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Since the Fermi Large Area Telescope launch, a large sample of blazars has been detected in the γ -ray band. One of the important parameters, the variability index (VI), is adopted to quantify the γ -ray blazar variability. The variability of blazars can be affected by the geometric jet structure, accretions, source sizes, or evolutions of particles. In this paper, we compiled a sample of 2250 blazars (792 flat spectrum radio quasars, 1458 BL Lacertae objects) with some physical parameters to investigate the correlations between the VI and beaming effects. The VI shows positive correlations with the Doppler factors, γ -ray luminosities, core dominances, and superluminal motions for both FSRQs and BL Lacs but only holds a positive correlation on polarizations for BL Lacs. The close correlations between VI and the beaming indicators reinforced the previous results that the γ -ray variability is related to the jet, and the VI can be regarded as an effective indicator for the jet beaming effects of Fermi blazars. [ABSTRACT FROM AUTHOR]

The family of coinage-metal-based cyclic trinuclear complexes exhibits abundant photophysical properties, promising for diverse applications. However, their utility in biochemistry is often hindered by large particle size and strong hydrophobicity. Meanwhile, the investigation into multi-photon excited luminescence within this family remained undocumented, limiting their potential in bio-imaging. Herein, we unveil the multi-photon excited luminescent properties of pyrazolate-based trinuclear gold(I) clusters, facilitated by excimeric gold(I)···gold(I) interactions, revealing a nonlinear optical phenomenon within this family. Furthermore, to address issues of poor biocompatibility, we employ electrospinning coupled with hydroxypropyl-beta-cyclodextrin as the matrix to fabricate a flexible, durable, transparent, and red emissive film with a photoluminescence quantum yield as high as 88.3%. This strategy not only produces the film with sufficient hydrophilicity and stability, but also achieves the downsizing of trinuclear gold(I) clusters from microscale to nanoscale. Following the instantaneous dissolution of the film in the media, the released trinuclear gold(I) nanoparticles have illuminated cells and bacteria through a real-time, non-toxic, multi-photon bio-imaging approach. This achievement offers a fresh approach for utilizing coinage-metal-based cyclic trinuclear complexes in biochemical fields.Coinage-metal-based cyclic trinuclear complexes have potential in diverse applications, but their use in biochemical applications has been limited due to particle size and hydrophobicity. Here, the authors report the development of such complexes with multi-photon luminescent properties for use in cell imaging. [ABSTRACT FROM AUTHOR]

Mitochondrial metabolism disorders play an important role in the occurrence and development of tumors, and iron–sulfur protein is an important molecule for maintaining the normal function of mitochondria. However, the relationship between the expression, prognostic value, and immune infiltration of MMDS-related iron–sulfur protein genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Based on online databases bioinformatics analysis was performed to evaluate the expression differences, survival impacts, immune infiltration, and prognostic significance of multiple mitochondrial dysfunction syndrome (MMDS)-related iron–sulfur protein genes in KIRC patients. For example, the protein–protein interaction (PPI) network was constructed using STRING and GEPIA database; Survival impacts were constructed by TCGA database; Immune infiltration was analyzed using TIMER database. There were significant differences in the mRNA expression levels of ISCA1, ISCA2, C1ORF69 and NFU1 in KIRC among different tumor grades and individual cancer stages. Furthermore, KIRC with high transcription levels of ISCA1, ISCA2, C1ORF69 and NFU1 (p < 0.01) was significantly associated with long overall survival (OS) and disease-free survival (DFS). In addition, overexpression of four genes, NFU1, ISCA1, ISCA2, and C1ORF69 in KIRC indicated a better prognosis. Further studies showed that immune cells had a significantly positive correlation with iron–sulfur protein family genes, including CD8+ T cells, CD4+ T cells and B cells. More importantly, the results of immunohistochemistry showed that the expression of NFU1, ISCA1, ISCA2 and C1ORF69 in normal tissues was higher than that in renal clear cell carcinoma tissues. In this study, we systematically analyzed the expression and prognostic value of iron–sulfur protein family genes in KIRC. More importantly, NFU1, ISCA1, ISCA2, and C1ORF69 are expected to become potential therapeutic targets for KIRC, as well as potential prognostic markers for improving the survival rate and prognostic accuracy of KIRC. [ABSTRACT FROM AUTHOR]

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Peripheral artery disease (PAD) is a common syndrome in elderly people. Recently, artificial intelligence (AI) algorithms, in particular machine-learning algorithms, have been increasingly used in disease diagnosis. Aim: In this study, we designed an effective diagnostic model of PAD in the elderly patients using artificial intelligence. Methods: The study was performed with 539 participants, all over 80 years in age, who underwent the measurements of Doppler ultrasonography and ankle–brachial pressure index (ABI). Blood samples were collected. ABI and two machine-learning algorithms (MLAs)—logistic regression and a random forest (RF) model—were established to diagnose PAD. The sensitivity and specificity of the models were analyzed. An additional RF model was designed based on the most significant features of the original RF model and a prospective study was conducted to demonstrate its external validity. Results: Thirteen of the 28 features introduced to the MLAs differed significantly between PAD and non-PAD participants. The respective sensitivities and specificities of logistic regression, RF, and ABI were as follows: logistic regression (81.5%, 83.8%), RF (89.3%, 91.6%) and ABI (85.1%, 84.5%). In the prospective study, the newly designed RF model based on the most significant seven features exhibited an acceptable performance rate for the diagnosis of PAD with 100.0% sensitivity and 90.3% specificity. Conclusions: An RF model was a more effective method than the logistic regression and ABI for the diagnosis of PAD in an elderly cohort. [ABSTRACT FROM AUTHOR]

