A novel role for WZ3146 in the inhibition of cell proliferation via ERK and AKT pathway in the rare EGFR G719X mutant cells.

Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.

TERT promoter mutations contribute to adverse clinical outcomes and poor prognosis in radioiodine refractory differentiated thyroid cancer.

Telomerase reverse transcriptase promoter (TERTp) mutations are associated with non-radioiodine avidity. However, the role of these mutations in the clinical outcomes of patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) remains unknown. Herein, we aim to analyze gene mutations and clinical manifestations to verify TERTp's role in driving disease progression to RAIR-DTC and clinical outcomes. Next-generation sequencing data and clinical data were obtained from 243 patients with DTC. Of the 25 patients with TERTp mutations, 80% (20/25) had RAIR-DTC. RAIR-DTC was significantly less prevalent in patients with BRAFV600E (9/143, 6.3%) than those with both BRAFV600E and TERTp mutations (14/17, 82.4%). Patients with RAIR-DTC harboring both BRAFV600E and TERTp mutations were more likely to have > 3 distant metastatic sites (85.7%, 12/14) than those with BRAFV600E alone (33.3%, 3/9). Only one patient with both BRAFV600E and TERTp mutations had non-RAIR-DTC. The time from initial radioactive iodine therapy to RAIR-DTC diagnosis was significantly shorter in patients with TERTp mutations than in those without. Patients with BRAFV600E and TERTp mutations progressed faster to RAIR-DTC than those with BRAFV600E alone (p < 0.01). Our findings suggest that molecular testing for TERTp and other mutations like BRAFV600E may inform early diagnosis, prognosis, and treatment strategies before progression to RAIR-DTC.

Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer.

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.

Comparative transcriptome profiling reveals the key genes and molecular mechanisms involved in rice under blast infection.

The aim of this study was to analyze the resistance genes and molecular mechanisms involved in rice blast infection. The contents of seven hormones and eight biochemical indicators in the leaves and spikes were at dynamic levels after inoculation with rice blast strains over time. The mRNA and protein expression of the six genes were consistent with the transcriptome analysis results. In addition, KEGG enrichment analysis showed that Os03g0132000, Os06g0215600, and Os06g0215500 were significantly enriched in the alpha-linolenic acid metabolism KEGG pathway, whereas Os05g0311801 was significantly enriched in the zeatin biosynthesis KEGG pathway. Furthermore, Os03g0180900 and Os09g0439200 were significantly enriched in the plant hormone signal transduction KEGG pathways. Therefore, blast infection could alter the hormones, biochemical indicators, and traits of rice. Moreover, genes including Os03g0132000, Os03g0180900, and Os05g0311801 were identified as rice blast resistance genes, and the mechanism might involve alpha-linolenic acid metabolism, zeatin biosynthesis, and plant hormone signal transduction KEGG pathways.

Schizophyllum commune fruiting body polysaccharides inhibit glioma by mediating ARHI regulation of PI3K/AKT signalling pathway.

Glioma poses a serious threat to human health and has a high mortality rate. Therefore, developing natural anti-tumour drugs for cancer treatment is an urgent priority. Schizophyllum commune is an edible and medicinal fungus, with polysaccharides as its main active components, which may have anti-tumour properties. Herein, we characterised S. commune fruiting body polysaccharides (SCFP) structure and evaluated its anti-glioma activity in vitro and in vivo. UV and FTIR spectra, high-performance gel chromatography, and monosaccharide composition analyses demonstrated that SCFP was a heteropolysaccharide with a molecular weight of 290.92 kDa. Among the monosaccharide compositions, mannose, galactose, and glucose were the most abundant. SCFP significantly inhibited the survival of the glioma cell lines U251 and U-87MG. U251 xenograft tumours treated with SCFP via gavage showed a 47.39 % inhibition, with no significant toxic side effects observed. SCFP upregulated aplasia Ras homologue member I (ARHI) expression, thereby regulating PI3K/AKT signalling, inhibiting tumour migration, and inducing apoptosis, to inhibit tumour growth. Furthermore, SCFP treatment increased the relative abundance of beneficial bacteria, including Akkermansia muciniphila, Ligilactobacillus murinus, and Parabacteroides goldsteinii, in tumour-bearing mice and restored the gut microbiota structure to that of the normal group (NG group) mice without tumours. Thus, SCFP has the potential for application as a natural anticancer drug.

