Terahertz metalens for generating multi-polarized focal points and images with uniform intensity distributions.

Metasurfaces have provided a flexible platform for designing ultracompact metalenses with unusual functionalities. However, traditional multi-foci metalenses are limited to generating circularly polarized (CP) or linearly polarized (LP) focal points, and the intensity distributions are always inhomogeneous/chaotical between the multiple focal points. Here, an inverse design approach is proposed to optimize the in-plane orientation of each meta-atom in a terahertz (THz) multi-foci metalens that can generate multi-polarized focal points with nearly uniform intensity distributions. As a proof-of-principle example, we numerically and experimentally demonstrate an inversely designed metalens for simultaneously generating multiple CP- and LP-based focal points with homogeneous intensity distributions, leading to a multi-polarized image (rather than the holography). Furthermore, the multi-channel and multi-polarized images consisting of multiple focal points with homogeneous intensity distributions are also numerically demonstrated. The unique approach for inversely designing multi-foci metalens that can generate multi-polarized focal points and images with uniform intensity distributions will enable potential applications in imaging and sensing.

Clinical significance of peripheral T-cell receptor repertoire profiling and individualized nomograms in patients with gastrointestinal cancer treated with anti-programmed death 1 antibody.

Background: Immune checkpoint inhibitors (ICIs) have significant clinical benefit for a subset of patients with gastrointestinal cancers (GICs) including esophageal cancer, gastric cancer and colorectal cancer. However, it is difficult to predict which patients will respond favorably to immune checkpoint blockade therapy. Thus, this study was initiated to determine if peripheral T-cell receptor (TCR) repertoire profiling could predict the clinical efficacy of anti-programmed death 1 (PD-1) treatment. Methods: Blood samples from 31 patients with GICs were collected before anti-PD-1 antibody treatment initiation. The clinical significance of the combinatorial diversity evenness of the TCR repertoire [the diversity evenness 50 (DE50), with high values corresponding to less clonality and higher TCR diversity] from peripheral blood mononuclear cells (PBMCs) was evaluated in all the enrolled patients. A highly predictive nomogram was set up based on peripheral TCR repertoire profiling. The performance of the nomogram was assessed by receiver operating characteristic (ROC) curve, concordance index (C-index), and calibration curves, and decision curve analysis (DCA) was used to assess its clinical applicability. Results: Compared to non-responders [progression disease (PD)], the DE50 scores were significantly higher in responders [stable disease (SD) and partial response (PR)] (P=0.018). Patients with a high DE50 score showed better progression-free survival (PFS) than those with a low DE50 score (P=0.0022). The multivariable Cox regression demonstrated that high DE50 and low platelet-lymphocyte ratio (PLR) were significant independent predictors for better PFS when treated with anti-PD-1 antibody. Furthermore, a highly predictive nomogram was set up based on peripheral TCR repertoire profiling. The area under the curves (AUCs) of this system at 3-, 6- and 12-month PFS reached 0.825, 0.802, and 0.954, respectively. The nomogram had a C-index of 0.768 [95% confidence interval (CI): 0.658-0.879]. Meanwhile, the calibration curves also demonstrated the reliability and stability of the model. Conclusions: High DE50 scores were predictive of a favorable response and longer PFS to anti-PD-1 treatment in GIC patients. The nomogram based on TCR repertoire profiling was a reliable and practical tool, which could provide risk assessment and clinical decision-making for individualized treatment of patients.

Analysis of sustainable water resource management and driving mechanism in arid region: a case study of Xinjiang, China, from 2005 to 2020.

