Exosomes originating from neural stem cells undergoing necroptosis participate in cellular communication by inducing TSC2 upregulation of recipient cells following spinal cord injury.

ABSTRACT: We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury. While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function, their precise function in spinal cord injury remains unclear. To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury, we conducted single-cell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury. Subsequently, we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes. The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes. Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs, 104 long non-coding RNAs, 720 circular RNAs, and 14 microRNAs compared with the control group. Construction of a competing endogenous RNA network identified the following hub genes: tuberous sclerosis 2 (Tsc2), solute carrier family 16 member 3 (Slc16a3), and forkhead box protein P1 (Foxpl). Notably, a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury. TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone. Furthermore, in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells. Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways. In addition, Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways. Collectively, these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.

ISIS 449884 Injection Add-On to Metformin in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Study.

INTRODUCTION: ISIS 449884, a 2'-O-methoxyethyl antisense oligonucleotide that targets the glucagon receptor (GCGR), has demonstrated an ability to reduce hepatic glucose output and lower the blood glucose level. The primary objective of this study was to investigate the safety and efficacy of ISIS 449884 as an add-on to metformin in a population of Chinese patients with type 2 diabetes mellitus (T2DM). METHOD: This was a multicenter, placebo-controlled (2:1), randomized, double-blind, parallel-enrollment, multiple-dose phase II study in Chinese patients with T2DM. A total of 90 patients who were uncontrolled by stable metformin monotherapy were randomized into three cohorts. Thirty subjects were enrolled in each cohort and received injections of ISIS 449884 (50 mg or 60 mg weekly or 100 mg every other week) or a corresponding volume of placebo (0.25 mL and 0.3 mL weekly or 0.5 mL every other week) subcutaneously in a 2:1 ratio for 16 weeks. RESULTS: The primary efficacy endpoint was analyzed in 88 subjects (ISIS 449884, n = 59; placebo, n = 29). The corrected LS mean change from baseline in glycated hemoglobin (HbA1c) at week 17 in the pooled ISIS 449884 treatment group was - 1.31% (95% CI - 1.66%, - 0.96%), and that in the pooled placebo group was 0.15% (95% CI - 0.37%, 0.66%). The LS mean difference between the two groups was - 1.46% (95% CI - 1.92%, - 1.00%, P < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 53/60 subjects (88.3%) and 25/30 subjects (83.3%) in the pooled ISIS 449884 treatment group and the pooled placebo group, respectively, with similar incidences. Drug-related TEAEs occurred in 41/60 subjects (68.3%) and 9/30 subjects (30.0%), respectively. TEAEs of grade 3 or higher occurred in 5/60 (8.3%) subjects and 2/30 (6.7%) subjects, respectively, and none of them were drug related. CONCLUSIONS: The ISIS 449884 injection add-on to metformin significantly reduced HbA1c in patients with T2DM uncontrolled by stable metformin monotherapy and showed an acceptable benefit/risk profile. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn , CTR20191096.

Genome-editing of a circadian clock gene TaPRR95 facilitates wheat peduncle growth and heading date.

Plant height and heading date are important agronomic traits in wheat (Triticum aestivum L.) that affect final grain yield. In wheat, knowledge of pseudo-response regulator (PRR) genes on agronomic traits is limited. Here, we identify a wheat TaPRR95 gene by genome-wide association study to be associated with plant height. Triple allele mutant plants produced by CRISPR/Cas9 show increased plant height, particularly the peduncle, with an earlier heading date. The longer peduncle is mainly caused by the increased cell elongation at its upper section, whilst the early heading date is accompanied by elevated expression of flowering genes, such as TaFT and TaCO1. A peduncle-specific transcriptome analysis reveals up-regulated photosynthesis genes and down-regulated IAA/Aux genes for auxin signaling in prr95aabbdd plants that may act as a regulatory mechanism to promote robust plant growth. A haplotype analysis identifies a TaPRR95-B haplotype (Hap2) to be closely associated with reduced plant height and increased thousand-grain weight. Moreover, the Hap2 frequency is higher in cultivars than that in landraces, suggesting the artificial selection on the allele during wheat breeding. These findings suggest that TaPRR95 is a regulator for plant height and heading date, thereby providing an important target for wheat yield improvement.

A quinolinyl resveratrol derivative alleviates acute ischemic stroke injury by promoting mitophagy for neuroprotection via targeting CK2α'.

Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.

Lower psoas mass indicates worse prognosis in percutaneous vertebroplasty-treated osteoporotic vertebral compression fracture.

