Circadian modulation of glucose utilization via CRY1-mediated repression of Pdk1 expression.

Life adapts to daily environmental changes through circadian rhythms, exhibiting spontaneous oscillations of biological processes. These daily functional oscillations must match the metabolic requirements responding to the time of the day. We focus on the molecular mechanism of how the circadian clock regulates glucose, the primary resource for energy production and other biosynthetic pathways. The complex regulation of the circadian rhythm includes many proteins that control this process at the transcriptional and translational levels and by protein-protein interactions. We have investigated the action of one of these proteins, cryptochrome (CRY), whose elevated mRNA and protein levels repress the function of an activator in the transcription-translation feedback loop, and this activator causes elevated Cry1 mRNA. We used a genome-edited cell line model to investigate downstream genes affected explicitly by the repressor CRY. We found that CRY can repress glycolytic genes, particularly that of the gatekeeper, pyruvate dehydrogenase kinase 1 (Pdk1), decreasing lactate accumulation and glucose utilization. CRY1-mediated decrease of Pdk1 expression can also be observed in a breast cancer cell line MDA-MB-231, whose glycolysis is associated with Pdk1 expression. We also found that exogenous expression of CRY1 in the MDA-MB-231 decreases glucose usage and growth rate. Furthermore, reduced CRY1 levels and the increased phosphorylation of PDK1 substrate were observed when cells were grown in suspension compared to cells grown in adhesion. Our data supports a model that the transcription-translation feedback loop can regulate the glucose metabolic pathway through Pdk1 gene expression according to the time of the day.

Development and experimental validation of a machine learning-based disulfidptosis-related ferroptosis score for hepatocellular carcinoma.

Disulfidoptosis and ferroptosis are two distinct programmed cell death pathways that have garnered considerable attention due to their potential as therapeutic targets. However, despite their significance of these pathways, the role of disulfidoptosis-related ferroptosis genes in hepatocellular carcinoma (HCC) remains unclear. In this study, we employed a comprehensive approach that utilized various sophisticated techniques such as Pearson analysis, differential analysis, uniCox regression, lasso, ranger, and multivariable Cox regression to develop the disulfidoptosis-related ferroptosis (DRF) score. We then classified patients with HCC into high- and low-score groups to examine the association between the DRF score and various outcomes, including prognosis, functional enrichment, immune infiltration, immunotherapy, TACE sensitivity, drug sensitivity, and single-cell level function. Finally, we conducted in vitro experiments to validate the function of KIF20A. Our analysis revealed that KIF20A, G6PD, SLC7A11, and SLC2A1 were integral to constructing the DRF score. Our findings showed that patients with low DRF scores had significantly better prognoses and were more responsive to immunotherapy, TACE, and chemotherapy than those with high DRF scores. Based on our results obtained from bulk RNA-seq, single-cell RNA-seq, and in vitro experiments, we identified the cell cycle pathway as the primary distinguished factor between high-score and low-score groups. This study sheds light on the contribution of disulfidoptosis-related ferroptosis genes to the development and progression of HCC. The information gleaned from this study can be leveraged to improve our understanding of their potential as therapeutic targets for HCC treatment.

ZmMPK6, a mitogen-activated protein kinase, regulates maize kernel weight.

Kernel weight is a critical agronomic trait in maize production. Many genes are related to kernel weight but only a few of them have been applied to maize breeding and cultivation. Here, we identify a novel function of maize mitogen-activated protein kinase 6 (ZmMPK6) in the regulation of maize kernel weight. Kernel weight was reduced in zmmpk6 mutants and increased in ZmMPK6-overexpressing lines. In addition, starch granules, starch content, protein content, and grain-filling characteristics were also affected by the ZmMPK6 expression level. ZmMPK6 is mainly localized in the nucleus and cytoplasm, widely distributed across various tissues, and is expressed during kernel development, which is consistent with its role in kernel weight. Thus, these results provide new insights into the role of ZmMPK6, a mitogen-activated protein kinase, in maize kernel weight, and could be applied to further molecular breeding for kernel quality and yield in maize.

An integrative analysis reveals the prognostic value and potential functions of PSMD11 in hepatocellular carcinoma.