The long-term dynamic comprehensive evaluation of the water resource carrying capacity (WRCC) and the analysis of its potential driving mechanism in arid areas are contemporary research issues and technical means of mitigating and coordinating the conflict between severe resource shortages and human needs. The purpose of this study was to explore the distribution of the WRCC and the spatiotemporal heterogeneity of drivers in arid areas based on an improved two-dimensional spatiotemporal dynamic evaluation model. The results show that (1) the spatial distribution of the WRCC in Xinjiang, China, is high in the north, low in the south, high in the west, and low in the east. (2) From 2005 to 2020, the centers of gravity of the WRCC in northern and southern Xinjiang moved to the southeast and west, respectively, and the spatial distribution exhibited slight diffusion. (3) The factors influencing the WRCC exhibit more obvious spatial and temporal heterogeneity. The domestic waste disposal rate and ecological water use rate were the main factors influencing the WRCC in the early stage, while the GDP per capita gradually played a dominant role in the later stage. (4) In the next 30 years, the WRCC in Xinjiang will increase. The results provide a theoretical reference for the sustainable development of water resources in arid areas.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+T anti-tumor immunity.

Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is emerging as a promising form of chemotherapy utilization. LDM chemotherapy exerts immunomodulatory effects. However, the underlying mechanism is not fully understood. Here we found that suppressing tumor growth by LDM chemotherapy was dependent on the activation of CD8+T cells. LDM chemotherapy potentiated the cytotoxic function of CD8+T cells by stimulating cancer-cell autonomous type I interferon (IFN) induction. Mechanistically, LDM chemotherapy evoked mitochondrial dysfunction and increased reactive oxygen species (ROS) production. ROS triggered the oxidation of cytosolic mtDNA, which was sensed by cGAS-STING, consequently inducing type I IFN production in the cancer cells. Moreover, the cGAS-STING-IFN axis increased PD-L1 expression and predicted favorable clinical responses to chemoimmunotherapy. Antioxidant N-acetylcysteine inhibited oxidized mtDNA-induced type I IFN production and attenuated the efficacy of combination therapy with LDM chemotherapy and PD-L1 blockade. This study elucidates the critical role of intratumoral oxidized mtDNA sensing in LDM chemotherapy-mediated activation of CD8+T cell immune response. These findings may provide new insights for designing combinatorial immunotherapy for cancer patients.

Time-feature attention-based convolutional auto-encoder for flight feature extraction.

Quick Access Recorders (QARs) provide an important data source for Flight Operation Quality Assurance (FOQA) and flight safety. It is generally characterized by large volume, high-dimensionality and high frequency, and these features result in extreme complexities and uncertainties in its usage and comprehension. In this study, we proposed a Time-Feature Attention (TFA)-based Convolutional Auto-Encoder (TFA-CAE) network model to extract essential flight features from QAR data. As a case study, we used the QAR data landing at the Kunming Changshui International Airport and Lhasa Gonggar International Airport as the experimental data. The results show that (1) the TFA-CAE model performs the best in extracting representative flight features in comparison to some traditional or similar approaches, such as Principal Component Analysis (PCA), Convolutional Auto-Encoder (CAE), Self-Attention-based CAE (SA-CAE), Gate Recurrent Unit based Auto-Encoder (GRU-AE) and TFA-GRU-AE models; (2) flight patterns corresponding to different runways can be recognized; and (3) anomalous flights can effectively deviate from many observations. Overall, the TFA-CAE model provides a well-established technique for further usage of QAR data, such as flight risk detection or FOQA.

A novel target state detection method for accurate cardiopulmonary signal extraction based on FMCW radar signals.

Frequency-modulated continuous wave radar is capable of constant, real-time detection of human presence and monitoring of cardiopulmonary signals such as respiration and heartbeat. In highly cluttered environments or when the human body moves randomly, noise signals may be relatively large in some range bins, making it crucial to accurately select the range bin containing the target cardiopulmonary signal. In this paper, we propose a target range bin selection algorithm based on a mixed-modal information threshold. We introduce a confidence value in the frequency domain to determine the state of the human target and employ the range bin variance in the time domain to determine the range bin change status of the target. The proposed method accurately detects the state of the target and effectively selects the range bin containing the cardiopulmonary signal with a high signal-to-noise ratio. Experimental results demonstrate that the proposed method achieves better accuracy in cardiopulmonary signal rate estimation. Moreover, the proposed algorithm is lightweight in data processing and has good real-time performance.

