Search

OBJECTIVE To investigate the effectiveness of a circulating tumor cell (CTC)-based classifier in stratifying stage IB lung adenocarcinoma (LUAD). SUMMARY BACKGROUND DATA Stage IB LUADs have an approximately 70% 5-year survival rate. The clinical application of adjuvant chemotherapy (ACT) is controversial due to inconsistent results in a series of trials and few useful guide biomarkers. Thus, there is a pressing need for robust biomarkers to stratify stage IB patients to define which group would most likely benefit from ACT. METHODS 212 stage IB LUAD patients were enrolled and were divided into three independent cohorts. The aptamer-modified NanoVelcro system was used to enrich the CTCs. RESULTS A cutoff of < 4 or ≥ 4 CTCs as the optimal prognostic threshold for stage IB LUAD was generated to stratify the patients in a 70-patient cohort into low-risk and high-risk groups. Patients with ≥ 4 CTCs in the training cohort had shorter progression-free survival (PFS, P < 0.0001) and overall survival (OS, P < 0.0001) than patients with < 4 CTCs. CTC number remained the strongest predictor of PFS and OS even in a multivariate analysis including other clinicopathological parameters. Furthermore, a nomogram based on the CTC count was developed to predict the 3-year and 5-year survival in the training cohort and performed well in the other two validation cohorts (C-index: 0.862, 0.853 and 0.877). CONCLUSION The presence of ≥ 4 CTCs can define a high-risk subgroup, providing a new strategy to make optimal clinical decisions for stage IB LUAD.

Within the context of the COVID-19 pandemic, community-level medical institutions as health service centres have been gaining importance in the medical reform expansion. As prior research has not fully addressed how to index and evaluate the quality of medical service, this article proposes a framework based on the service quality gap theory and the three-faceted “structure–process–outcome” quality evaluation theory. The study took the medical services at Beijing’s Tianqiao Community Health Service Centre as an example to construct an index system for medical service quality evaluations. Data was collected from 211 people, and SPSS software was used for data processing and analysis. Due to the COVID-19 pandemic, patients without serious diseases tend to choose community hospitals to reduce their infection risk. As a result, they have growing requirements for clinics to have more departments and specialists. The studied community health service centre has encountered difficulties connected to low patient expectations, a poor medical environment, outdated hardware and equipment, and a low level of medical services. Some suggestions have been made to add specialised departments and consider the convenience of medical treatment for the elderly.

ObjectiveMonocyte chemotactic protein-1-induced protein 1 (MCPIP1) is highly expressed in inflamed mucosa of inflammatory bowel disease (IBD) and negatively regulates immune response, while the underlying mechanisms regulating mucosal macrophage functions remain unknown. Here, we investigated the roles of MCPIP1 in modulating the differentiation and functions of intestinal macrophages in the pathogenesis of IBD.DesignScRNA-seq was used to cluster the monocyte/macrophage lineage from macrophage-specificMcpip1-deficient (Mcpip1∆Mye) mice andMcpip1fl/fllittermates. The differentially expressed genes were confirmed by RNA-seq, luciferase assay, CUT&Tag assay and Western blotting. Effects of MCPIP1 and the activating transcription factor 3 (ATF3)-AP1S2 axis were assessed in patients with IBD.ResultsMcpip1∆Myemice developed more severe dextran sulfate sodium (DSS)-induced colitis characterised by an increase in macrophage migratory capacity and M1 macrophage polarisation but a decrease in the monocyte-to-macrophage maturation in gut mucosa compared with their littermates. ScRNA-seq unravelled a proinflammatory population (Ccr2+Il-1β+Tlr2+Cx3cr1−Cd163−Mrc1−Ly6c+) of the monocyte/macrophage lineage from lamina propria CD11b+cells and an arrest ofMcpip1∆Myemonocyte-to-macrophage maturation in an Atf3-Ap1s2 axis-dependent manner. Silencing of Ap1s2 or Atf3 markedly suppressedMcpip1∆Myemacrophage migration, M1-like polarisation, and production of proinflammatory cytokines and chemokines. Notably, in vivo blockage of Ap1s2 ameliorated DSS-induced colitis inMcpip1ΔMyemice through enhancing intestinal macrophage maturation. Furthermore, MCPIP1, ATF3 and AP1S2 were highly expressed in inflamed mucosa of active patients with IBD and blockage of ATF3 or AP1S2 significantly suppressed IBD CD14+-derived M1-like macrophage polarisation and proinflammatory cytokine production.ConclusionsMacrophage-specificMcpip1deficiency polarises macrophages towards M1-like phenotype, arrests macrophage maturation and exacerbates intestinal inflammation in an Atf3-Ap1s2-dependent manner, thus providing novel mechanistic insight into intestinal macrophage functions during IBD.

