Integrative analysis of aging-related genes reveals CEBPA as a novel therapeutic target in non-small cell lung cancer.

BACKGROUND: To explore the impact of ARGs on the prognosis of NSCLC, and its correlation with clinicopathological parameters and immune microenvironment. Preliminary research on the biological functions of CEBPA in NSCLC. METHODS: Using consensus clustering analysis to identify molecular subtypes of ARGs in NSCLC patients; employing LASSO regression and multivariate Cox analysis to select 7 prognostic risk genes and construct a prognostic risk model; validating independent prognostic factors of NSCLC using forest plot analysis; analyzing immune microenvironment correlations using ESTIMATE and ssGSEA; assessing correlations between prognostic risk genes via qPCR and Western blot in NSCLC; measuring mRNA and protein expression levels of knocked down and overexpressed CEBPA in NSCLC using CCK-8 and EdU assays; evaluating the effects of knocked down and overexpressed CEBPA on cell proliferation using Transwell experiments; examining the correlation of CEBPA with T cells and B cells using mIHC analysis. RESULTS: Consensus clustering analysis identified three molecular subtypes, suggesting significant differential expression of these ARGs in NSCLC prognosis and clinical pathological parameters. There was significant differential expression between the two risk groups in the prognostic risk model, with P < 0.001. The risk score of the prognostic risk model was also P < 0.001. CEBPA exhibited higher mRNA and protein expression levels in NSCLC cell lines. Knockdown of CEBPA significantly reduced mRNA and protein expression levels of CEBPB, YWHAZ, ABL1, and CDK1 in H1650 and A549 cells. siRNA-mediated knockdown of CEBPA markedly inhibited proliferation, migration, and invasion of NSCLC cells, whereas overexpression of CEBPA showed the opposite trend. mIHC results indicated a significant increase in CD3 + CD4+, CD3 + CD8+, and CD20 + cell counts in the high CEBPA expression group. CONCLUSIONS: The risk score of the prognostic risk model can serve as an independent prognostic factor, guiding the diagnosis and treatment of NSCLC. CEBPA may serve as a potential tumor biomarker and immune target, facilitating further exploration of the biological functions and immunological relevance in NSCLC.

Growth and Fabrication of High-Quality Single Nanowire Devices with Radial p-i-n Junctions.

Nanowires (NWs) with radial p-i-n junction have advantages, such as large junction area and small influence from the surface states, which can lead to highly efficient material use and good device quantum efficiency. However, it is difficult to make high-quality core-shell NW devices, especially single NW devices. Here, the key factors during the growth and fabrication process that influence the quality of single core-shell p-i-n NW devices are studied using GaAs(P) NW photovoltaics as an example. By p-doping and annealing, good ohmic contact is achieved on NWs with a diameter as small as 50-60 nm. Single NW photovoltaics are subsequently developed and a record fill factor of 80.5% is shown. These results bring valuable information for making single NW devices, which can further benefit the development of high-density integration circuits.

Electron-initiated low noise 1064 nm InGaAsP/InAlAs avalanche photodetectors.

We report an electron-initiated 1064 nm InGaAsP avalanche photodetectors (APDs) with an InAlAs multiplier. By utilizing a tailored digital alloy superlattice grading structure, a charge layer and a p type InAlAs multiplier, an unity gain quantum efficiency of 48%, a low room temperature dark current of 470 pA at 90% breakdown voltage, and a low multiplication noise with an effective k ratio of ∼0.2 are achieved. The measured maximum gain factor is 5 at room temperature, which is currently limited by the non-optimized electric field profiles, and can be readily enhanced by modifying the doping and thickness parameters for the multiplier and the charge layer.

IGA-rule 17 for performance estimation of wavelength-extended InGaAs photodetectors: validity and limitations.

A rule of thumb, denoted as IGA-rule 17, has been developed to describe the temperature and cutoff wavelength-dependent dark currents of wavelength-extended InGaAs photodetectors in a 2-3 µm band. The validity and limitations of the rule are discussed. This rule is intended as an index for device developers to evaluate their technologies in processing, a simple tool for device users to estimate reachable performance at various conditions in their design, and an effective bridge between the two.

Impact of etching on the surface leakage generation in mesa-type InGaAs/InAlAs avalanche photodetectors.