Important role of precipitation in controlling a more uniform spring phenology in the Qinba Mountains, China.

Under global warming, the gradual pattern of spring phenology along elevation gradients (EG) has significantly changed. However, current knowledge on the phenomenon of a more uniform spring phenology is mainly focused on the effect of temperature and neglected precipitation. This study aimed to determine whether a more uniform spring phenology occurs along EG in the Qinba Mountains (QB) and explore the effect of precipitation on this pattern. We used Savitzky-Golay (S-G) filtering to extract the start of season (SOS) of the forest from the MODIS Enhanced Vegetation Index (EVI) during 2001-2018 and determined the main drivers of the SOS patterns along EG by partial correlation analyses. The SOS showed a more uniform trend along EG in the QB with a rate of 0.26 ± 0.01 days 100 m-1 per decade during 2001-2018, but there were differences around 2011. A delayed SOS at low elevations was possibly due to the reduced spring precipitation (SP) and spring temperature (ST) between 2001 and 2011. Additionally, an advanced SOS at high elevations may have been caused by the increased SP and reduced winter temperature (WT). These divergent trends contributed to a significant uniform trend of SOS with a rate of 0.85 ± 0.02 days 100 m-1 per decade. Since 2011, significantly higher SP (especially at low elevations) and rising ST advanced the SOS, and the SOS at lower altitudes was more advanced than at higher altitudes, resulting in greater SOS differences along EG (0.54 ± 0.02 days 100 m-1 per decade). The SP determined the direction of the uniform trend in SOS by controlling the SOS patterns at low elevations. A more uniform SOS may have important effects on local ecosystem stability. Our findings could provide a theoretical basis for establishing ecological restoration measures in areas experiencing similar trends.

Postoperative circulating tumor DNA combined with consensus molecular subtypes can better predict outcomes in stage III colon cancers: A prospective cohort study.

BACKGROUND: Precise methods for risk stratification to guide adjuvant chemotherapy for stage III colon cancers are needed. Here, we combined circulating tumor DNA (ctDNA) with consensus molecular subtype (CMS) to improve risk stratification in stage III colon cancers. METHODS: We conducted a prospective, observational cohort study of 165 patients with stage III colon cancers. Somatic variants in tumor tissues and plasmas collected pre- and post-chemo were detected via a targeted sequencing panel of 197 cancer-related genes. CMSs classification was characterized using a targeted RNA sequencing panel of 788 genes. RESULTS: We analyzed 151 pre-chemo and 124 post-chemo plasmas, while 130 patients were CMSs classified. ctDNA was detectable in 15.9% pre-chemo and 8.9% post-chemo samples. Significantly worse recurrence-free survival (RFS) was seen if ctDNA was detectable in pre-chemo samples (hazard ratio [HR], 3.585; P < 0.001) or in post-chemo samples (HR, 3.337; P = 0.005). Pre-chemo ctDNA (HR, 5.538; P < 0.001) and post-chemo ctDNA status (HR, 3.272; P = 0.037) remained independently associated with RFS in multivariate analysis. According to the redefined recurrence risk stratification, mid-risk patients (ctDNA-negative with CMS4/T4 or N2 tumors) were 5.3 times (HR, 5.269; P = 0.025) more likely to relapse than low-risk patients (ctDNA-negative with CMS1-3/T3N1 tumors), while high-risk patients (ctDNA-positive) were 14.6 times (HR, 14.590; P < 0.001) more likely to relapse. CONCLUSIONS: Postoperative ctDNA indicating residual disease, combined with CMSs classification and clinical risk reflecting the intrinsic characteristics of tumors, can redefine risk stratification of stage III colon cancers and better predict relapse.

5-methylcytosine modification by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes.