Combined single cell and spatial transcriptome analysis reveals cellular heterogeneity of hedgehog pathway in gastric cancer.

Gastric cancer (GC) is one of the most common and deadly malignancies in the world. Abnormal activation of hedgehog pathway is closely related to tumor development and progression. However, potential therapeutic targets for GC based on the hedgehog pathway have not been clearly identified. In the present study, we combined single-cell sequencing data and spatial transcriptomics to deeply investigate the role of hedgehog pathway in GC. Based on a comprehensive scoring algorithm, we found that fibroblasts from GC tumor tissues were characterized by a highly enriched hedgehog pathway. By analyzing the development process of fibroblasts, we found that CCND1 plays an important role at the end stage of fibroblast development, which may be related to the formation of tumor-associated fibroblasts. Based on spatial transcriptome data, we deeply mined the role of CCND1 in fibroblasts. We found that CCND1-negative and -positive fibroblasts have distinct characteristics. Based on bulk transcriptome data, we verified that highly infiltrating CCND1 + fibroblasts are a risk factor for GC patients and can influence the immune and chemotherapeutic efficacy of GC patients. Our study provides unique insights into GC and hedgehog pathways and also new directions for cancer treatment strategies.

Protective effects of Ganoderma lucidum spores on estradiol benzoate-induced TEC apoptosis and compromised double-positive thymocyte development.

Backgroud: Thymic atrophy marks the onset of immune aging, precipitating developmental anomalies in T cells. Numerous clinical and preclinical investigations have underscored the regulatory role of Ganoderma lucidum spores (GLS) in T cell development. However, the precise mechanisms underlying this regulation remain elusive. Methods: In this study, a mice model of estradiol benzoate (EB)-induced thymic atrophy was constructed, and the improvement effect of GLS on thymic atrophy was evaluated. Then, we employs multi-omics techniques to elucidate how GLS modulates T cell development amidst EB-induced thymic atrophy in mice. Results: GLS effectively mitigates EB-induced thymic damage by attenuating apoptotic thymic epithelial cells (TECs) and enhancing the output of CD4+ T cells into peripheral blood. During thymic T cell development, sporoderm-removed GLS (RGLS) promotes T cell receptor (TCR) α rearrangement by augmenting V-J fragment rearrangement frequency and efficiency. Notably, biased Vα14-Jα18 rearrangement fosters double-positive (DP) to invariant natural killer T (iNKT) cell differentiation, partially contingent on RGLS-mediated restriction of peptide-major histocompatibility complex I (pMHCⅠ)-CD8 interaction and augmented CD1d expression in DP thymocytes, thereby promoting DP to CD4+ iNKT cell development. Furthermore, RGLS amplifies interaction between a DP subpopulation, termed DPsel-7, and plasmacytoid dendritic cells (pDCs), likely facilitating the subsequent development of double-negative iNKT1 cells. Lastly, RGLS suppresses EB-induced upregulation of Abpob and Apoa4, curbing the clearance of CD4+Abpob+ and CD4+Apoa4+ T cells by mTECs, resulting in enhanced CD4+ T cell output. Discussion: These findings indicate that the RGLS effectively mitigates EB-induced TEC apoptosis and compromised double-positive thymocyte development. These insights into RGLS's immunoregulatory role pave the way for its potential as a T-cell regeneration inducer.

Rational Design and Fine Fabrication of Passive Daytime Radiative Cooling Textiles Integrate Antibacterial, UV-Shielding, and Self-Cleaning Characteristics.