It has been suggested that more globalized cities are more polarized and segregated than other cities. However, this is mainly evidenced by advanced capitalist cities and other selected developed cities, while less developed cities are clearly under-researched. This paper draws on both developed and less developed cities in Guangdong province, and asks how socio-economic segregation levels differ among cities of varying economic development levels. We find that, contrary to expectation, less developed cities are showing higher levels of segregation than well-developed cities. We suggest that the key contributing factor is that the well-developed cities in Guangdong province are characterized by manufacturing-dominant economic structures and industrialization-based economic transformation. Correspondingly, their occupational structures are predominantly characterized by employees with a recent agricultural background; the restructuring process is therefore dominated by professionalization of the lower class. The stronger and faster industrialization and professionalization processes produce lower segregation levels in those more developed cities.

High-quality motion estimation is essential for ultrasound elastography (USE). Traditional motion estimation algorithms based on speckle tracking such as normalized cross correlation (NCC) or regularization such as global ultrasound elastography (GLUE) are time-consuming. In order to reduce the computational cost and ensure the accuracy of motion estimation, many convolutional neural networks have been introduced into USE. Most of these networks such as radio-frequency modified pyramid, warping and cost volume network (RFMPWC-Net) are supervised and need many ground truths as labels in network training. However, the ground truths are laborious to collect for USE. In this study, we proposed a MaskFlownet-based unsupervised convolutional neural network (MF-UCNN) for fast and high-quality motion estimation in USE. The inputs to MF-UCNN are the concatenation of RF, envelope, and B-mode images before and after deformation, while the outputs are the axial and lateral displacement fields. The similarity between the predeformed image and the warped image (i.e., the postdeformed image compensated by the estimated displacement fields) and the smoothness of the estimated displacement fields were incorporated in the loss function. The network was compared with modified pyramid, warping and cost volume network (MPWC-Net)++, RFMPWC-Net, GLUE, and NCC. Results of simulations, breast phantom, and in vivo experiments show that MF-UCNN obtains higher signal-to-noise ratio (SNR) and higher contrast-to-noise ratio (CNR). MF-UCNN achieves high-quality motion estimation with significantly reduced computation time. It is unsupervised and does not need any ground truths as labels in the training, and, thus, has great potential for motion estimation in USE.

Unprecedented urbanisation in China has profoundly reshaped the country’s social-spatial structure. Owing to economic suburbanisation and urban redevelopment processes, migrants coming from rural areas are increasingly concentrated in suburbs rather than city centres. Against this backdrop, this paper focuses on residential segregation between migrants and locals, and on geographical (re)structuring between the city centre and suburb. Theil’s H Index is used to disaggregate the migrant segregation of each municipality into a within-suburb, a within-centre and a between-centre-suburb component. We use Census data for 258 municipalities in 2000 and 2010; we find that migrant segregation increased in this period. We ascribe this to the increasing segregation of migrants in suburban areas, which offsets the increasingly balanced distribution of migrants between the city centre and suburb. Segregation in city centres also increased slightly in this period. Unexpectedly, less economically developed municipalities, defined by their per capita GDP, tend to be more segregated than their more developed counterparts. Less developed municipalities also have a higher level of suburban employment and housing opportunities in the whole municipality, but feature more segregated suburban spaces and a polarised distribution of migrants between the centre and suburb.

The change of microvasculature is associated with the occurrence and development of many diseases. Ultrafast power Doppler imaging (uPDI) is an emerging technology for the visualization of microvessels due to the development of ultrafast plane wave (PW) imaging and advanced clutter filters. However, the low signal-to-noise ratio (SNR) caused by unfocused transmit of PW imaging deteriorates the subsequent imaging of microvasculature. Nonlocal means (NLM) filtering has been demonstrated to be effective in the denoising of both natural and medical images, including ultrasound power Doppler images. However, the feasibility and performance of applying an NLM filter on the ultrasound radio frequency (RF) data have not been investigated so far. In this study, we propose to apply an NLM filter on the spatiotemporal domain of clutter filtered blood flow RF data (St-NLM) to improve the quality of uPDI. Experiments were conducted to compare the proposed method with three different methods (under various similarity window sizes), including conventional uPDI without NLM filtering (Non-NLM), NLM filtering on the obtained power Doppler images (PD-NLM), and NLM filtering on the spatial domain of clutter filtered blood flow RF data (S-NLM). Phantom experiments, in vivo contrast-enhanced human spinal cord tumor experiments, and in vivo contrast-free human liver experiments were performed to demonstrate the superiority of the proposed St-NLM method over the other three methods. Qualitative and quantitative results show that the proposed St-NLM method can effectively suppress the background noise, improve the contrast between vessels and background, and preserve the details of small vessels at the same time. In the human liver study, the proposed St-NLM method achieves 31.05-, 24.49-, and 11.15-dB higher contrast-to-noise ratios (CNRs) and 36.86-, 36.86-, and 15.22-dB lower noise powers than Non-NLM, PD-NLM, and S-NLM, respectively. In the human spinal cord tumor, the full-width at half-maximums (FWHMs) of vessel cross Section are 76, 201, and [Formula: see text] for St-NLM, Non-NLM, and S-NLM, respectively. The proposed St-NLM method can enhance the microvascular visualization in uPDI and has the potential for the diagnosis of many microvessel-change-related diseases.