5-methylcytosine (m5C) is an important epitranscriptomic modification involved in messenger RNA (mRNA) stability and translation efficiency in various biological processes. However, it remains unclear if m5C modification contributes to the dynamic regulation of the transcriptome during the developmental cycles of Plasmodium parasites. Here, we characterize the landscape of m5C mRNA modifications at single nucleotide resolution in the asexual replication stages and gametocyte sexual stages of rodent (Plasmodium yoelii) and human (Plasmodium falciparum) malaria parasites. While different representations of m5C-modified mRNAs are associated with the different stages, the abundance of the m5C marker is strikingly enhanced in the transcriptomes of gametocytes. Our results show that m5C modifications confer stability to the Plasmodium transcripts and that a Plasmodium ortholog of NSUN2 is a major mRNA m5C methyltransferase in malaria parasites. Upon knockout of P. yoelii nsun2 (pynsun2), marked reductions of m5C modification were observed in a panel of gametocytogenesis-associated transcripts. These reductions correlated with impaired gametocyte production in the knockout rodent malaria parasites. Restoration of the nsun2 gene in the knockout parasites rescued the gametocyte production phenotype as well as m5C modification of the gametocytogenesis-associated transcripts. Together with the mRNA m5C profiles for two species of Plasmodium, our findings demonstrate a major role for NSUN2-mediated m5C modifications in mRNA transcript stability and sexual differentiation in malaria parasites.

The impacts of landscape patterns spatio-temporal changes on land surface temperature from a multi-scale perspective: A case study of the Yangtze River Delta.

Unordered and speedy urbanization is the foremost cause of land surface temperature (LST) rise in an urban area. Understanding the effects of landscape changes on LST is crucial for the urban sustainable development. In this study, we retrieved the LSTs of 26 cities in the Yangtze River Delta Urban Agglomeration with the Landsat images during the summer time (from June to August) of 2000 and 2019. From a multi-scale perspective, i.e. grids of 10 km and 20 km, county and city level, the partial correlation analysis, geographically weighted correlation analysis and local bivariate Moran's I were conducted to explore the influence of the landscape pattern changes of the built-ups on LST change. Our results have shown that, the scale change impacts the relationships between the landscape metric changes of built-ups and the LST change. As the scale upscales, the correlation between different landscape metric changes of built-ups and the LST change continues to increase. Among them, the area-related metrics (percentage and largest patch index) have the most significant impact on LST change, showing a positive correlation. Moreover, there are obvious spatial autocorrelation and spatial spillover effects between the landscape metric changes of built-ups and the LST change. These findings are helpful for understanding regional ecology as well as land use/land cover planning to minimize the negative environmental impacts of urbanization.

Spatial disparities of self-reported COVID-19 cases and influencing factors in Wuhan, China.

The lack of detailed COVID-19 cases at a fine spatial resolution restricts the investigation of spatial disparities of its attack rate. Here, we collected nearly one thousand self-reported cases from a social media platform during the early stage of COVID-19 epidemic in Wuhan, China. We used kernel density estimation (KDE) to explore spatial disparities of epidemic intensity and adopted geographically weighted regression (GWR) model to quantify influences of population dynamics, transportation, and social interactions on COVID-19 epidemic. Results show that self-reported COVID-19 cases concentrated in commercial centers and populous residential areas. Blocks with higher population density, higher aging rate, more metro stations, more main roads, and more commercial point-of-interests (POIs) have a higher density of COVID-19 cases. These five explanatory variables explain 76% variance of self-reported cases using an OLS model. Commercial POIs have the strongest influence, which increase COVID-19 cases by 28% with one standard deviation increase. The GWR model performs better than OLS model with the adjusted R 2 of 0.96. Spatial heterogeneities of coefficients in the GWR model show that influencing factors play different roles in diverse communities. We further discussed potential implications for the healthy city and urban planning for the sustainable development of cities.

Case Report: Long-Term Survival With Anlotinib in a Patient With Advanced Undifferentiated Large-Cell Lung Cancer and Rare Tonsillar Metastasis.

