The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA-binding domain, known ...as ‘forkhead box’ domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here, we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.
To investigate the risk factors associated with the development of thrombocytopenia, and define the thresholds of efficacy and safety in critically ill patients who received linezolid therapy. A ...retrospective study was performed in critically ill patients treated with linezolid. Risk factors associated with thrombocytopenia were identified via medical records and trough levels (C
min
) measured during linezolid treatment. By establishing a logistic model, the risks were predicted by the receiver operating characteristic (ROC) curve and the thresholds of efficacy and safety were identified in the patients. Logistic analysis showed that, weight (OR = 0.906; 95 % CI, 0.839–0.978;
P
= 0.011), baseline platelet count (OR = 0.989; 95 % CI, 0.977–1.000;
P
= 0.049), C
min
(OR = 1.545; 95 % CI, 1.203–1.983;
P
= 0.001), and APACHE II score (OR = 1.130; 95 % CI, 1.003–1.273;
P
= 0.044) were significant factors for linezolid-associated thrombocytopenia. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was the maximum, the best optimal cut-off point was 205.6 on the ROC curve; when C
min
≥ 2 mg/L, the probability of bacterial eradication was more than 80 %; when C
min
≥ 6.3 mg/L, the probability of thrombocytopenia was more than 50 %. In clinical practice, when the calculating results of the combined predictor ≤205.6, the risk of the development of thrombocytopenia may be higher. Furthermore, maintenance of C
min
between 2 and 6.3 mg/L over time may be helpful in retaining appropriate efficacy and reducing the associated thrombocytopenia.
Recently, crack segmentation studies have been investigated using deep convolutional neural networks. However, significant deficiencies remain in the preparation of ground truth data, consideration ...of complex scenes, development of an object-specific network for crack segmentation, and use of an evaluation method, among other issues. In this paper, a novel semantic transformer representation network (STRNet) is developed for crack segmentation at the pixel level in complex scenes in a real-time manner. STRNet is composed of a squeeze and excitation attention-based encoder, a multi head attention-based decoder, coarse upsampling, a focal-Tversky loss function, and a learnable swish activation function to design the network concisely by keeping its fast-processing speed. A method for evaluating the level of complexity of image scenes was also proposed. The proposed network is trained with 1203 images with further extensive synthesis-based augmentation, and it is investigated with 545 testing images (1280 × 720, 1024 × 512); it achieves 91.7%, 92.7%, 92.2%, and 92.6% in terms of precision, recall, F1 score, and mIoU (mean intersection over union), respectively. Its performance is compared with those of recently developed advanced networks (Attention U-net, CrackSegNet, Deeplab V3+, FPHBN, and Unet++), with STRNet showing the best performance in the evaluation metrics-it achieves the fastest processing at 49.2 frames per second.
Air pollution is a major environmental concern during all seasons in the megacity of Beijing, China. Here we present the results from a winter study that was conducted from 21 November 2011 to 20 ...January 2012 with an Aerodyne Aerosol Chemical Speciation Monitor (ACSM) and various collocated instruments. The non-refractory submicron aerosol (NR-PM1) species vary dramatically with clean periods and pollution episodes alternating frequently. Compared to summer, wintertime submicron aerosols show much enhanced organics and chloride, which on average account for 52% and 5%, respectively, of the total NR-PM1 mass. All NR-PM1 species show quite different diurnal behaviors between summer and winter. For example, the wintertime nitrate presents a gradual increase during daytime and correlates well with secondary organic aerosol (OA), indicating a dominant role of photochemical production over gas–particle partitioning. Positive matrix factorization was performed on ACSM OA mass spectra, and identified three primary OA (POA) factors, i.e., hydrocarbon-like OA (HOA), cooking OA (COA), and coal combustion OA (CCOA), and one secondary factor, i.e., oxygenated OA (OOA). The POA dominates OA during wintertime, contributing 69%, with the other 31% being SOA. Further, all POA components show pronounced diurnal cycles with the highest concentrations occurring at nighttime. CCOA is the largest primary source during the heating season, on average accounting for 33% of OA and 17% of NR-PM1. CCOA also plays a significant role in chemically resolved particulate matter (PM) pollution as its mass contribution increases linearly as a function of NR-PM1 mass loadings. The SOA, however, presents a reverse trend, which might indicate the limited SOA formation during high PM pollution episodes in winter. The effects of meteorology on PM pollution and aerosol processing were also explored. In particular, the sulfate mass is largely enhanced during periods with high humidity because of fog processing of high concentration of precursor SO2. In addition, the increased traffic-related HOA emission at low temperature is also highlighted.