The aim of this study is to fabricate high-strength steel with exceptional yield strength and superior ductility by employing a novel design approach of nanolamellar/equiaxial crystal “sandwich” heterostructures, utilizing rolling and electron-beam-welding techniques. The microstructural heterogeneity of the steel is manifested in the phase content and grain size, ranging from nanolamellae comprising a small quantity of martensite on both sides to the completely coarse austenite in the center, which are interconnected via gradient interfaces. The structural heterogeneity and phase-transformation-induced plasticity (TIRP) offer remarkable strength and ductility for the samples. Furthermore, the synergistic confinement of the heterogeneous structures leads to the formation of Lüders bands, which exhibit stable propagation under the TIRP effect and impede the onset of plastic instability, ultimately resulting in a significant improvement in the ductility of the high-strength steel.

Dynamical controls on terahertz (THz) wavefronts are crucial for many applications, but available mechanism requests tunable elements with sub-micrometer sizes that are difficult to find in the THz regime. Here, different from the local-tuning mechanism, we propose an alternative approach to construct wavefront-control meta-devices combining specifically designed metasurfaces and globally tuned graphene layers. Coupled-mode-theory (CMT) analyses reveal that graphene serves as a tunable loss to drive the whole meta-device to transit from one functional phase to another passing through an intermediate regime, exhibiting distinct far-field (FF) reflection wavefronts. As a proof of concept, we design/fabricate a graphene meta-device and experimentally demonstrate that it can reflect normally incident THz wave to pre-designed directions with different polarizations under appropriate gating voltages. We finally design a graphene meta-device and numerically demonstrate that it can generate vectorial THz beams with continuously varying polarization distributions upon gating. These findings pave the road to realizing a wide range of THz applications, such as sensing, imaging, and wireless communications.

Achieving a pre-designed scattering pattern from an ultra-compact platform is highly desired for on-chip integration optics, but conventional techniques suffer from the limitations of bulky size, wavelength-scale modulation and low efficiency. Here, we propose a new strategy to efficiently generate arbitrary spin-polarized scattering far-field patterns from surface-wave (SW) excitations on a designer Pancharatnam–Berry (PB) metasurface. We find that a PB meta-atom serves as a subwavelength scatter to decouple impinging SW to a spin-polarized propagating wave (PW) with tailored amplitude and phase, and thus interference among PWs generated by scatterings at different PB meta-atoms can generate a tailored far-field pattern. As a proof of concept, we design and fabricate a series of PB metasurfaces in the microwave regime and experimentally demonstrate that they can generate desired radiation patterns within a broad frequency band, including unidirectional radiation, line/point focusing, vortex beam and hologram. These findings may stimulate important applications in on-chip integrated photonics.