Effects of mesa etching and geometry on InGaAs/InAlAs avalanche photodiodes (APDs) were investigated by using both wet and inductively coupled plasma (ICP) etching with different mesa shapes as well as etchants. It was found that the mesa geometry had no evident impact on APDs' characteristics regardless of the etching techniques applied. Besides, ICP-etched APDs showed faster punch-through, suppressed premature surface breakdown and lower dark current behaviors compared to the wet-etched devices. Substantially suppressed surface leakage was also observed for ICP-etched devices, showing 1 and 3 orders of magnitude better at room temperature and 77 K respectively, and over 1 order of magnitude higher surface resistivity up to 4×107 Ω cm, in comparison to the wet-etched APDs. Introduction of extra hydrogen and Ar plasma in ICP etching led to detrimental effects to APDs' performance by enhancing the tunneling or recombination at surfaces. Those experimental results were clearly interpreted based on the surface state theories.

Tailoring the performances of low operating voltage InAlAs/InGaAs avalanche photodetectors.

We present tailoring of the performances of thin multiplication layer InAlAs/InGaAs avalanche photodetectors (APDs) with operating voltages lower than 20 V. Their operating voltages, gain-voltage slopes and dark currents were successfully tailored by changing the electric field distributions in avalanche region. The thin multiplication layer APDs show small activation energies of the dark current ranging from 0.12 to 0.19 eV at temperatures above 220 K, suggesting a band-trap-band tunneling dominant dark current mechanism over this temperature range. The dark currents show very weak temperature dependences at temperatures lower than 175 K, which mainly originate from the band-to-band tunneling and the surface leakage currents. The spectral responsivity of those APDs show anomalous negative temperature coefficients at gain factors larger than 1, which is attributed to the enhanced phonon scattering effect of carriers in the avalanche region at higher temperatures. Good gain factor uniformity at a given bias is observed for those APDs, and the charge layer is found to help improve the gain uniformity.

The role of noncoding RNAs in beta cell biology and tissue engineering.

The loss or dysfunction of pancreatic ß-cells, which are responsible for insulin secretion, constitutes the foundation of all forms of diabetes, a widely prevalent disease worldwide. The replacement of damaged ß-cells with regenerated or transplanted cells derived from stem cells is a promising therapeutic strategy. However, inducing the differentiation of stem cells into fully functional glucose-responsive ß-cells in vitro has proven to be challenging. Noncoding RNAs (ncRNAs) have emerged as critical regulatory factors governing the differentiation, identity, and function of ß-cells. Furthermore, engineered hydrogel systems, biomaterials, and organ-like structures possess engineering characteristics that can provide a three-dimensional (3D) microenvironment that supports stem cell differentiation. This review summarizes the roles and contributions of ncRNAs in maintaining the differentiation, identity, and function of ß-cells. And it focuses on regulating the levels of ncRNAs in stem cells to activate ß-cell genetic programs for generating alternative ß-cells and discusses how to manipulate ncRNA expression by combining hydrogel systems and other tissue engineering materials. Elucidating the patterns of ncRNA-mediated regulation in ß-cell biology and utilizing this knowledge to control stem cell differentiation may offer promising therapeutic strategies for generating functional insulin-producing cells in diabetes cell replacement therapy and tissue engineering.

MicroRNA-508-3p regulates the proliferation of human lung cancer cells by targeting G1 to S phase transition 1 (GSPT1) protein.

PURPOSE: Due to its crucial cancer regulatory role, microRNA-508-3p has been reported as a potential therapeutic anticancer molecular target. The present work encompassed the molecular characterization of microRNA-508-3p in lung cancer emphasizing on understanding the possible mechanism of its regulatory action. METHODS: qRT-PCR was performed to estimate the relative gene expression of microRNA-508-p in the tissue samples. The proliferation of cancer cells was determined by cell counting kit-8. The colony formation from cancer cells was analyzed by clonogenic assay. Mitotic phase distribution was understood by employing the flow cytometric technique. Edu-Hoechst staining was used for the assessment of cell viability. In silico analysis and dual-luciferase assay were used for target identification of microRNA-508-3p in lung cancer. Immunofluorescence and western blotting studies were carried out for relative protein expression. The rat models were used for performing the in vivo experimental procedures. RESULTS: The study showed the significant down-regulation of microRNA-508-3p in lung cancer. The lower expression levels of microRNA-508-3p were shown to be associated with poor survival of lung cancer patients. The over-expression of microRNA-508-3p was found to decline the proliferation and viability of cancer cells together with the induction of mitotic cell cycle arrest at G1 by targeting G1 to S phase transition 1 (GSPT1) protein. MicroRNA-508-3p up-regulation inhibited the in vivo tumor growth in rat models. CONCLUSION: Our study identifies miR-508-3p as a pivotal regulator of lung cancer cell proliferation by targeting the GSPT1 protein. This highlights its potential as a tumor suppressor and a therapeutic target for lung cancer. Our findings offer mechanistic insights into miRNA-mediated cancer progression, prompting further research in this intricate regulatory network.