The correlation between lower psoas mass and the prognosis of osteoporotic vertebral compression fractures (OVCF) is still unclear. This study aims to investigate the impact of lower psoas mass on the prognosis of patients undergoing percutaneous vertebroplasty (PVP). One hundred and sixty-three elderly patients who underwent single-segment PVP from January 2018 to December 2021 were included. The psoas to L4 vertebral index (PLVI) via MRI were measured to assess psoas mass. Patients were divided into high PLVI (> 0.79) and low PLVI (≤ 0.79) groups based on the median PLVI in the cohort. The basic information (age, gender, body mass index (BMI) and bone mineral density (BMD)), surgical intervention-related elements (duration of operation, latency to ambulation, period of hospital stay, and surgical site), postoperative clinical outcomes (Visual Analog Scale (VAS) scores, Oswestry Disability Index (ODI) scores, Japanese Orthopaedic Association (JOA) scores), and incidence of secondary fractures) were compared. Patients showed no statistically significant differences in terms of age, gender, surgical sute, BMI, BMD and preoperative VAS, ODI, JOA scores (P > 0.05) between the two groups. However, there were significant differences in terms of latency to ambulation, period of hospital stay (P < 0.05). VAS, ODI, and JOA scores at 1, 6, and 12 months after surgery showed that the high PLVI group had significantly better outcomes than the low PLVI group (P < 0.05). Additionally, the low PLVI group had a significantly higher incidence of recurrent fracture (P < 0.05). Lower psoas mass can reduce the clinical effect of PVP in patients with osteoporotic vertebral compression fractures, and is a risk factor for recurrent vertebral fracture.

2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer.

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

Parasite-derived microRNA let-7-5p detection for metacestodiasis based on rolling circular amplification-assisted CRISPR/Cas9.

Metacestodiasis is an infectious disease caused by the larval stage of cestode parasites. This disease poses a serious health hazard to wildlife, livestock, and humans, and it incurs substantial economic losses by impacting the safety of the livestock industry, the quality of meat production, and public health security. Unfortunately, there is currently no available molecular diagnostic method capable of distinguishing cysticercus- and Echinococcus-derived microRNAs (miRNAs) from other helminthes and hosts in the plasma of metacestode-infected animals. This study aims to develop a specific, sensitive, and cost-efficient molecular diagnostic method for cysticercosis and echinococcosis, particularly for early detection. The study developed a rolling circular amplification (RCA)-assisted CRISPR/Cas9 detection method based on parasite-derived miRNA let-7-5p. Using a series of dilutions of the let-7 standard, the limit of detection (LOD) of the qPCR, RCA, and RCA-assisted CRISPR/Cas9 methods was compared. The specificity of qPCR and CRISPR/Cas9 was evaluated using four artificially synthesized let-7 standards from different species. A total of 151 plasma samples were used to evaluate the diagnostic performance. Additionally, the study also assessed the correlation between plasma levels of let-7-5p, the number of Taenia pisiformis cysticerci, and the weight of Echinococcus multilocularis cysts. The results demonstrated that the RCA-assisted CRISPR/Cas9 assay could significantly distinguish let-7 from cestodes and other species, achieving a LOD of 10 aM; the diagnostic sensitivity and specificity for rabbit cysticercosis and mouse E. multilocularis were 100% and 97.67%, and 100% and 100%, respectively. Notably, let-7-5p gradually increased in the plasma of T. pisiformis-infected rabbits from 15 days post infection (dpi), peaked at 60 dpi, and persisted until 120 dpi. In E. multilocularis-infected mice, let-7-5p gradually increased from 15 dpi and persisted until 90 dpi. Furthermore, the expression of let-7-5p positively correlated with the number of cysticerci and cyst weight. These results indicated that the let-7-5p-based RCA-assisted CRISPR/Cas9 assay is a sensitive and specific detection method that can be used as a universal diagnostic method for metacestodiasis, particularly for early diagnosis (15 dpi).

Murine skeletal muscle satellite cells isolation and preliminary study on regulation in immune microenvironment during nurse cells formation of Trichinella spiralis infection.

