in recent decades, a range of exciting properties of sericin are studied and uncovered, including cytocompatibility, low-immunogenicity, photo-luminescence, antioxidant properties, as well as cell-function regulating activities. These properties make sericin-based biomaterials promising candidates for biomedical applications. This review summarizes the properties and bioactivities of silk sericin and highlights the latest developments in sericin in tissue engineering and regenerative medicine. Furthermore, the extended application of sericin in developing flexible electronic devices and 3D bioprinting is also discussed. It is believed that sericin-based biomaterials have great potential of being developed into novel tissue engineering products and smart implantable devices for various medical applications toward improving clinical outcomes.

Identification of crucial ubiquitin-associated genes for predicting the effects of immunotherapy and therapeutic agents in colorectal cancer.

BACKGROUND: A growing body of research indicates that colorectal cancer (CRC) is significantly influenced by the ubiquitin-proteasome system. Nevertheless, reliable immune landscapes and ubiquitin-associated prognostic markers are still scarce. METHODS: We systematically analyzed the RNA-seq data of 2,830 ubiquitin-related genes from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). A CRC prognostic risk model was developed based on ubiquitin-associated gene signatures. In-depth multi-dimensional analyses were performed on ubiquitin-related subgroups with high and low risk. Drug response sensitivity for high-risk CRC patients was also predicted. RESULTS: A total of 131 ubiquitin-related differentially expressed genes were retrieved, of which 9 prognostic genes for CRC were ultimately identified and further validated by our clinical CRC tumor and adjacent normal samples. The expression pattern of these 9 ubiquitin-associated genes was found to be strongly related to overall survival, immune cell fractions, and immune-related genes of CRC patients. CRC patients stratified by the ubiquitin prognostic model exhibited distinct clinicopathological characteristics and immune landscapes. A comprehensive framework for personalized medicine prediction identified regorafenib and sorafenib as the most promising therapeutic agents for high ubiquitin-related risk CRC patients, which was confirmed in cell viability assays. CONCLUSIONS: Ubiquitin characteristics can reflect CRC prognosis and help develop innovative biomarkers for precision treatment.

Correction: Enhancing osteogenic differentiation of MC3T3-E1 cells during inflammation using UPPE/ß-TCP/TTC composites via the Wnt/ß-catenin pathway.

[This corrects the article DOI: 10.1039/D3RA05529A.].

Erzhiwan Ameliorates Restraint Stress- and Monobenzone-Induced Depigmentation in Mice by Inhibiting Macrophage Migration Inhibitory Factor and 8-Hydroxy-2-Deoxyguanosine.

Purpose: Vitiligo is an autoimmune disease that results in the loss of epidermal melanocytes. The treatments for patients with vitiligo remain lacking. Erzhiwan (EZW), a traditional Chinese Medicine composed of Ligustri Lucidi Fructus and Ecliptae Herba, was used to ameliorate depigmentation since ancient China. This study aims to investigate the effect of EZW on vitiligo-related depigmentation. Methods: A vitiligo-related depigmentation mouse model was induced by monobenzone and restraint stress. The experimental depigmentation mice were treated with EZW. Histological observation of skin was conducted. Cutaneous oxidative damage and inflammation were determined. A network pharmacology analysis was carried out. Results: EZW reduced depigmentation score (p<0.01), cutaneous inflammatory infiltration (p<0.01), and CD8α-positive expression (p<0.01), and increased cutaneous melanin content in experimental depigmentation mice. EZW reduced stress reaction in experimental depigmentation mice (p<0.01). EZW inhibited 8-hydroxy-2-deoxyguanosine (8-OHdG)-related DNA oxidative damage in the skin (p<0.05, p<0.01). In addition, EZW reduced cutaneous macrophage migration inhibitory factor (MIF)-CD74-NF-κB signaling (p<0.01). The network pharmacology analysis demonstrated that EZW regulated necroptosis, apoptosis, and FoxO signaling pathways in vitiligo. An in vitro experiment showed that the main ingredient of EZW, specnuezhenide, protected against monobenzone and MIF-induced cell death in HaCaT cells (p<0.01). Conclusion: EZW ameliorates restraint stress- and monobenzone-induced depigmentation via the inhibition of MIF and 8-OHdG signaling. The findings provide a data basis of an utilization of EZW in vitiligo.

Enhancing osteogenic differentiation of MC3T3-E1 cells during inflammation using UPPE/ß-TCP/TTC composites via the Wnt/ß-catenin pathway.