The global burden of hepatocellular carcinoma (HCC) as a preeminent etiology of cancer-related mortalities sheds light on the imperative necessity for a more profound comprehension of its fundamental biological mechanisms. In this context, the precise function of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in HCC remains equivocal. To address this vital knowledge gap, we interrogated the cancer genome atlas, genotype-tissue expression, International cancer genome consortium, gene expression omnibus, the cancer cell line encyclopedia, and tumor immune single-cell hub databases to evaluate the expression pattern of PSMD11, further confirmed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, MHCC-97H, HepG2, and SMMC7721 cell lines. Additionally, we meticulously assessed the clinical significance and prognostic value of PSMD11, while also exploring its potential molecular mechanisms in HCC. Our findings demonstrated that PSMD11 was highly expressed in HCC tissues, correlating with pathologic stage and histologic grade, thereby conferring a poor prognosis. Mechanistically, PSMD11 appears to exert its tumorigenic effects through the modulation of tumor metabolism-related pathways. Impressively, low PSMD11 expression was associated with increased immune effector cell infiltration, heightened responsiveness to molecular targeted drugs such as dasatinib, erlotinib, gefitinib, and imatinib, as well as reduced somatic mutation rate. Additionally, we demonstrated that PSMD11 might modulate HCC development through intricate interactions with cuproptosis-related genes ATP7A, DLAT, and PDHA1. Our comprehensive analyses collectively suggest that PSMD11 represents a promising therapeutic target in HCC.

OIP5-AS1 Inhibits Oxidative Stress and Inflammation in Ischemic Stroke Through miR-155-5p/IRF2BP2 Axis.

BACKGROUND: Ischemic stroke is a very dangerous disease with high incidence, fatality and disability rate in human beings. Massive evidence has indicated that oxidative stress and inflammation are intimately correlated with progression of ischemic stroke. Additionally, LncRNAs were reported to be involved in ischemic stroke. Here, we aim to explore the effects and molecular mechanism of lncRNA OIP5-AS1 on oxidative stress and inflammation in ischemic stroke. METHODS: HMC3 and SH-SY5Y cells were under the condition of oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to establish cell models of ischemic stroke. Commercial kits were employed to detect the indicators of oxidative stress including ROS, MDA and SOD. The expression of OIP5-AS1, miR-155-5p and IRF2BP2 mRNA was determined using RT-qPCR. The protein levels of inflammatory factors including TNF-α, IL-1ß and IL-6 and IRF2BP2 were assessed by western blot and/or ELISA. Luciferase activity assay was employed to validate their correlations among OIP5-AS1, miR-155-5p and IRF2BP2. RESULTS: In OGD/R-induced HMC3 and SH-SY5Y cells, the expression of OIP5-AS1 and IRF2BP2 was reduced while miR-155-5p was elevated. OGD/R induction promoted oxidative stress and inflammatory response in HMC3 and SH-SY5Y cells, while OIP5-AS1 or IRF2BP2 sufficiency as well as miR-155-5p inhibitor attenuated OGD/R-induced these influences. In addition, IRF2BP2 knockdown abolished the suppressive impacts of OIP5-AS1 overexpression on oxidative stress and inflammatory response in OGD/R-induced HMC3 and SH-SY5Y cells. Mechanistically, OIP5-AS1 enhanced IRF2BP2 expression via sponging miR-155-5p. CONCLUSION: OIP5-AS1 suppressed oxidative stress and inflammatory response to alleviate cell injury caused by OGD/R induction in HMC3 and SH-SY5Y cells through regulating miR-155-5p/IRF2BP2 axis, which might offer novel targeted molecules for ischemic stroke therapy.

M2 Macrophage-Derived Exosomes Regulate miR-199a-3p Promoter Methylation Through the LINC00470-Mediated myc/DNMT3a Axis to Promote Breast Cancer Development.