As an intracellular parasitic nematode, Trichinella spiralis (T. spiralis) can induce the formation of nurse cells (NC) in host muscles and keep it to survive within the NC for an extended period. The formation of NC is similar to muscle cell injury and repair which lead to the arrest of satellite cells in the G2/M phase and build a suitable parasitic environment for the muscle larvae of T. spiralis. However, the molecular mechanisms involved in skeletal muscle repair through skeletal muscle satellite cells (SMSC) and the host immune response during T. spiralis infection have not been fully elucidated. In this study, histopathological examination revealed that the severity of damage increased as the infection progressed in the soleus muscle. SMSCs were isolated from BALB/c mice infected with T. spiralis at 4, 21 and 35 days post-infection (dpi). The immunological characteristics of these cells were analyzed by real-time PCR and flow cytometry (FCM). FCM analysis revealed a notable increase in the expression of B7 homolog 1 (B7-H1) in SMSCs following T. spiralis infection, while conversely, the expression of inducible costimulatory ligand (ICOSL) significantly decreased. Furthermore, real-time PCR results showed that toll like receptor 3 (TLR3) expression in SMSCs of the infected mice was upregulated at 21 dpi. The expression levels of three subtypes (PPARα, PPARß and PPARγ) of peroxisome proliferator-activated receptors (PPARs) also increased in the cells. This study highlights the immunological regulation significance of SMSCs host during T. spiralis infection and suggests that SMSCs actively participant in the local immune response to T. spiralis by regulating the interaction between the parasite and the host.

Anti-inflammatory effects of quinolinyl analog of resveratrol targeting TLR4 in MCAO/R ischemic stroke rat model.

BACKGROUND: Among adults, stroke is the main causes of mortality and permanent disability. Neuroinflammation is one of the main causes of stoke-mediated neuronal death. Our previous study revealed that (E)-5-(2-(Quinolin-4-yl) vinyl) benzene-1, 3-diol (RV01), a quinolinyl analog of resveratrol, inhibits microglia-induced neuroinflammation and safeguards neurons from inflammatory harm. The preventive role of RV01 in ischemic stroke and its underlying cellular mechanisms and molecular targets remain poorly understood. PURPOSE: To investigate whether RV01 alleviates ischemia-reperfusion (I/R) injury by inhibiting microglia-mediated neuroinflammation and determine the potential molecular mechanisms and targets by which RV01 inhibits the I/R-mediated microglia activation. METHODS: Rat middle cerebral artery occlusion and reperfusion (MCAO/R) and BV-2 or primary microglial cells oxygen-glucose deprivation and reperfusion (OGD/R) models were established. The neurological behavior scores, 2, 3, 5-triphenyl tetrazolium chloride staining and immunofluorescence were used to detect the neuroprotective effect of RV01 in the MCAO/R rats. In addition, the mRNA expression levels of IL-6, TNF-α, and IL-1ß were detected to reveal the antineuroinflammatory effect of RV01. Moreover, a western blot assay was performed to explore the protein expression changes in NF-κB-mediated neuroinflammation. Finally, we identified TLR4 as an RV01 target through molecular docking, drug sensitivity target stability analysis, cellular thermal shift analysis, and surface plasmon resonance techniques. RESULTS: RV01 reduced the infarct volume and neurological deficits, increased the rotarod duration, and decreased the number of rightward deflections in the MCAO/R rats. RV01 inhibited the NF-κB signaling pathway in vitro and in vivo, as demonstrated by the reduction in the transcription factor p65-mediated expression of several inflammatory factors including IL-6, TNF-α, and IL-1ß. Further studies showed that its protective effect was associated with targeting the TLR4 protein. Notably, the anti-inflammatory effect of RV01 was markedly reinforced by the TLR4 knockdown, but inhibited by the overexpression of TLR4. Results revealed that the conditioned medium derived from the RV01-treated BV-2 cells significantly decreased the OGD/R-mediated neuronal damage. CONCLUSION: Our results are the first to reveal the protective effects of RV01 on cerebral ischemia, depending on its inhibitory effect on the NF-κB pathway by targeting TLR4. RV01 could be a potential protective agent in ischemic stroke treatment.