Periodontitis can lead to defects in the alveolar bone, thus increasing the demand for dependable biomaterials to repair these defects. This study aims to examine the pro-osteogenic and anti-bacterial properties of UPPE/ß-TCP/TTC composites (composed of unsaturated polyphosphoester [UPPE], ß-tricalcium phosphate [ß-TCP], and tetracycline [TTC]) under an inflammatory condition. The morphology of MC3T3-E1 cells on the composite was examined using scanning electron microscopy. The toxicity of the composite to MC3T3-E1 cells was assessed using the Alamar-blue assay. The pro-osteogenic potential of the composite was assessed through ALP staining, ARS staining, RT-PCR, and WB. The antimicrobial properties of the composite were assessed using the zone inhibition assay. The results suggest that: (1) MC3T3-E1 cells exhibited stable adhesion to the surfaces of all four composite groups; (2) the UPPE/ß-TCP/TTC composite demonstrated significantly lower toxicity to MC3T3-E1 cells; and (3) the UPPE/ß-TCP/TTC composite had the most pronounced pro-osteogenic effect on MC3T3-E1 cells by activating the WNT/ß-catenin pathway and displaying superior antibacterial properties. UPPE/ß-TCP/TTC, as a biocomposite, has been shown to possess antibacterial properties and exhibit excellent potential in facilitating osteogenic differentiation of MC3T3-E1 cells.

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy.

Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

A Foundation Model for Cell Segmentation.

Cells are a fundamental unit of biological organization, and identifying them in imaging data - cell segmentation - is a critical task for various cellular imaging experiments. While deep learning methods have led to substantial progress on this problem, most models in use are specialist models that work well for specific domains. Methods that have learned the general notion of "what is a cell" and can identify them across different domains of cellular imaging data have proven elusive. In this work, we present CellSAM, a foundation model for cell segmentation that generalizes across diverse cellular imaging data. CellSAM builds on top of the Segment Anything Model (SAM) by developing a prompt engineering approach for mask generation. We train an object detector, CellFinder, to automatically detect cells and prompt SAM to generate segmentations. We show that this approach allows a single model to achieve human-level performance for segmenting images of mammalian cells (in tissues and cell culture), yeast, and bacteria collected across various imaging modalities. We show that CellSAM has strong zero-shot performance and can be improved with a few examples via few-shot learning. We also show that CellSAM can unify bioimaging analysis workflows such as spatial transcriptomics and cell tracking. A deployed version of CellSAM is available at https://cellsam.deepcell.org/.

The BRCA1/BARD1 complex recognizes pre-ribosomal RNA to facilitate homologous recombination.

The BRCA1/BARD1 complex plays a key role in the repair of DNA double-strand breaks (DSBs) in both somatic cells and germ cells. However, the underlying molecular mechanism by which this complex mediates DSB repair is not fully understood. Here, we examined the XY body of male germ cells, where DSBs are accumulated. We show that the recruitment of the BRCA1/BARD1 complex to the unsynapsed axis of the XY body is mediated by pre-ribosomal RNA (pre-rRNA). Similarly, the BRCA1/BARD1 complex associates with pre-rRNA in somatic cells, which not only forms nuclear foci in response to DSBs, but also targets the BRCA1/BARD1 complex to DSBs. The interactions between the BRCT domains of the BRCA1/BARD1 complex and pre-rRNA induce liquid-liquid phase separations, which may be the molecular basis of DSB-induced nuclear foci formation of the BRCA1/BARD1 complex. Moreover, cancer-associated mutations in the BRCT domains of BRCA1 and BARD1 abolish their interactions with pre-rRNA. Pre-rRNA also mediates BRCA1-dependent homologous recombination, and suppression of pre-rRNA biogenesis sensitizes cells to PARP inhibitor treatment. Collectively, this study reveals that pre-rRNA is a functional partner of the BRCA1/BARD1 complex in the DSB repair.

THBS1-Mediated Degradation of Collagen via the PI3K/AKT Pathway Facilitates the Metastasis and Poor Prognosis of OSCC.

Oral squamous cell carcinoma (OSCC) is a prevalent form of malignant tumor, characterized by a persistently high incidence and mortality rate. The extracellular matrix (ECM) plays a crucial role in the initiation, progression, and diverse biological behaviors of OSCC, facilitated by mechanisms such as providing structural support, promoting cell migration and invasion, regulating cell morphology, and modulating signal transduction. This study investigated the involvement of ECM-related genes, particularly THBS1, in the prognosis and cellular behavior of OSCC. The analysis of ECM-related gene data from OSCC samples identified 165 differentially expressed genes forming two clusters with distinct prognostic outcomes. Seventeen ECM-related genes showed a significant correlation with survival. Experimental methods were employed to demonstrate the impact of THBS1 on proliferation, migration, invasion, and ECM degradation in OSCC cells. A risk-prediction model utilizing four differentially prognostic genes demonstrated significant predictive value in overall survival. THBS1 exhibited enrichment of the PI3K/AKT pathway, indicating its potential role in modulating OSCC. In conclusion, this study observed and verified that ECM-related genes, particularly THBS1, have the potential to influence the prognosis, biological behavior, and immunotherapy of OSCC. These findings hold significant implications for enhancing survival outcomes and providing guidance for precise treatment of OSCC.