As a typical chronic kidney disease (CKD), hypertensive nephrosclerosis (HN) is a common syndrome of hypertension, characterized by chronic kidney microvascular damage. Early diagnosis of microvascular damage using conventional ultrasound imaging encounters challenges in sensitivity and specificity owing to the inherent diffraction limit. Ultrasound localization microscopy (ULM) has been developed to obtain microvasculature and microvascular hemodynamics within the kidney, and would be a promising tool for the early diagnosis of CKD.In this study, the advantage of quantitative indexes obtained by using ULM (mean arterial blood flow speeds of different segments of interlobular arteries) over indexes obtained using conventional clinical serum (β2-microglobulin, serum urea nitrogen, and creatinine) and urine (24-h urine volume and urine protein) tests and ultrasound Doppler imaging (peak systolic velocity [PSV], end-diastolic velocity [EDV], and resistance index [RI]) and contrast-enhanced ultrasound imaging (CEUS; rise time [RT], peak intensity [IMAX], mean transit time [mTT], and area under the time-intensity curve [AUC]) for early diagnosis of HN were investigated. Examinations were carried out on six spontaneously hypertensive rats (SHR) and five normal Wistar-Kyoto (WKY) rats at the age of 10 weeks.The experimental results show that the indicators derived from conventional clinical inspections (serum and urine tests) and ultrasound imaging (PSV, EDV, RI, RT, IMAX, mTT, and AUC) do not show significant difference between hypertensive and healthy rats (p 0.05), while the TTP of the SHR group (28.52 ± 5.52 s) derived from CEUS is significantly higher than that of the WKY group (18.68 ± 7.32 s; p 0.05). The mean blood flow speed in interlobular artery of SHR (12.47 ± 1.06 mm/s) derived from ULM is significantly higher than that of WKY rats (10.13 ± 1.17 mm/s; p 0.01).The advantages of ULM over conventional clinical inspections and ultrasound imaging methods for early diagnosis of HN were validated. The quantitative results show that ULM can effectively diagnose HN at the early stage by detecting the blood flow speed changes of interlobular arteries. ULM may promise a reliable technique for early diagnosis of HN in the future.

Alkali (Li/Na/K) metal anodes (AMAs), because of their remarkably high energy density and low redox potential, are considered as the most promising anodes for next-generation high-energy battery systems. Nevertheless, high reactivity and uncontrollable volume change of metal anodes during plating/striping inevitably generate dendritic metal and unstable solid electrolyte interphase, inducing low Coulombic efficiency, inferior cycling stability and even safety issues. Architecture design is emerged as an effective approach to address these fatal issues and plenty of attempts have been conducted so far. Instead of simply summarizing the structure-designing strategies to modify AMAs, the review is dedicated to overviewing and categorizing the strategies of architecture design towards the challenges of AMAs by their fundamental design principles from the perspective of electrochemical reaction. Besides, the similarities and differences of three types of alkali metals, in terms of mechanical and chemical properties, have been systematically discussed. Finally, we overviewed the existing challenges, perspectives on further development direction, and outlook for practical applications for AMAs.

Bismuth-containing quadruple therapy for Helicobacter pylori (H. pylori) eradication has a relatively high rate of side effects and high cost, thus the option of a high-dose dual therapy with a high eradication rate and fewer adverse events is a consideration. However, studies of dual therapy are still scarce and are mostly single-center studies with limited generalizability. Large-scale, multicenter studies are required. Our study investigated and compared the effectiveness, adverse events, patient compliance, and costs of high-dose dual therapy with those of bismuth-containing quadruple therapy in H. pylori-infected treatment-naive patients in a prospective, multicenter, open-label, randomized controlled trial.Treatment-naive patients infected with H. pylori were randomly assigned to receive high-dose dual therapy (esomeprazole 20 mg 4 times daily and amoxicillin 1000 mg 3 times daily, for 14 days) or bismuth-containing quadruple therapy (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, all twice daily for 14 days). The effectiveness, adverse events, patient compliance, and costs of both groups were compared.A total of 700 patients were enrolled. The high-dose dual therapy group (N = 350) achieved eradication rates of 89.4% (intention-to-treat), 90.4% (modified intention-to-treat), and 90.6% (per-protocol), which were similar to rates in the bismuth-containing quadruple therapy group (N = 350), 84.6%, 88.0%, and 88.2%, respectively (p 0.05). The high-dose dual therapy group had a lower rate of adverse events (12.9% vs. 28.1%, p 0.001) and lower costs (¥590.2 vs. ¥723.22) compared with the quadruple therapy group, respectively. The compliance of both groups was satisfactory (97.7% high-dose dual vs. 96.8% quadruple, p 0.05).High-dose dual therapy for H. pylori eradication had similar efficacy and compliance, fewer adverse events, and lower costs than bismuth-containing quadruple therapy for treatment-naive patients.