Breast cancer (BC) is the most common invasive cancer in women. M2 macrophage exosomes promote cancer development and play multiple roles in the tumor microenvironment, but the mechanism of action by which M2 macrophage exosomes promote BC remains unclear. Therefore, the purpose of this study was to investigate the mechanism by which M2 macrophage-derived exosomes promote the development of breast cancer. We collected BC tissues and determined the expression of LINC00470, followed by the establishment of M2 macrophages in culture and the isolation and identification of M2 macrophage exosomes. Next, we investigated the effects of M2 macrophage exosomes on BC cell proliferation, invasion, miR-199a-3p promoter methylation, and the expression of LINC00470, myc, DNMT3A, and miR-199a-3p. Finally, LINC00470 expression was inhibited in M2 macrophage exosomes, while miR-199a-3p expression was inhibited in BC cells, and changes in BC cell proliferation, invasion, miR-199a-3p promoter methylation, and the expression of LINC00470, myc, DNMT3A, and miR-199a-3p were analyzed. We demonstrated that LINC00470 was highly expressed in BC tissues, M2-type macrophages were successfully induced in vitro, and Dil-labeled M2 macrophage exosomes could successfully enter MDA-MB-231 and MCF-7 cells. Coculture of M2 macrophage exosomes with MDA-MB-231 and MCF-7 cells significantly enhanced the proliferation and invasion of MDA-MB-231 and MCF-7 cells, upregulated the expression of LINC00470, myc, and DNMT3A and downregulated the expression of miR-199a-3p. Moreover, the inhibition of LINC00470 expression in M2 macrophage exosomes significantly downregulated the expression of LINC00470, myc, and DNMT3A in MDA-MB-231 and MCF-7 cells, upregulated the expression of miR-199a-3p, and hypomethylated the promoter of the miR-199a-3p locus. Moreover, inhibition of LINC00470 expression in M2 macrophage-derived exosomes significantly attenuated the proliferation and invasive ability of MDA-MB-231 and MCF-7 cells, while miR-199a-3p inhibitor transfection reversed this effect. Collectively, these findings indicated that M2-type macrophage-derived exosomes promote BC proliferation and migration by regulating miR-199a-3p promoter methylation through the LINC00470-mediated myc/DNMT3a axis.

Polyetherketoneketone, a high-performance polymer for splinting mobile teeth: A clinical report.

A digital workflow for fabricating a polyetherketoneketone (PEKK) periodontal splint is described. The antibacterial properties of PEKK and the precision and efficiency of digital technology led to the provision of a splint with no adverse effects on oral hygiene or periodontal maintenance during a 2-year follow-up.

NIR-Absorbing B,N-Heteroarene as Photosensitizer for High-Performance NIR-to-Blue Triplet-Triplet Annihilation Upconversion.

Triplet-triplet annihilation upconversion (TTA-UC) with near-infrared (NIR) photosensitizers is highly desirable for a variety of emerging applications. However, the development of NIR-to-blue TTA-UC with a large anti-Stokes shift is extremely challenging because of the energy loss during the intersystem crossing (ISC). Here, we develop the first NIR-absorbing B,N-heteroarene-based sensitizer (BNS) with multi-resonance thermally activated delayed fluorescence (MR-TADF) characters to achieve efficient NIR-to-blue TTA-UC. The small energy gap between the singlet and triplet excited states (0.14 eV) of BNS suppresses the ISC energy loss, and its long-delayed fluorescence lifetime (115 µs) contributes to efficient triplet energy transfer. As a result, the largest anti-Stokes shift (1.03 eV) among all heavy-atom-free NIR-activatable TTA-UC systems is obtained with a high TTA-UC quantum yield of 2.9 % (upper limit 50 %).

Synthesis of Highly Luminescent Chiral Nanographene.

Chiral nanographenes with both high fluorescence quantum yields (ΦF ) and large dissymmetry factors (glum ) are essential to the development of circularly polarized luminescence (CPL) materials. However, most studies have been focused on the improvement of glum , whereas how to design highly emissive chiral nanographenes is still unclear. In this work, we propose a new design strategy to achieve chiral nanographenes with high ΦF by helical π-extension of strongly luminescent chromophores while maintaining the frontier molecular orbital (FMO) distribution pattern. Chiral nanographene with perylene as the core and two dibenzo[6]helicene fragments as the wings has been synthesized, which exhibits a record high ΦF of 93 % among the reported chiral nanographenes and excellent CPL brightness (BCPL ) of 32 M-1 cm-1 .