CircRNA ARHGAP10 promotes osteogenic differentiation through the miR-335-3p/RUNX2 pathway in aortic valve calcification.

Background: Calcific aortic valve disease (CAVD) is a common cardiovascular disease with high morbidity and mortality, and no effective prevention or treatment is available. In recent years, increasing evidence has shown that noncoding RNAs (ncRNAs) play an important role in the pathogenesis and prognosis of CAVD. Several associated circular RNAs (circRNAs) have been reported to be involved in CAVD, such as circRIC3 and TGFBR2. However, the limited number of circRNAs identified in CAVD warrants further in-depth investigation, and the comprehensive elucidation of their role in the key mechanisms of this disease is needed. Methods: The expression of circRNAs and microRNAs (miRNAs) were analyzed by RNA sequencing. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze the expression of circRNA ARHGAP10 (circARHGAP10), miR-335-3p, and RUNX2. Luciferase reporter assay, pull-down assay, and RNA binding protein immunoprecipitation (RIP) assay were performed to evaluate the binding of miR-335-3p to circARHGAP10 or RUNX2. Alizarin red S staining showed the formation of calcified nodules in valve interstitial cells (VICs). The expression of circARHGAP10 and miR-335-3p was altered through lentivirus infection. Alkaline phosphatase (ALP) activity was used to verify the correlation between circARHGAP10 and miR-335-3p. The expression of proteins was assessed via Western blot. RNA fluorescence in situ hybridization (FISH) was used to confirm the localization of circARHGAP10 in the cytoplasm of VICs. Immunofluorescence was used to detect the expression level of RUNX2. ApoE-/- mice were used to construct a CAVD model, circARHGAP10 short hairpin RNA (shRNA) and miR-335-3p inhibitor lentivirus were intraperitoneally injected, and scramble and inhibitor normal control (NC) lentivirus were injected as controls, followed by hematoxylin and eosin (HE) staining. Results: Through RNA sequencing, we found that circARHGAP10 (hsa_circ_0008975) was highly expressed in calcific aortic valves. CircARHGAP10 knockdown effectively inhibited the extent of osteogenic differentiation of VICs. We then found that circARHGAP10 was a competing endogenous RNA (ceRNA) of miR-355-3p and that miR-355-3p targeted RUNX2. In vitro experiments confirmed that circARHGAP10 regulated the osteogenic differentiation of VICs through the miR-355-3p/RUNX2 pathway, and this was validated in vivo using an ApoE-/- mouse model. Conclusions: These findings provide a foundation for circRNA-directed diagnostics and therapeutics for CAVD.

Abnormal angiogenesis of placenta in progranulin­deficient mice.

Progranulin (PGRN) is a secreted growth factor involved in pleiotropic functions, particularly angiogenesis. A distinctly different placental expression of PGRN has been reported between normal pregnancies and pregnancies with complications, such as pre­eclampsia or fetal growth restriction. However, the role of PGRN in placental vascular development remains to be elucidated. In the present study, PGRN­knockout mice (PGRN­/­) were used to investigate the role of PGRN in the development of placental blood vessels and placental formation. Placental weights and pup body weights were significantly lower in the PGRN­/­ mice compared with the wild­type mice. Reduced labyrinthine layer areas and aberrant vascularization were also observed via hematoxylin and eosin staining of PGRN­/­ mice at embryonic day 14.5 (E14.5) and E17.5. In addition, the morphological data obtained via immunohistochemistry, immunofluorescence staining and western blotting demonstrated decreased expression levels of the blood vessel markers α­smooth muscle actin and CD31 in PGRN­/­ placentas. Furthermore, vasodilator endothelial nitric oxide synthase was reduced in the PGRN­/­ placenta. These results indicated that PGRN serves an essential role in the normal angiogenesis of the placental labyrinth in mice.