Background Evidence has shown that the traditional Chinese herbal medicine Wumei decoction (WMD) has a protective effect on ulcerative colitis. Here, we studied the anti-inflammatory effects and potential mechanisms of WMD on chronic colitis in mice. Methods A dextran sulfate sodium (DSS)–induced chronic colitis model and CD45RBhighCD4+ T cell transfer model were established in mice. Body weight, Disease Activity Index, and colon length were assessed, and histopathology was confirmed by hematoxylin and eosin staining. Colon tissue samples were collected to detect the frequencies of various immune cells, expression of cytokines, and tight junction–related proteins using flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. 16S ribosomal DNA sequencing was performed to distinguish differential microbiota of fecal samples. Results Severe chronic colitis was observed in mice after DSS exposure and in Rag1-/- mice reconstituted with CD45RBhighCD4+ T cells, as manifested by weight loss, hematochezia, and shortening and thickening of the colon, which were reversed by WMD treatment. WMD markedly suppressed intestinal mucosal CD4+ T cell differentiation and the secretion of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin-1β, interferon γ, and IL-17A) by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Moreover, WMD promoted the expression of occludin, zonula occludens-1, and E-cadherin, thereby maintaining the epithelial barrier function. Additionally, 16S ribosomal DNA sequencing revealed that WMD regulated the dysbiosis of gut microbiota in CD45RBhighCD4+ T cell-reconstituted Rag1-/- mice, evidenced by an increase of Allobaculum and Bacteroides and a decrease of Ileibacterium. Conclusions WMD ameliorates chronic colitis in mice induced by DSS or reconstituted with CD45RBhighCD4+ T cells through suppressing Th1/Th17 cell differentiation and the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving the dysbiosis.

Background and Aims Non-invasive biomarkers in sera of patients with inflammatory bowel disease [IBD] are not currently available for rapidly and accurately diagnosing the disease. We aimed to investigate and validate the potential roles of anti-paratuberculosis-nocardia polypeptide antibodies [anti-pTNP] in the diagnosis of IBD. Methods Serum samples were collected from 502 patients with diagnosed Crohn’s disease [CD], 141 patients with ulcerative colitis [UC], and 109 healthy donors. The levels of anti-pTNPs and anti-Saccharomyces cerevisiae antibodies [ASCAs] were determined by enzyme-linked immunosorbent assay. The effects of each variable on the diagnosis were analysed by receiver operating characteristic [ROC] analysis. We also performed an estimate study by first developing a clinical prediction model, with external validation in CD patients from nine IBD medical centres in China. Results The levels of anti-pTNPs in sera of CD patients were higher than those in UC patients and healthy donors. The positive rates of anti-pTNPs were significantly higher in ileal CD patients than in ileocolonic and colonic CD patients, and the levels of anti-pTNP IgG in perianal patients were significantly higher than those in non-perianal CD patients. Of note, anti-pTNPs and perianal diseases were important predictors for active stage of CD patients. Discriminative ability to predict active CD patients was 0.918 (95% confidence interval [CI]:0.886–0.949). Conclusions Anti-pTNP functions as a novel biological marker for diagnosing CD and can be used to assess disease severity, particularly in those with lesion locations in the terminal ileum and stricturing and perianal diseases. A validated prediction model reveals that anti-pTNPs are useful for estimating the likelihood of active CD.

BACKGROUND Tissue resident memory T (TRM) cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema. AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil (5-FU) and triamcinolone (TA) with those associated with TA alone for the treatment of chronic eczema. METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only. Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes. All patients were followed up monthly for up to 1 year. RESULTS No serious adverse event was observed in either group. Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment, the relapse rate was significantly lower in the 5-FU+TA group than in the TA group. Histological examination showed significantly fewer CD8+ and CD103+ T cells but not CD4+ T cells in the 5-FU+TA group. CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of TRM cells in the lesional skin and the relapse rate of chronic eczema.

Specific patterns of lung ultrasound (LUS) images are used to assess the severity of coronavirus disease 2019 (COVID-19) pneumonia, while such assessment is mainly based on clinicians' qualitative and subjective observations. In this study, we quantitatively analyze the LUS images to assess the severity of COVID-19 pneumonia by characterizing the patterns related to the pleural line (PL) and B-lines (BLs). Twenty-seven patients with COVID-19 pneumonia, including 13 moderate cases, seven severe cases, and seven critical cases, are enrolled. Features related to the PL, including the thickness (TPL) and roughness of the PL (RPL), and the mean (MPLI) and standard deviation (SDPLI) of the PL intensities are extracted from the LUS images. Features related to the BLs, including the number (NBL), accumulated width (AWBL), attenuation coefficient (ACBL), and accumulated intensity (AIBL) of BLs, are also extracted. The correlations of these features with the disease severity are evaluated. The performances of the binary severe/non-severe classification are assessed for each feature and support vector machine (SVM) classifiers with various combinations of features as input. Several features, including the RPL, NBL, AWBL, and AIBL, show significant correlations with disease severity (all ). The classification performance is optimal using the SVM classifier using all the features as input (area under the receiver operating characteristic (ROC) curve = 0.96, sensitivity = 0.93, and specificity = 1). These findings demonstrate that the proposed method may be a promising tool for automatic grading diagnosis and follow-up of patients with COVID-19 pneumonia.