The mutations of myeloproliferative neoplasma (MPN) mainly include driver mutations and non-driver mutations. The driver mutations mainly include JAK2 mutations, CALR mutations and MPL mutations and ...non-driver mutations mainly include ASXL1, DNMT3A, TET2, SF3B1, EZH2, TP53, SRSF2, USAF1, etc. Driver and non-driver mutations and their clonal evolution affect the thrombosis and disease transformation of MPN. Clonal hematopoiesis of MPN can occur decades before diagnosis, even in the fetal stage. After the emergence of clonal hematopoiesis, until the emergence and progression of MPN, gene mutation order, inflammation, interferon therapy affect the disease phenotype and clonal hematopoiesis of MPN. Although great progress has been made in the understanding of MPN clonal hematopoiesis and its evolution with the development of next-generation sequencing, there are still many limitations. In this study, we mainly discuss gene mutations of MPN and their influences on the thrombosis, leukemia and fibrosis transformati
The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria ...and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo. The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.
Since the first description by Fievet, Lagier and Figlarz in 1989, the synthesis of nanoparticles in high-boiling, multivalent alcohols - so-called polyols - has been developed into a widely applied ...strategy, and nowadays belongs to the standard repertoire for preparing high-quality nanomaterials. The polyols take advantage of several features such as: (i) water-comparable solubility of simple metal-salt precursors; (ii) high boiling points (up to 320 °C); (iii) reducing properties for the instantaneous synthesis of metals; (iv) coordinating properties for surface functionalization and colloidal stabilisation of nanoparticles; (v) wide adaptability of the polyols ranging from low-weight ethylene glycol (EG) to high-weight polyethylene glycols (PEGs). This review summarises the status and perspectives on nanoscaled elemental metals, metal oxides, metal chalcogenides, and non-metal elements that were prepared
via
the polyol synthesis. Moreover, we summarize our results and concepts to expand the limits of the polyol synthesis. This includes strategies for less-noble metal synthesis, phase transfer reactions, photochemical reduction, NMR-based characterisation of polyol-functionalised nanoparticles, realisation of phase-pure and readily crystalline metal tungstates, stabilisation of low-melting elements, and controlled thermal decomposition of polyols to obtain high-quality, lanthanide-modified carbon dots (C-dots).
The polyol synthesis of nanoparticles is reviewed, including metals, oxides, main-group elements and recent strategies to expand the method's limits.
In this paper, we report on the design, modeling, and experimental testing of a piezoelectric-driven microgripper making use of both an integrated gripping force sensor and an integrated tip ...displacement sensor. In the developed microgripper, a stack piezoelectric ceramic actuator is used to simultaneously obtain the tip displacement and the gripping force. A novel monolithic compliant mechanism is proposed to act as the microdisplacement transmission mechanism to obtain the large tip displacement and to provide the possibility of integrating both the gripping force sensor and the tip displacement sensor into the microgripper. The relationship between the gripping force, tip displacement, input force, and input displacement of the piezoelectric-driven microgripper and the dynamic model are established using the pseudorigid-body-model method. The characteristics of the developed microgripper are tested and the case of gripping an optical fiber is presented. The experimental results indicate that: 1) the theoretical model for the developed microgripper matched well with the measured results; 2) the integrated gripping force sensor and tip displacement sensor could accurately measure the gripping force and tip displacement; 3) the developed microgripper could achieve a displacement magnification of 16.0 × with respect to the stack piezoelectric ceramic actuator to realize the large tip displacement with high resolution but is also able to possess the parallel movement of its gripping jaws and the constant displacement magnification.
The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes ...(TILs) in patients with lung cancer-related brain metastases.
Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ2 or Fisher's exact test were used for analysis.
We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009).
We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.
PDF