The Integrated Prediction of Clinical and Pathological Factors on the Prognosis of Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The primary objective was to construct a high-performing prognostic risk model to accurately forecast the prognosis of patients diagnosed with intrahepatic cholangiocarcinoma (iCCA). METHODS: We retrospectively collected clinical data from the MSK database on 125 patients diagnosed with iCCA. Random sampling was utilized to divide patients into a training set and a validation set, maintaining a ratio of 7:3. Univariate and multivariate Cox proportional hazards regression models were utilized to identify independent prognostic factors influencing OS. Based on these independent factors, a model nomogram was established. The performance of the prognostic prediction models was assessed through calibration curves and C-index calculations. The Kaplan-Meier method was used to plot survival curves. Time-dependent ROC curve was used to evaluate the accuracy of the model. RESULTS: A nomogram was developed, incorporating hepatitis C, CA19, tumor extent, tumor size, LVI, positive lymph nodes, and TMB as predictive factors. The C-index for the training set was .78 and the validation set was .68. Using the riskscore derived from the nomogram, patients were stratified into high- and low-risk groups. The high-risk group exhibited considerably lower OS and RFS compared to the low-risk group in the training set (P < .05). However, no significant difference was detected in RFS among different risk groups in the validation set (P > .05). The AUC for 1-year, 3-year, and 5-year survival was .89, .69, and .69, respectively. CONCLUSION: We successfully developed and validated a prognostic nomogram for iCCA, demonstrating its excellent accuracy in predicting patient outcomes and providing clinicians with a potential prognostic tool.

Synthesis and evaluation of L-quebrachitol derivatives against platelet aggregation.

Thrombosis plays an important role in the occurrence and development of cardiovascular and cerebrovascular diseases that contribute to high mortality and morbidity in patients. L-(-)-Quebrachitol (QCT), a natural product, was first isolated from quebracho bark. It can inhibit PAF receptor and decrease gastric damage induced by indomethacin, as a drug against platelet aggregation. Here, five QCT derivatives were synthesized and investigated for their inhibitory effects on platelet aggregation. Among them, compound 3a showed anticoagulant effects comparable to aspirin, while compound 4b showed dose-independent inhibitory activities in rats that were stronger than aspirin.

mmu-miR-374b-5p modulated inflammatory factors via downregulation of C/EBP ß/NF-κB signaling in Kupffer cells during Echinococcus multilocularis infection.

BACKGROUND: Alveolar echinococcosis (AE) is an important infectious disease caused by the metacestode larvae of Echinococcus multilocularis, seriously threatening global public health security. Kupffer cells (KCs) play important roles in liver inflammatory response. However, their role in hepatic alveolar echinococcosis has not yet been fully elucidated. METHODS: In this study, qRT-PCR was used to detect the expression level of miR-374b-5p in KCs. The target gene of miR-374b-5p was identified through luciferase reporter assays and loss of function and gains. Critical genes involved in NFκB signaling pathway were analyzed by qRT-PCR and western blot. RESULTS: This study reported that miR-374b-5p was significantly upregulated in KCs during E. multilocularis infection and further showed that miR-374b-5p was able to bind to the 3'-UTR of the C/EBP ß gene and suppressed its expression. The expression levels of NF-κBp65, p-NF-κBp65 and pro-inflammatory factors including iNOS, TNFα and IL6 were attenuated after overexpression of miR-374b-5p while enhanced after suppression of miR-374b-5p. However, the Arg1 expression level was promoted after overexpression of miR-374b-5p while suppressed after downregulation of miR-374b-5p. Additionally, increased protein levels of NF-κBp65 and p-NF-κBp65 were found in the C/EBP ß-overexpressed KCs. CONCLUSIONS: These results demonstrated that miR-374b-5p probably regulated the expression of inflammatory factors via C/EBP ß/NF-κB signaling. This finding is helpful to explore the mechanism of inflammation regulation during E. multilocularis infection.

What are exposure biomarkers of rare earth elements for the ionic rare earth occupational population?

Rare earth elements (REEs) are widely utilized in industries. However, The specific exposure features of REEs and potential biomarkers of exposure in occupational populations remain unclear. In this study, we evaluated the external and internal REEs exposure levels among the participants working in the ionic rare earth smelting plant. For the external exposure, the concentrations of 14 REEs and total rare earth elements (ΣREEs) in airborne particles were significantly elevated in the REEs-exposed versus non-exposed group (P < 0.05). Meanwhile, the levels of Yttrium (Y), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Thulium (Tm), Ytterbium (Yb), and ΣREEs in urine were higher in the REEs-exposed group compared to the non-exposed group (P < 0.05). Notably, a significant positive correlation was observed between Y in both the airborne particles and urine samples as well as Gd, and the Spearman correlation coefficient was 0.53 and 0.39 respectively, both P < 0.05. Conversely, no statistically significant differences were found in the levels of 15 REEs or ΣREEs in the blood samples between the REEs-exposed group and non-exposed group. Moreover, the concentrations of ΣREEs and 9 REEs in nail samples of the exposed group were significantly higher than those of the non-exposed group (P < 0.05), and the composition ratios of REEs in the nail samples closely resembled those found in individual airborne particles. Therefore, nail and urine samples were proposed to reflect long-term and short-term exposure to ionic rare earth respectively. Exposure biomarkers confirmed by external and internal exposure characteristics accurately provide the situation of human exposure to REEs environment, and have profound significance for monitoring and evaluating the level of REEs pollution in human body. It also provides a vital basis to find out the effect biomarkers, susceptible biomarkers and the health effects of rare earth environment for the future research.