Supplementary Table S1 shows the list of primary antibodies used for immunohistochemical staining and immunoblotting assays. Supplementary Table S2 shows the clinical characteristics of 626"driver-gene-negative" LUAD patients from four cohorts. Supplementary Table S3 shows the clinical characteristics of 52 "driver-gene-negative" LUAD patients whose samples were used for microarray analysis. Supplementary Table S4 shows the microarray results of the genes in the Wnt-signaling pathway. Supplementary Table S5 shows the univariate association of 41 candidate genes with overall survival in the training SYSUFH cohort. Supplementary Table S6 shows the C-index of the three enrolled factors in the nomogram in the SYSUFH training cohort. Supplementary Table S7 indicates the summary of relevant findings of ITH analysis of twenty-one patients with "driver-gene-negative" LUAD. Supplementary Figure S1 shows the workflow to determine "driver-gene-negative" status in LUAD patients. Supplementary Figure S2 shows the pathological diagnosis of enrolled LUAD patients. Supplementary Figure S3 shows the study flowchart. Supplementary Figure S4 shows the signaling GO analysis and cellular component classification analysis for the genome-wide microarray. Supplementary Figure S5 shows the β-Catenin expression characteristics in patients with "driver-gene-negative" LUAD from the SYSUFH training cohort. Supplementary Figure S6 shows the different expression profiles of β-catenin in EGFRmt, KRASmt, and ALKft LUAD. Supplementary Figure S7 shows the protein expression characteristics of 41 candidate genes in 8 "driver-gene-negative" LUAD patients. Supplementary Figure S8 shows these representative immunohistochemical staining for 41 candidate molecules in 626 "driver-gene-negative" LUAD patient tissue samples. Supplementary Figure S9 shows kaplan-Meier estimates of progression-free survival (PFS) based on the CSDW signature in the four cohorts. Supplementary Figure S10 shows that the CSDW signature predicts clinical outcomes in all 626 patients with "driver-gene-negative" LAUD. Supplementary Figure S11 shows that the optimum cutoff value of the four prognostic markers was determined using the X-tile program in the training set and Kaplan-Meier analysis of all 626 LUAD samples. Supplementary Figure S12 shows the correlation between the four genes in the CSDW signature and tumor size, lymphatic metastasis and distant organ metastasis. Supplementary Figure S13 shows that kaplan-Meier analysis was used to compare the performance of the CSDW signature in all 626 LUAD patients with different clinicopathological risk factors. Supplementary Figure S14 shows that the nomogram to predict the 3-year and 5-year overall survival (OS) of "driver-gene-negative" LUAD patients. Supplementary Figure S15 shows that time-dependent ROC curves to evaluate the sensitivity and specificity of the nomogram in predicting overall survival in "driver-gene-negative" LUAD patients. Supplementary Figure S16 shows that intra- and inter-sample variability of β-catenin, SOX9, DVL3 and Wnt2b protein levels detected by IHC.

Purpose:Examining the role of developmental signaling pathways in “driver gene–negative” lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as “driver gene–negative”) may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of “driver gene–negative” lung adenocarcinoma.Experimental Design:In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature.Results:Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “driver gene–negative” lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway–based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway–based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46–16.79; P < 0.001) than patients with low-risk scores.Conclusions:The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for “driver gene–negative” lung adenocarcinoma.

In Chinese cabbage breeding, hybrids have made a terrific contribution due to heterosis, the superior performance of offspring compared to their inbred parents. Since the development of new, top-performing hybrids requires a large scale of human and material resources, the prediction of hybrid performance is of utmost interest to plant breeders. In our research, leaf transcriptome data from eight parents were used to investigate if they might be employed as markers to predict hybrid performance and heterosis. In Chinese cabbage, heterosis of plant growth weight (PGW) and heterosis of head weight (HW) were more obvious than other traits. The number of differential expression genes (DEGs) between parents was related to the PGW, length of the biggest outer leaf (LOL), leaf head height (LHH), leaf head width (LHW), HW, leaf number of head (LNH) and plant height (PH) of hybrids, and up-regulated DEGs number was also associated with these traits. Euclidean and binary distances of parental gene expression levels were significantly correlated with the PGW, LOL, LHH, LHW, HW and PH of hybrids. Additionally, there was a significant correlation between the parental expression levels of multiple genes involved in the ribosomal metabolic pathway and hybrid observations and heterosis in PGW, with the BrRPL23A gene showing the highest correlation with the MPH of PGW(r = 0.75). Therefore, leaf transcriptome data can preliminarily predict the hybrid performance and select parents in Chinese cabbage.