Undifferentiated large-cell lung cancer is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis. It is insensitive to chemotherapy and easily develops drug resistance. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that patients with stage IV undifferentiated large-cell lung cancer had a median overall survival (OS) of only 4 months and that those who received chemotherapy had a median OS of only 5 months longer than those who did not. For the first time, we report a case of advanced large-cell undifferentiated lung cancer with rare tonsil metastasis. The patient developed resistance after 3 months of platinum-based systemic chemotherapy and local treatment. Antiangiogenic therapy has been continuously progressing and has shown certain efficacy in treating many malignant tumors, such as lung cancer. However, there are no relevant studies or case reports on antiangiogenic therapy in the treatment of undifferentiated large-cell lung cancer. Anlotinib, an orally delivered small-molecule antiangiogenic tyrosine kinase inhibitor (TKI), was administered to this patient after chemotherapy resistance occurred, and the outcome was assessed as continued stable disease (SD). As of the last follow-up evaluation, the progression-free survival (PFS) of the patient was 21.5 months, and the OS was 27.5 months. Retrospective immunohistochemical analysis showed that the patient was positive for one of the targets of anlotinib (PDGFR). In general, the findings in this case suggest that anlotinib may be an option with good efficacy for patients with large-cell undifferentiated lung cancer after chemotherapy resistance that may have good efficacy and also suggest that PDGFR may be the target underlying this effect.

A hypoxia risk signature for the tumor immune microenvironment evaluation and prognosis prediction in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia. Patients with AML often have poor clinical prognoses. Hypoxia can activate a series of immunosuppressive processes in tumors, resulting in diseases and poor clinical prognoses. However, how to evaluate the severity of hypoxia in tumor immune microenvironment remains unknown. In this study, we downloaded the profiles of RNA sequence and clinicopathological data of pediatric AML patients from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, as well as those of AML patients from Gene Expression Omnibus (GEO). In order to explore the immune microenvironment in AML, we established a risk signature to predict clinical prognosis. Our data showed that patients with high hypoxia risk score had shorter overall survival, indicating that higher hypoxia risk scores was significantly linked to immunosuppressive microenvironment in AML. Further analysis showed that the hypoxia could be used to serve as an independent prognostic indicator for AML patients. Moreover, we found gene sets enriched in high-risk AML group participated in the carcinogenesis. In summary, the established hypoxia-related risk model could act as an independent predictor for the clinical prognosis of AML, and also reflect the response intensity of the immune microenvironment in AML.

The Architectural Factor HMGB1 Is Involved in Genome Organization in the Human Malaria Parasite Plasmodium falciparum.

The three-dimensional (3D) genome organization plays a critical role in the regulation of gene expression in eukaryotic organisms. In the unicellular malaria parasite Plasmodium falciparum, the high-order chromosome organization has emerged as an important epigenetic pathway mediating gene expression, particularly for virulence genes, but the related architectural factors and underlying mechanism remain elusive. Herein, we have identified the high-mobility-group protein HMGB1 as a critical architectural factor for maintenance of genome organization in P. falciparum Genome-wide occupancy analysis (chromatin immunoprecipitation sequencing [ChIP-seq]) shows that the HMGB1 protein is recruited mainly to centromeric regions likely via a DNA-binding-independent pathway. Chromosome conformation capture coupled with next-generation sequencing (Hi-C-seq) and 3D modeling analysis show that the loss of HMGB1 disrupts the integrity of centromere/telomere-based chromosome organization accompanied with diminished interaction frequency among centromere clusters. This triggers local chromatin alteration and dysregulated gene expression. Notably, the entire repertoire of the primary virulence genes (var) was completely silenced in the absence of P. falciparum HMGB1 (PfHMGB1). Furthermore, the disrupted nuclear organization was reconstituted by complementation of HMGB1, thereby rescuing the mutually exclusive expression of the var gene family. Collectively, these data demonstrate that the architectural factor HMGB1 is associated with gene expression via mediating the high-order structure of genome organization. This finding not only contributes better understanding of the epigenetic regulation of gene expression but may also provide novel targets for antimalarial strategies.IMPORTANCE Malaria remains a major public health and economic burden currently. The mutually exclusive expression of the virulence genes is associated with the pathogenesis and immune evasion of human malaria parasites in the host. The nuclear architecture provides a well-organized environment for differential gene expression in the nucleus, but the underlying mechanism remains largely unknown. In this study, we have identified the highly conserved high-mobility-group protein HMGB1 as a key architecture regulator involved in virulence gene expression by establishing high-order genome organization in the nucleus of P. falciparum Mechanistic investigation revealed that the specific interaction of HMGB1 and centromeres constructed the precisely organized nuclear architecture, which coordinated with local chromatin structure to control the singular expression of virulence genes. Hence, this protein appears to be a critical architectural regulator for the pathogenesis of malaria infection and may be a new target for the development of an intervention strategy against malaria.