Passive daytime radiative cooling (PDRC) textiles hold substantial potential for localized outdoor cooling of the human body without additional energy consumption, but their limited multifunctional integration severely hinders their practical application. Herein, aluminum-doped zinc oxide (AZO) nanoparticles were purposefully introduced into poly(vinylidene fluoride) (PVDF) nanofibers via a facile electrospinning process, forming a large-scale and flexible PDRC textile with the desired antibacterial, UV-shielding, and self-cleaning capabilities. These prepared PDRC textiles present a weighted sunlight reflection rate of 92.3% and a weighted emissivity of 89.5% in the mid-infrared region. Furthermore, outdoor tests with an average solar intensity of ∼715 W/m2 demonstrated that a skin simulator temperature could be cooled by ∼16.1 °C below the ambient temperature, outperforming cotton fabric by ∼6.3 °C. Owing to the outstanding photocatalytic properties of the AZO nanoparticles, these prepared PVDF textiles exhibit antibacterial properties (Escherichia coli: 99.99%), UV-shielding performance (UPF > 50+), and superior self-cleaning capabilities, providing a cost-effective and eco-friendly avenue for daytime personal thermal management.

Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer.

Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER+ breast cancer (BC). By analysing the well-established fulvestrant-resistant ER+ BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2high signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.

Foliar application of melatonin improve the number of secondary branches and secondary branch grains quality of rice.

Melatonin plays an important role in plant growth and development. However, little information is available about melatonin regulating rice panicle structure and yield. This study explored the regulatory effects and mechanisms of melatonin spraying before the panicle differentiation stage on rice panicle structure and grain quality. The results showed that spraying melatonin before panicle differentiation increased rice yield, which was mainly reflected in the increase in spikelets per panicle and the percentage of filled grains. In addition, melatonin treatment significantly increased the panicle length. The results of panicle structure analysis showed that the increase in spikelets per panicle caused by melatonin was attributed to the significant increase in the number of secondary branches, total number of secondary branch spikelets, and number of spikelets per secondary branch. The results showed that melatonin can increase the content of zeatin, auxin, and gibberellin, and reduce the content of abscisic acid. These results showed that melatonin affected panicle structure by regulating hormone content, thereby improving yield. In addition, melatonin improves the processing quality, appearance quality, and nutritional quality of secondary branch grains. The above results indicate that application of melatonin improves the number of secondary branches and the quality of grainss on secondary branches.

Dataset of wheat HSP90.2 chaperome.

Wheat (Triticum aestivum L.) is one of the world's most important staple crops, whose production is critical to feed the expanding population worldwide. The 90-kDa Heat Shock Protein 90 (HSP90) is a highly abundant chaperone protein involved in multiple cellular processes. It facilitates the folding of nascent preproteins for their maturation and functioning. This data described HSP90.2 clients identified from the whole genome of wheat. The HSP90.2 chaperome contains over 1500 proteins, most detected by the C terminus and full-length of HSP90.2. Over 60 % of the clients reside in the cytosol, nucleus, and chloroplasts. Cytoskeleton-related proteins are enriched in the chaperome of the N terminus of HSP90.2. The clients of the middle part of HSP90.2 contains several factors involved in ethylene biosynthesis and extracellular vesicle or organelle-related activities. Some clients related to plant hypersensitive response are induced by stripe rust. The presented dataset could isolate proteins regulated by HSP90.2 at the post-translational level.

Cordycepin inhibits glioma growth by downregulating PD-L1 expression via the NOD-like receptor/NFKB1/STAT1 axis.