Theoretically, the topological charge l in the vortex can be any integer or fraction, thus the vortex carrying different topological charges can form an infinitely orthogonal orbital angular momentum state space, which can provide new dimensional resources for optical communication. However, high-capacity optical communication requires low delay, thus real-time detection of the OAM is significant for communication. Metasurfaces have the characteristics of low loss, ultra-thin, easy integration, and flexible phase controls, which provide a meaningful way to realize integrated OAM generation and detection. Here, an optimized streamlined metasurface (OSM) is presented, which can detect high-order vortex beams in a single, simple, and rapid manner by photon momentum transformation (PMT). Since different vortices are converted into focusing modes with distinct azimuthal coordinates on a transverse plane through PMT, a single measurement can determine OAMs in an ample mode space. In addition, the OSM can detect more and higher order OAMs compared with a discrete metasurface (DM) at the same size, due to its better wavefront sampling capabilities. With the merits of an ultra-compact device size, simple optical structure, and outstanding vortex recognition ability, our approach may underpin the development of integrated optics and quantum systems.

Designing perfect anomalous reflectors is crucial for achieving many metasurface-based applications, but available design approaches for the cases of extremely large bending angles either require unrealistic gain–loss materials or rely on brute-force optimizations lacking physical guidance. Here, we propose a deterministic approach to design passive metasurfaces that can reflect impinging light to arbitrary nonspecular directions with almost 100% efficiencies. With both incident and out-going far-field waves given, we can retrieve the surface-impedance profile of the target metadevice by matching boundary conditions with all allowed near-field modes added self-consistently and then construct the metadevices deterministically based on passive meta-atoms exhibiting local responses. We design/fabricate two proof-of-concept microwave metadevices and experimentally demonstrate that the first one achieves anomalous reflection to a 70° angle with efficiency ∼98%, and the second one can generate multiple reflected beams with desired bending angles and power allocations. Our findings pave the way for realizing high-efficiency wave-control metadevices with desired functionalities.

Freely switching light transmission and absorption via an achromatic reflectionless screen is highly desired for many photonic applications (e.g., energy-harvesting, cloaking, etc.), but available meta-devices often exhibit reflections out of their narrow working bands. Here, we rigorously demonstrate that an optical metasurface formed by two resonator arrays coupled vertically can be perfectly reflectionless at all frequencies below the first diffraction mode, when the near-field (NF) and far-field (FF) couplings between two constitutional resonators satisfy certain conditions. Tuning intrinsic loss of the system can further modulate the ratio between light transmission and absorption, yet keeping reflection diminished strictly. Designing/fabricating a series of metasurfaces with different inter-resonator configurations, we experimentally illustrate how varying inter-resonator NF and FF couplings can drive the system to transit between different phase regions in a generic phase diagram. In particular, we experimentally demonstrate that a realistic metasurface satisfying the discovered criteria exhibits the desired achromatic reflectionless property within 160–220 THz (0–225 THz in simulation), yet behaving as a perfect absorber at ~ 203 THz. Our findings pave the road to realize meta-devices exhibiting designable transmission/absorption spectra immune from reflections, which may find many applications in practice.

Aim Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. Subjects and method In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C > A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. Results The most frequent base substitutions were G:C > A:T transition in all the areas investigated. The G:C > A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C > A:T transition in CpG sites and A:T > G:C mutation was more prevalent in Asian countries. Conclusion The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.

Sarcopenia is a common geriatric disorder characterized by decreased muscle strength, low muscle mass and poor physical performance. This aging-related skeletal muscle deterioration leads to adverse outcomes and severely impairs the quality of life of patients. The accumulation of dysfunctional mitochondria with aging is an important factor in the occurrence and progression of sarcopenia. Mitochondrial quality control (MQC) fundamentally ensures the normal mitochondrial functions and is comprised of four main parts: proteostasis, biogenesis, dynamics and autophagy. Therefore, any pathophysiologic factors compromising the quality control of homeostasis in the skeletal muscle may lead to sarcopenia. However, the specific theoretical aspects of these processes have not been fully elucidated. Current therapeutic interventions using nutritional and pharmaceutical treatments show a modest therapeutic efficacy; however, only physical exercise is recommended as the first-line therapy for sarcopenia, which can ameliorate skeletal muscle deficiency by maintaining the homeostatic MQC. In this review, we summarized the known mechanisms that contribute to the pathogenesis of sarcopenia by impairing normal mitochondrial functions and described potential interventions that mitigate sarcopenia through improving MQC.