Effects of qufeng xuanfei formula in guinea pig model of airway hyperergy.

This work aimed to clarify the potential regulating effects of Qufeng Xuanfei formula (QFXF) on airway neurogenic inflammation and its underlying target signal pathway. Guinea pig model of airway hyperergy (AHR) was used. The relative susceptibility of major proteins to airway neurogenic inflammation was assessed using Western blot immunoassay followed by being separated by SDS-PAGE. Compared to the model group, QFXF of all concentrations effectively depressed the capsaicin enhanced cough in guinea pigs and the peak values of airway resistance significantly decreased. The results illustrated that QFXF alleviated cough symptom in guinea pigs and reduced airway neurogenic inflammation when compared to AHR model group. Airway inflammation and damage, as well as the levels of NGF, SP and c-Fos in QFXF decreased the most in the high-dose group. The mechanism of antitussive activity may be associated with reducing airway inflammation. QFXF displayed effect on chronic cough through reducing the levels of neuropeptides, attenuating airway inflammation and promoting recovery from disease to decrease the airway neuro sensitivity, suggesting that the potential mechanism may be related to Ras/ERK/c-Fos pathway.

Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases.

BACKGROUND: Liver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor. METHODS: Tissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (< 150 µm from the tumor center, TF) and peritumoral region (≥ 150 µm from the tumor center, PT) was evaluated via comparison. The expression of CD68 and CD163 in different regions was further analyzed based on the cell colocalization method. In addition, different immune phenotypes were studied and compared according to the degree of CD8 infiltration. RESULTS: The expression trends of 12 markers in the TF and TC regions were basically the same in the primary tumor and liver metastasis lesions. However, in comparison of the TF and PT regions, the expression trends were not identical between primary and liver metastases, especially CD163, which was more highly expressed in the PT region relative to the TF region. In the contrast of different space distribution, the expression of CD163 was higher in liver metastases than in the primary foci. Further analysis of CD68 and CD163 via colocalization revealed that the distribution of macrophages in liver metastases was significantly different from that in the primary foci, with CD68-CD163+ macrophages predominating in liver metastases. In addition, among the three immunophenotypes, CD163 expression was highest in the immune rejection phenotype. CONCLUSIONS: The immune cells found in the primary tumors of colorectal cancer differed from those in liver metastases in terms of their spatial distribution. More immunosuppressive cells were present in the liver metastases, with the most pronounced differential distribution found for macrophages. CD68-CD163+ macrophages may be associated with intrahepatic immunosuppression and weak immunotherapeutic effects.

The Intervention of Nano-targeted Drugs & Angioplastryin Treatment and Prevention of Vascular Restenosis and its Influence on Monocyte Chemotactic Protein-1 in Lower Extremity Angiopathy.

It was to make use of the nano-targeted drugs and angioplastry to treat and prevent the vascular restenosis and analyze its influence on monocyte chemotactic protein 1 (MCP-1) of lower extremity angiopathy (LEA) patients since the patients with diabetic lower extremity angiopathy may be easily infected with vascular restenosis. In this article, the dexamethasone nano drugs were firstly prepared. After that, its related physical and chemical properties were tested, then, dexamethasone nano drugs were applied in treating patients with diabetic lower extremity angiopathy. The results showed that the prepared dexamethasone nanoparticles' encapsulation rate attained 99.2%. The laser light scattering experiment manifested that the particle size of the nanoparticles ranged from 200 to 300nm, and the average particle size was 258nm. The MCP-1 of the control group, conventional group, and observation group were 33.28±1.93 µg/mL, 78.27±9.73 µg/mL, and 75.29±8.99 µg/mL, respectively. The MCP-1 values of the conventional and observation groups were higher than that of the control group, and there was a notable difference (P<0.05). After interventional treatment, the MCP-1 level of the conventional group was 57.82±5.82 µg/mL, and that of the observation group was 41.93±6.92 µg/mL. The MCP-1 level of the group which received the treatment of nano-targeted drugs and angioplastry was superior to that of the conventional group which received the traditional operation, and there was a notable difference (P<0.05). In conclusion, MCP-1 is one of the major causes of lower extremity angiopathy. The nano-targeted drugs and angioplastry can raise the expression level of MCP-1 in patients with lower extremity angiopathy. The experimental results had a high application value and the nano-targeted drugs & angioplastry can be promoted clinically.