Sialic Acid Conjugate-Modified Cationic Liposomal Paclitaxel for Targeted Therapy of Lung Metastasis in Breast Cancer: What a Difference the Cation Content Makes.

Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells in vitro due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis in vivo. By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.

Molecular evolution and phylogeographic analysis of wheat dwarf virus.

Wheat dwarf virus (WDV) has caused considerable economic loss in the global production of grain crops. Knowledge of the evolutionary biology and population history of the pathogen remain poorly understood. We performed molecular evolution and worldwide phylodynamic analyses of the virus based on the genes in the protein-coding region of the entire viral genome. Our results showed that host-driven and geography-driven adaptation are major factors that affects the evolution of WDV. Bayesian phylogenetic analysis estimates that the average WDV substitution rate was 4.240 × 10-4 substitutions/site/year (95% credibility interval, 2.828 × 10-4-5.723 × 10-4), and the evolutionary rates of genes encoding proteins with virion-sense transcripts and genes encoding proteins with complementary-sense transcripts were different. The positively selected sites were detected in only two genes encoding proteins with complementary-sense, and WDV-barley are subject to stronger purifying selection than WDV-wheat. The time since the most recent common WDV ancestor was 1746 (95% credibility interval, 1517-1893) CE. Further analyses identified that the WDV-barley population and WDV-wheat population experienced dramatic expansion-decline episodes, and the expansion time of the WDV-barley population was earlier than that of the WDV-wheat population. Our phylogeographic analysis showed that the WDV population originating in Iran was subsequently introduced to Europe, and then spread from Eastern Europe to China.

EZH2/G9a interact to mediate drug resistance in non-small-cell lung cancer by regulating the SMAD4/ERK/c-Myc signaling axis.

Drug resistance is the leading problem in non-small-cell lung cancer (NSCLC) therapy. The contribution of histone methylation in mediating malignant phenotypes of NSCLC is well known. However, the role of histone methylation in NSCLC drug-resistance mechanisms remains unclear. Here, our data show that EZH2 and G9a, two histone methyltransferases, are involved in the drug resistance of NSCLC. Gene manipulation results indicate that the combination of EZH2 and G9a promotes tumor growth and mediates drug resistance in a complementary manner. Importantly, clinical study demonstrates that co-expression of both enzymes predicts a poor outcome in patients with NSCLC. Mechanistically, G9a and EZH2 interact and promote the silencing of the tumor-suppressor gene SMAD4, activating the ERK/c-Myc signaling pathway. Finally, SU08, a compound targeting both EZH2 and G9a, is demonstrated to sensitize resistant cells to therapeutic drugs by regulating the SMAD4/ERK/c-Myc signaling axis. These findings uncover the resistance mechanism and a strategy for reversing NSCLC drug resistance.

MRI-based central sarcopenia negatively impacts the therapeutic effectiveness of single-segment lumbar fusion surgery in the elderly.

Central sarcopenia is associated with the prognosis of various orthopedic surgeries in the elderly. This study aims to investigate its impact on the outcomes of single-segment lumbar fusion surgery in elderly patients. Retrospective analysis was conducted on 314 patients aged 60 to 80 who underwent single-segment posterior lumbar fusion surgery due to degenerative lumbar diseases. Patients were categorized into high psoas and L4 vertebral index (PLVI) and low PLVI groups according to the MRI-measured PLVI for central sarcopenia. Basic patient data, surgery-related parameters, functional assessments at preoperative and postoperative 3, 6, and 12 months, and X-ray-based fusion status were compared. The basic data of the two groups showed no significant differences. Parameters including the operative segment, preoperative hemoglobin levels, surgical duration, and intraoperative blood loss exhibited no significant variances. However, notable differences were observed in postoperative initial hemoglobin levels, transfusion requirements, and length of hospital stay between the two groups. During the postoperative follow-ups at 3, 6, and 12 months, the VAS scores for lower back pain and ODI scores in the lower PLVI group were significantly higher compared to the high PLVI group. Additionally, the EuroQoL 5D scores were notably lower in the low PLVI group. There were no significant differences between the groups in terms of leg pain VAS scores at each time point and the fusion status at 12 months postoperatively. MRI-based central sarcopenia has a negative impact on the therapeutic effectiveness following single-segment lumbar fusion surgery in elderly patients.