Background. Breast cancer is the most common cancer in women. miR-520b had binding sites with PTEN through the bioinformatics prediction. But few studies have been conducted on miR-520b and PTEN in breast cancer. We aimed to explore the effect of miR-520b and PTEN on breast cancer and the mechanisms involved. Methods. Clinical samples of breast cancer were collected. Bioinformatics analysis was performed to screen the differentially expressed miRNAs. CD4 T cells and CD8 T cells were cocultured with MCF-7 cells in the Transwell system. Moreover, MCF-7 cells and M0 macrophage cocultured cell lines were constructed. qRT-PCR, IF, western blot, flow cytometry, and ELISA were performed to detect related factors expression. Starbase and dual-luciferase reporter assay verified the binding of miR-520b to PTEN. The tumor formation model was established to study miR-520b and PTEN effects in vivo. Results. The differentially expressed miR-520b was screened via miRNAs sequencing and cell verification. miR-520b expression was high, PTEN was low in tumor tissues, T cells and NK cells were inhibited, and macrophages were transformed into M2 type, promoting immune escape. In addition, miR-520b bound to PTEN. Then, splenic CD4 T cells and CD8 T cells were successfully sorted. During CD4 T cell differentiation to Th1 and Treg, Th1 was inhibited, and Treg was activated. We found the polarization of macrophages was related to breast cancer. The proportion of CD206 cells increased and CD68 cells decreased in the miR-520b mimics group compared with the mimic NC group. Compared with the inhibitor NC group, the proportion of CD206 cells decreased, and CD68 cells increased in the miR-520b inhibitor group. In vivo experiments showed that miR-520b inhibitor inhibited tumor growth and promoted PTEN expression. The proportion of CD3, CD4, CD8, NK1.1, CD4+IFNγ, and CD68 cells increased, while FOXP3 and CD206 cells decreased in the miR-520b inhibitor group compared with the inhibitor NC group. However, the proportion of CD3, CD4, CD8, NK1.1, CD4+IFNγ, and CD68 cells decreased, while FOXP3 and CD206 cells increased after the addition of siPTEN. Conclusions. miR-520b inhibited PTEN and aggravated breast tumors. miR-520b inhibitor enhanced CD4 and CD8 cell populations in the tumor immune microenvironment and inhibited tumor growth.

Timely diagnosis of apple tree nutrition is very important for efficient utilization of nutrients and improvement of apple yield and quality. This study aims to establish an accurate prediction model of nitrogen (N), phosphorus (P), and potassium (K) contents in apple tree leaves based on canopy hyperspectral reflectance. Two-year field experiments with four levels of N application were conducted in 2018 and 2019. The data, including canopy scale hyperspectral reflectance and leaf N, P, and K contents, were collected from young fruit stage to fruit enlargement stage. The stacked ensemble model was applied to build prediction model. The extreme learning machine (ELM) optimized by differential evolution (DE) or self-adaptive differential evolution (SaDE) algorithm and the unoptimized ELM were used to build sub-models, and the weighting strategy based on RMSE or partial least squares (PLS) was applied to combine the sub-models. Results showed that, the stacked ensemble model based on optimized ELM had achieved better prediction results, but the results of model optimized by DE algorithm were prone to over fitting. In the sub-model combination process, PLS could provide the optimal weigh to combine sub-models and correct the over fitting problem. The stacked ensemble SaDE_ELM and PLS (SE-SaDE_ELM-PLS) method for predicting N, P, K contents in apple tree leaves had achieved the best results (N, R2P = 0.844, RMSEP = 1.709 g kg−1, RRMSE = 7.654%; P, R2P = 0.931, RMSEP = 0.137 g kg−1, RRMSE = 6.402%; K, R2P = 0.725, RMSEP = 1.071 g kg−1, RRMSE = 8.747%). The SE-SaDE_ELM-PLS method was reliable for in-situ prediction of N, P, and K contents in apple tree leaves.

The demand for emerging applications at the terahertz frequencies motivates the development of novel and multifunctional devices for the generation and manipulation of terahertz waves. In this work, we report the realization of multifunctional spintronic-metasurface emitters, which allow simultaneous beam-steering and full polarization control over a broadband terahertz beam. This is achieved through engineering individual meta-atoms with nanoscale magnetic heterostructures and, thus, implementing microscopical control over the laser-induced spin and charge dynamics. By arranging the spintronic meta-atoms in the metagrating geometry, the generated terahertz beam can be flexibly steered in space between different orders of diffraction. Furthermore, we demonstrate a simultaneous control over the terahertz polarization states at different emission angles and show that the two control capabilities are mutually independent of each other. The nanoengineered multifunctional terahertz emitter demonstrated in this work can provide a solution to the challenge associated with a growing variety of applications of terahertz technology.

Li