Glioma is a serious primary malignant tumor of the human central nervous system with a poor prognosis and a high recurrence rate; however, inhibition of immune checkpoints can greatly improve the survival rate of patients. The purpose of this study was to investigate the regulation of PD-L1 by cordycepin and the mechanism of its anti-tumor action. The results of previous studies indicate that cordycepin has good anti-proliferative and anti-migratory activities and can induce apoptosis in U251 and T98G cells in vitro. Here, transcriptome sequencing showed that cordycepin may exert anti-tumor effects through the NOD-like receptor signaling pathway. Further intervention with BMS-1, a small molecule inhibitor of PD-L1, was used to explore whether inhibition of PD-L1 affected the regulation of the NOD-like receptor signaling pathway by cordycepin. Mechanistically, on the one hand, cordycepin regulated the expression of NFKB1 and STAT1 through the NOD-like receptor signaling pathway, thereby inhibiting the expression of PD-L1. In addition, inhibition of PD-L1 enhanced the regulation by cordycepin of the NOD-like receptor signaling pathway. On the other hand, cordycepin directly upregulated expression of STAT1 and downregulated that of PD-L1. In vivo studies further showed that cordycepin could downregulate expression of PD-L1 and NFKB1 and upregulate that of STAT1 in glioma xenograft tumor tissues, consistent with the results of in vitro studies. The results suggest that cordycepin may down-regulate the expression of PD-L1 through NOD-like receptor signaling pathway and NFKB signaling pathway, thereby inhibiting the immune escape of glioma, and can be developed as a PD-L1 inhibitor. Our results therefore provide a theoretical foundation for the use of cordycepin in treatment of glioma and enrich our understanding of its pharmacological mechanism.

The decrease in panicle number is the main reason for the yield reduction of japonica rice caused by 1,2,4-trichlorobenzene stress.

Persistent organic pollutants seriously affect the growth and development of crops. 1,2,4-Trichlorobenzene (TCB), as one of the most widely used chlorobenzenes, can affect the yield of japonica rice. However, existing research on the effect of TCB on japonica rice yield is not in-depth, and a basic understanding of commonality has not yet been formed. In this study, 28 conventional japonica rice varieties were selected to investigate the effects of TCB stress on their yield, yield composition, and TCB accumulation. This study also evaluated the efficiency of conventional tolerance indices in evaluating the TCB stress tolerance of japonica rice. The results showed that TCB caused sustained inhibition of the growth of japonica rice, which was considerably manifested in plant height, root length, soil plant analysis development (SPAD), and dry weight at different growth stages. Under TCB stress, TCB accumulation in various tissues of japonica rice increased sharply. TCB stress reduces the yield of japonica rice by reducing the number of panicles per hill, the number of spikelets per panicle, the grain filling percentage, and the grain weight. Overall, the results of this study indicate that TCB stress can cause a decrease in the yield of japonica rice, and the decrease in panicle number is the main reason. The conventional tolerance index can effectively evaluate the tolerance of japonica rice to TCB. The results of this study are substantial for the breeding and cultivation of japonica rice.

Repetitive Transcranial Magnetic Stimulation-Mediated Neuroprotection in the 5xFAD Mouse Model of Alzheimer's Disease Through GABRG2 and SNAP25 Modulation.

Alzheimer's disease (AD) is a leading neurodegenerative disorder with substantial impacts on cognition and behavior. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, has been used to treat various neuropsychiatric disorders, but its efficacy in AD has not been thoroughly investigated. This study examines the neuroprotective effects of rTMS in the 5xFAD mouse model of AD, with a particular focus on its modulation of GABAergic neuronal activity via the GABRG2 and SNAP25 proteins. Transcriptomic sequencing of rTMS-treated 5xFAD mice revealed 32 genes influenced by the treatment, among which GABRG2 was identified as a critical modulatory target. Electrophysiological assessments, including whole-cell patch clamp recordings from frontal cortex neurons, demonstrated significant alterations in inhibitory synaptic currents following rTMS. Subsequent experiments involved sh-GABRG2 transduction combined with rTMS treatment (20Hz, 14 days), examining behavioral responses, GABAergic neuron functionality, cortical GABA expression, cerebrospinal fluid GABA concentrations, ß-amyloid accumulation, and pro-inflammatory cytokine levels. The results indicated notable improvements in behavioral performance, enhanced functionality of GABAergic neurons, and reductions in ß-amyloid deposition and neuroinflammation after rTMS treatment. Further analysis revealed that SNAP25 overexpression could counteract the negative effects of GABRG2 silencing, highlighting the crucial role of SNAP25 downstream of GABRG2 in mediating rTMS's therapeutic effects in AD. This research highlights rTMS's potential to modulate synaptic and vesicular transport mechanisms, offering a promising avenue for ameliorating symptoms of AD through neuroprotective pathways.