Endoscopic and surgical treatment of T1N0M0 colorectal neuroendocrine tumors: a population-based comparative study.

BACKGROUND: With the rapid advances in endoscopic technology, endoscopic therapy (ET) is increasingly applied to the treatment of small (≤ 20 mm) colorectal neuroendocrine tumors (NETs). However, long-term data comparing ET and surgery for management of T1N0M0 colorectal NETs are lacking. The purpose of this work was to compare overall survival (OS) and cancer-specific survival (CSS) of such patients with ET or surgery. METHODS: Patients with T1N0M0 colorectal NETs were identified within the Surveillance Epidemiology and End Results (SEER) database (2004-2016). Demographics, tumor characteristics, therapeutic methods, and survival were compared. Propensity score matching (PSM) was used 1:3 and among this cohort, Cox proportional hazards regression models were performed to evaluate correlation between treatment and outcomes. RESULTS: Of 4487 patients with T1N0M0 colorectal NETs, 1125 were identified in the matched cohort, among whom 819 (72.8%) underwent ET and 306 (27.2%) underwent surgery. There was no difference in the 5-year and 10-year OS and CSS rates between the 2 treatment modalities. Likewise, analyses stratified by tumor size and site showed that patients did not benefit more from surgery compared with ET. Moreover, multivariate analyses found no significant differences in OS [Hazard Ratio (HR) = 0.857, 95% Confidence Interval (CI): 0.513-1.431, P = 0.555] and CSS (HR = 0.925, 95% CI: 0.282-3.040, P = 0.898) between the 2 groups. Similar results were observed when comparisons were limited to patients with different tumor size and site. CONCLUSIONS: In this population-based study, patients with lesions < 10 mm treated endoscopically had comparable long-term survival compared with those treated surgically, which demonstrates ET as an alternative to surgery in T1N0M0 colorectal NETs of < 10 mm. Further high-quality prospective studies are warranted to comprehensively evaluate the role of ET in patients with tumors 10 to 20 mm.

Association of PM2.5 and PM10 with Acute Exacerbation of Chronic Obstructive Pulmonary Disease at lag0 to lag7: A Systematic Review and Meta-Analysis.

This study aimed to conduct a meta-analysis to investigate whether short-term exposure to fine (PM2.5) and coarse (PM10) particulate matter was associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalization, emergency room visit, and outpatient visit at different lag values. PubMed, Embase, and the Cochrane Library were searched for relevant papers published up to March 2021. For studies reporting results per 1-µg/m3 increase in PM2.5, the results were recalculated as per 10-µg/m3 increase. We manually calculated the RRs for these two studies and transferred the RRs to estimate 10 µg/m3 increases in PM2.5. Automation tools were initially used to remove ineligible studies. Two reviewers independently screened the remaining records and retrieved reports. Twenty-six studies (28 datasets; 7,018,419 patients) were included. There was a significant association between PM2.5 and AECOPD events on lag0 (ES = 1.01, 95%CI: 1.01-1.02, p < 0.001; I2=88.6%, Pheterogeneity<0.001), lag1 (ES = 1.00, 95%CI: 1.00-1.01, p < 0.001; I2=82.5%, Pheterogeneity<0.001), lag2 (ES = 1.01, 95%CI: 1.01-1.01, p < 0.001; I2=90.6%, Pheterogeneity<0.001), lag3 (ES = 1.01, 95%CI: 1.00-1.01, p < 0.001; I2=88.9%, Pheterogeneity<0.001), lag4 (ES = 1.00, 95%CI: 1.00-1.01, p < 0.001; I2=83.7%, Pheterogeneity<0.001), and lag7 (ES = 1.00, 95%CI: 1.00-1.00, p < 0.001; I2=0.0%, Pheterogeneity=0.743). The subgroup analyses showed that PM2.5 influenced the rates of hospitalization, emergency room visits, and outpatient visits. Similar trends were observed with PM10. The risk of AECOPD events (hospitalization, emergency room visit, and outpatient visit) was significantly increased with a 10-µg/m3 increment in PM2.5 and PM10 from lag0 to lag7.List Of Abbreviations: particulate matter (PM2.5 and PM10); acute exacerbation of chronic obstructive pulmonary disease (AECOPD); Chronic obstructive pulmonary disease (COPD); Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA); Effect sizes [48]; confidence intervals (CIs).