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As an interdisciplinary subject of medicine and artificial intelligence, intelligent diagnosis and treatment has received extensive attention. The standardization of Chinese medicine (CM) diagnosis has been always a bottleneck in the modernization and globalization of CM. Studying the application technology of artificial intelligence in CM and solving the problems is an urgent need for the development of modern CM in the era of artificial intelligence. Taking the pneumonia with dyspnea and cough in CM as an example, this article gives an overview of intelligent medical technology and application development, brings forward the present technical problems faced and the new advances in intelligent technology on CM diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The expression of microRNA-19b (miR-19b) in acute necrotizing pancreatitis (ANP) and its functional role in acinar cell necrosis of SD rats were investigated. Twelve SD rats were divided into two groups randomly, including control group and ANP group. The rat ANP models were established by intraperitoneal injection of L-arginine (2400 mg/kg body weight), and equal volume of 0.9% NaCl was injected in the control group. MiRNA chip assay was performed to examine the expression of miRNAs in the pancreas in two different groups. Besides, to further explore the role of miR-19b in ANP in vitro, taurolithocholic acid 3-sulfate disodium salt (TLC-S) (200 μmol/L) was administrated to treat the rat pancreatic acinar cell line, AR42J, for establishing the ANP cells model. The quantitative real-time PCR (qRT-PCR) was adopted to measure the miR-19b expression. Moreover, the mimic miRNA, miRNA antisense oligonucleotide (AMO) and control vector were used to transfect AR42J cells, the expression of miR-19b was confirmed by qRT-PCR and the necrotizing rate of AR42J cells was detected with AO/EB method. The expression of miR-19b was significantly higher in ANP group than in control group as displayed by the miRNA chip assay. Furthermore, after inducing necrosis of AR42J cells in vitro, the expression of miR-19b was significantly increased by 2.51±0.14 times in comparison with the control group. As revealed by qRT-PCR assay, the expression of miR-19b was 5.94±0.95 times higher in the mimic miRNA group than in the control vector group, companied with an obviously increased acinar cell necrotizing rate (50.3%±1.5% vs. 39.6%±2.3%, P<0.05). Moreover, the expression of miR-19b in the miRNA AMO group was 0.38±0.15 times lower than in the control vector group, and the cell necrosis rate was much lower accordingly (23.1%±3.3% vs. 39.6%±2.3%, P<0.05). Besides, there was no significant difference between the control vector cells and the cells without treatment ( P>0.05). The expression of miR-19b was significantly induced in ANP. In addition, up-regulation of miR-19b could promote the necrosis of pancreatic acinar cells and miR-19b deficiency could decrease the rate of pancreatic acinar cell necrosis. [ABSTRACT FROM AUTHOR]

With the rapid development of optical elements with large capacity and high speed, the network architecture is of great importance in determing the performance of wavelength division multiplexing passive optical network (WDM-PON). This paper proposes a switching structure based on the tunable wavelength converter (TWC) and the arrayed-waveguide grating (AWG) for WDM-PON, in order to provide the function of opitcal virtual private network (OVPN). Using the tunable wavelength converter technology, this switch structure is designed and works between the optical line terminal (OLT) and optical network units (ONUs) in the WDM-PON system. Moreover, the wavelength assignment of upstream/downstream can be realized and direct communication between ONUs is also allowed by privite wavelength channel. Simulation results show that the proposed TWC and AWG based switching structure is able to achieve OVPN function and to gain better performances in terms of bite error rate (BER) and time delay. [ABSTRACT FROM AUTHOR]

The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. Here, we demonstrate that PTPN18 regulates HER2-mediated cellular functions through defining both its phosphorylation and ubiquitination barcodes. Enzymologic characterization and three crystal structures of PTPN18 in complex with HER2 phospho-peptides revealed the molecular basis for the recognition between PTPN18 and specific HER2 phosphorylation sites, which assumes two distinct conformations. Unique structural properties of PTPN18 contribute to the regulation of sub-cellular phosphorylation networks downstream of HER2, which are required for inhibition of HER2-mediated cell growth and migration. Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY1112, the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. In agreement with the negative regulatory role of PTPN18 in HER2 signaling, the HER2/PTPN18 ratio was correlated with breast cancer stage. Taken together, our study presents a structural basis for selective HER2 dephosphorylation, a previously uncharacterized mechanism for HER2 degradation and a novel function for the PTPN18 PEST domain. The new regulatory role of the PEST domain in the ubiquitination pathway will broaden our understanding of the functions of other important PEST domain-containing phosphatases, such as LYP and PTPN12. [ABSTRACT FROM AUTHOR]

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36–40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36–40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism. [ABSTRACT FROM AUTHOR]