Elevated Cancer-Associated Hyaluronan Correlates With Diagnosis and Lymph Node Metastasis of Papillary Thyroid Cancer.

The glycosaminoglycan hyaluronan (HA) plays an important role in tumor progression. However, its biological and clinical significance in papillary thyroid cancer (PTC) remains unknown. Immunohistochemistry was performed to examine HA expression in tissues from PTC patients. Two PTC cell lines were treated with HA synthesized inhibitor against HA production to assess its function. Serum HA levels from 107 PTC patients, 30 Hashimoto thyroiditis patients, and 45 normal controls (NC) were measured by chemiluminescence immunoassay. HA levels in fine needle aspiration (FNA) washouts obtained from thyroid nodules and lymph nodes (LNs) were measured by chemiluminescence immunoassay. Area under the curve (AUC) was computed to evaluate HA's clinical value. HA was highly expressed in PTC. Reducing HA production significantly inhibited PTC cell proliferation and invasion. Importantly, serum HA levels in PTC were significantly higher than those in NCs and Hashimoto thyroiditis and allowed distinguishing of thyroid cancers from NCs with high accuracy (AUC = 0.782). Moreover, elevated serum HA levels in PTC correlate with LN metastasis. HA levels in FNA washouts from PTC patients were significantly higher than those in benign controls, with a high AUC value (0.8644) for distinguishing PTC from benign controls. Furthermore, HA levels in FNA washouts from metastatic LN were significantly higher than those in nonmetastatic LN, with a high AUC value (0.8007) for distinguishing metastatic LNs from nonmetastatic LNs. HA levels in serum and FNA washout exhibited a potential significance for PTC diagnosis and an indicator for LN metastasis in patients with PTC.

Rhamnolipids stabilized essential oils microemulsion for antimicrobial and fruit preservation.

Essential oils, well-known for their antifungal properties, are widely utilized to combat fruit decay. However, their application faces big challenges due to their high volatility and hydrophobic traits, which leads to strong odor, short effective time and poor dispersivity. This study aimed to address these challenges by formulating microemulsions consisting of essential oils and rhamnolipids. The optimized microemulsion, featuring a small particle size of 6.8 nm, exhibited higher stability and lower volatility than conventional emulsion. Notably, the prepared microemulsions demonstrated remarkable antimicrobial efficacy against E. coli, S. aureus, C. albicans, S. cerevisiae, and A. niger. The application of these microemulsions proved to be highly effective in preventing blueberry decay while preserving fruit's quality, particularly by minimizing the loss of essential nutrients such as anthocyanins. Consequently, essential oil microemulsions emerge as a highly effective postharvest preservative for fruits, offering a promising solution to extend their shelf life and enhance overall quality.

Plasma immune profiling combined with machine learning contributes to diagnosis and prognosis of active pulmonary tuberculosis.

Tuberculosis (TB) remains one of the deadliest chronic infectious diseases globally. Early diagnosis not only prevents the spread of TB but also ensures effective treatment. However, the absence of non-sputum-based diagnostic tests often leads to delayed TB diagnoses. Inflammation is a hallmark of TB, we aimed to identify biomarkers associated with TB based on immune profiling. We collected 222 plasma samples from healthy controls (HCs), disease controls (non-TB pneumonia; PN), patients with TB (TB), and cured TB cases (RxTB). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure the levels of 92 immune proteins. Based on differential analysis and the correlation with TB severity, we selected 9 biomarkers (CXCL9, PDL1, CDCP1, CCL28, CCL23, CCL19, MMP1, IFNγ and TRANCE) and explored their diagnostic capabilities through 7 machine learning methods. We identified combination of these 9 biomarkers that distinguish TB cases from controls with an area under the receiver operating characteristic curve (AUROC) of 0.89-0.99, with a sensitivity of 82-93% at a specificity of 88-92%. Moreover, the model excels in distinguishing severe TB cases, achieving AUROC exceeding 0.95, sensitivities and specificities exceeding 93.3%. In summary, utilizing targeted proteomics and machine learning, we identified a 9 plasma proteins signature that demonstrates significant potential for accurate TB diagnosis and clinical outcome prediction.