B,N-Embedded Double Hetero[7]helicenes with Strong Chiroptical Responses in the Visible Light Region.

The development of helicene molecules with significant chiroptical responses covering a broad range of the visible spectrum is highly desirable for chiral optoelectronic applications; however, their absorption dissymmetry factors (gabs) have been mostly lower than 0.01. In this work, we report unprecedented B,N-embedded double hetero[7]helicenes with nonbonded B and N atoms, which exhibit excellent chiroptical properties, such as strong chiroptical activities from 300 to 700 nm, record high gabs up to 0.033 in the visible spectral range, and tunable circularly polarized luminescence (CPL) from red to near-infrared regions (600-800 nm) with high photoluminescence quantum yields (PLQYs) up to 100%. As revealed by theoretical analyses, the high gabs values are related to the separate molecular orbital distributions owing to the incorporation of nonbonded B and N atoms. The new type of B,N-embedded double heterohelicenes opens up an appealing avenue to the future exploitation of high-performance chiroptical materials.

Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism.

BACKGROUND: Microbiome studies of the lower airways based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short-chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary. METHODS: Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model. We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole-genome shotgun (WGS) and RNA metatranscriptome sequencing. SCFAs were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed. RESULTS: Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome data were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFA levels were compared with WGS and metatranscriptome data. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing. CONCLUSIONS: Functional characterisation of the lower airway microbiota through metatranscriptome data identifies metabolically active organisms capable of producing metabolites with immunomodulatory capacity, such as SCFAs.

Efficient Energy-Transfer-Induced High Photoelectric Conversion in a Dye-Encapsulated Ionic Pyrene-Based Metal-Organic Framework.

The relationship between the aggregation states of pyrene-based linkers and the photoluminescence/photoelectric performance was well studied by the formation of an anionic metal-organic framework, [BMI]2[Mg3(TBAPy)2(H2O)4]·2dioxane, which shows highly enhanced light-harvesting and photoelectric conversion efficiency by the encapsulation of D-π-A cation dyes.

Acid-activated nonviral peptide vector for gene delivery.

Nonviral vector-based gene therapy is a promising strategy for treating a myriad of diseases. Cell-penetrating peptides are gaining increasing attention as vectors for nucleic acid delivery. However, most studies have focused more on the transfection efficiency of these vectors than on their specificity and toxicity. To obtain ideal vectors with high efficiency and safety, we constructed the vector stearyl-TH by attaching a stearyl moiety to the N-terminus of the acid-activated cell penetrating peptide TH in this study. Under acidic conditions, stearyl-TH could bind to and condense plasmids into nanoparticle complexes, which displayed significantly enhanced cellular uptake and transfection efficiencies. In contrast, stearyl-TH lost the capacities of DNA binding and transfection at physiological pH. More importantly, stearyl-TH and the complexes formed by stearyl-TH and plasmids displayed no obvious toxicity at physiological pH. Consequently, the high transfection efficiency under acidic conditions and low toxicity make stearyl-TH a potential nucleic acid delivery vector for gene therapy.

Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2.

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.

Fast measurement of the laser beam quality factor based on phase retrieval with a liquid lens.

In this paper, a new method for measuring the beam quality (M2) of lasers based on phase retrieval with a liquid lens is proposed. With intensity profiles obtained under different focal lengths in a certain position, a variable-focus iterative retrieval algorithm is established for the reconstruction of the complex amplitude. Then M2 can be calculated with the angular spectrum theory. Feasibility of the proposed method is demonstrated with single- and multimode lasers through both simulations and experiments. Compared with the traditional liquid lens method, the M2 of lasers can be measured faster with the proposed method.