SP1 induced long non-coding RNA AGAP2-AS1 promotes cholangiocarcinoma proliferation via silencing of CDKN1A.

BACKGROUND: LncRNA can regulate gene at various levels such as apparent genetics, alternative splicing, and regulation of mRNA degradation. However, the molecular mechanism of LncRNA in cholangiocarcinoma is still unclear. This deserves further exploration. METHODS: We investigated the expression of AGAP2-AS1 in 32 CCA tissues and two CCA cell lines. We found a LncRNA AGAP2-AS1 which induced by SP1 has not been reported in CCA, and Knockdown and overexpression were used to investigate the biological role of AGAP2-AS1 in vitro. CHIP and RIP were performed to verify the putative targets of AGAP2-AS1. RESULTS: AGAP2-AS1 was significantly upregulated in CCA tumor tissues. SP1 induced AGAP2-AS1 plays an important role in tumorigenesis. AGAP2-AS1 knockdown significantly inhibited proliferation and caused apoptosis in CCA cells. In addition, we demonstrated that AGAP2-AS1 promotes the proliferation of CCA. CONCLUSIONS: We conclude that the long non-coding RNA AGAP2-AS1 plays a role in promoting the proliferation of cholangiocarcinoma.

Comparison of Interlaminar and Transforaminal Approaches for Treatment of L5 /S1 Disc Herniation by Percutaneous Endoscopic Discectomy.

OBJECTIVE: The aim of this study was to compare the clinical efficacy of percutaneous endoscopic interlaminar discectomy (PEID) and percutaneous endoscopic transforaminal discectomy (PETD) in treating L5 /S1 disc herniation. METHODS: A retrospective analysis of 76 patients with L5 /S1 intervertebral disc herniation was performed. There were two surgical treatment groups: one with patients receiving PEID and the other with patients receiving PETD. The two groups were compared by length of surgery, times of intraoperative X-ray exposure, postoperative time in bed, length of hospital stay, operative complications, patient's assessment of pain using a visual analogue scale (VAS), and disability using the Oswestry disability index (ODI) before and after surgery. RESULTS: Subjects in the PEID group were in surgery for 60.90 ± 13.11 min and needed intraoperative X-ray exposure 4.10 ± 1.09 times. Patients in this group were ambulatory by 7.52 ± 1.08 h after surgery and were hospitalized for 5.05 ± 0.92 days. In contrast, patients in the PETD group were in surgery for 84.06 ± 15.58 min and needed intraoperative X ray exposure 12.81 ± 8.46 times. These patients were ambulatory by 7.06 ± 0.91 h after surgery and remained in the hospital for 4.94 ± 0.80 days. Based on these data, operation time and fluoroscopy time were significantly less (P < 0.002 and P < 0.001, respectively) for subjects in the PEID group. However, ambulatory time and hospitalization were similar for both in terms of pain relief and decreased disability, and subjects in both groups responded well to the surgery and showed a significant decrease in both VAS and ODI scores at their 1-year follow-up (P < 0.01). Furthermore, there were no statistically significant differences between the two surgeries in terms of pain relief and decrease in disability. CONCLUSION: For L5 /S1 disc herniation, PEID and PETD provide similar results for patients. However, PEID has the advantage over PETD in that it is a shorter procedure and exposes the patient to less radiation.