Extracellular vesicles released by transforming growth factor-beta 1-preconditional mesenchymal stem cells promote recovery in mice with spinal cord injury.

Spinal cord injury (SCI) causes neuroinflammation, neuronal death, and severe axonal connections. Alleviating neuroinflammation, protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells (eNSCs) represent potential strategies for SCI treatment. Extracellular vesicles (EVs) released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI. In the present study, EVs isolated from untreated (control, C-EVs) and TGF-ß1-treated (T-EVs) mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms. Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro. The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia, alleviated neuroinflammation, and enhanced the neuroprotection of residual cells during the acute phase. Moreover, T-EVs increased the number of eNSCs around the epicenter. Consequently, T-EVs further promoted neurite outgrowth, increased axonal regrowth and remyelination, and facilitated locomotor recovery in the chronic stage. Furthermore, the use of T-EVs in Rictor-/- SCI mice (conditional knockout of Rictor in NSCs) showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently, which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway. Taken together, our findings indicate the prominent role of T-EVs in the treatment of SCI, and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.

Ultrasoft and High-Adhesion Block Copolymers for Neuromorphic Computing.

The "von Neumann bottleneck" is a formidable challenge in conventional computing, driving exploration into artificial synapses. Organic semiconductor materials show promise but are hindered by issues such as poor adhesion and a high elastic modulus. Here, we combine polyisoindigo-bithiophene (PIID-2T) with grafted poly(dimethylsiloxane) (PDMS) to synthesize the triblock-conjugated polymer (PIID-2T-PDMS). The polymer exhibited substantial enhancements in adhesion (4.8-68.8 nN) and reductions in elastic modulus (1.6-0.58 GPa) while maintaining the electrical characteristics of PIID-2T. The three-terminal organic synaptic transistor (three-terminal p-type organic artificial synapse (TPOAS)), constructed using PIID-2T-PDMS, exhibits an unprecedented analog switching range of 276×, surpassing previous records, and a remarkable memory on-off ratio of 106. Moreover, the device displays outstanding operational stability, retaining 99.6% of its original current after 1600 write-read events in the air. Notably, TPOAS replicates key biological synaptic behaviors, including paired-pulse facilitation (PPF), short-term plasticity (STP), and long-term plasticity (LTP). Simulations using handwritten digital data sets reveal an impressive recognition accuracy of 91.7%. This study presents a polyisoindigo-bithiophene-based block copolymer that offers enhanced adhesion, reduced elastic modulus, and high-performance artificial synapses, paving the way for the next generation of neuromorphic computing systems.

Scalable Production of Highly Conductive 2D NbSe2 Monolayers with Superior Electromagnetic Interference Shielding Performance.

Thin, flexible, and electrically conductive films are in demand for electromagnetic interference (EMI) shielding. Two-dimensional NbSe2 monolayers have an electrical conductivity comparable to those of metals (106-107 S m-1) but are challenging for high-quality and scalable production. Here, we show that electrochemical exfoliation of flake NbSe2 powder produces monolayers on a large scale (tens of grams), at a high yield (>75%, monolayer), and with a large average lateral size (>20 µm). The as-exfoliated NbSe2 monolayer flakes are easily dispersed in diverse organic solvents and solution-processed into various macroscopic structures (e.g., free-standing films, coatings, patterns, etc.). Thermal annealing of the free-standing NbSe2 films reduces the interlayer distance of restacked NbSe2 from 1.18 to 0.65 nm and consequently enhances the electrical conductivity to 1.16 × 106 S m-1, which is superior to those of MXenes and reduced graphene oxide. The optimized NbSe2 film shows an EMI shielding effectiveness (SE) of 65 dB at a thickness of 5 µm (>110 dB for a 48-µm-thick film), among the highest in materials of similar thicknesses. Moreover, a laminate of two layers of the NbSe2 film (2 µm thick) with an insulating interlayer shows a high SE of 85 dB, surpassing that of the 20-µm-thick NbSe2 film (83 dB). A two-layer theoretical model is proposed, and it agrees with the experimental EMI SE of the laminated NbSe2 films. The ability to produce NbSe2 monolayers on a tens of grams scale will enable their diverse applications beyond EMI shielding.