Strengthening mechanisms of graphene in copper matrix nanocomposites: A molecular dynamics study.

To clarify the strengthening mechanism of coated/embedded graphene in metal matrix nanocomposites, nanoindentation responses of graphene-coated/embedded copper nanocomposites are investigated using molecular dynamics simulations, with the consideration of indentation force-displacement relation, stress distribution, evolution of microstructure and dislocation, and elastic recovery. Results show that two mechanisms, graphene layer bearing surface tensile stress disperses the contact stress and blocks the propagation of dislocations, contribute to the enhanced hardness and improved load bearing capacity, but one is often dominant for different nanocomposites. The former dominates in graphene-coated structure while the latter dominates in graphene-embedded structure, and the reinforcement is more obvious in the coated structure. The graphene delays the plastic deformation of matrix, and its elastic recovery is boosted due to the stress homogenization effect. The embedded graphene promotes the stress concentration and accelerates the plastic deformation of up Cu film, weakening its width elastic recovery. The observations will provide a practical guide for the mechanical optimization and design of metal-graphene nanocomposites.

LncRNA UCA1 Induces Acquired Resistance to Gefitinib by Epigenetically Silencing CDKN1A Expression in Non-small-Cell Lung Cancer.

Lung cancer is the most common cancer globally and is associated with high morbidity and mortality. Gefitinib has been widely used for treating advanced non-small-cell lung cancer (NSCLC). However, acquired resistance usually develops, although we still know little about the mechanism underlying this. In the present study, we found that the lncRNA UCA1 was upregulated in NSCLC tissues and cells with acquired gefitinib resistance, indicating the special role of UCA1 in gefitinib resistance. Knockdown of UCA1 promoted the sensitivity to gefitinib both in vitro and in vivo by suppressing cell proliferation and inducing apoptosis. Moreover, UCA1 could interact with EZH2 (enhancer of zeste homolog 2) to epigenetically reduce the expression of CDKN1A. Taking the obtained findings together, our study suggests that UCA1 is important for NSCLC to develop gefitinib resistance, and is a potential biomarker for gefitinib resistance and a therapeutic target for advanced NSCLC.

Integrative Analysis of NSCLC Identifies LINC01234 as an Oncogenic lncRNA that Interacts with HNRNPA2B1 and Regulates miR-106b Biogenesis.

The discovery of long noncoding RNAs (lncRNAs) has increased our understanding of the development and progression of many cancers, but their contributions to non-small cell lung cancer (NSCLC) remain poorly understood. Here, we profiled lncRNA expression in NSCLC and investigated in detail the molecular function of one upregulated lncRNA, LINC01234. LINC01234 was overexpressed in NSCLC compared with normal lung tissue and correlated positively with poor prognosis. Downregulation of LINC01234 impaired cell proliferation in vitro and tumor growth in vivo. RNA pull-down/mass spectrometry experiments showed that LINC01234 interacted with the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), which, in turn, led to the recruitment of DiGeorge syndrome critical region gene 8 (DGCR8), a subunit of the microRNA (miRNA) microprocessor complex. Accordingly, depletion of either LINC01234 or HNRNPA2B1 reduced the processing of several miRNA precursors, including primary microRNA (pri-miR)-106b. miR-106b-5p enhanced NSCLC cell growth by downregulating cryptochrome 2 (CRY2), thereby increasing c-Myc expression. Finally, we found that activated c-Myc binds to the LINC01234 promoter to increase its transcription, creating a c-Myc-LINC01234-HNRNPA2B1-miR-106b-5p-CRY2-c-Myc positive-feedback loop. We identified numerous lncRNAs with dysregulated expression in NSCLC and demonstrated a novel oncogenic axis involving LINC01234, HNRNPA2B1, miR-106b-5p, CRY2, and c-Myc. Components of this axis may be potential novel targets for NSCLC.