Mix-Key: graph mixup with key structures for molecular property prediction.

Molecular property prediction faces the challenge of limited labeled data as it necessitates a series of specialized experiments to annotate target molecules. Data augmentation techniques can effectively address the issue of data scarcity. In recent years, Mixup has achieved significant success in traditional domains such as image processing. However, its application in molecular property prediction is relatively limited due to the irregular, non-Euclidean nature of graphs and the fact that minor variations in molecular structures can lead to alterations in their properties. To address these challenges, we propose a novel data augmentation method called Mix-Key tailored for molecular property prediction. Mix-Key aims to capture crucial features of molecular graphs, focusing separately on the molecular scaffolds and functional groups. By generating isomers that are relatively invariant to the scaffolds or functional groups, we effectively preserve the core information of molecules. Additionally, to capture interactive information between the scaffolds and functional groups while ensuring correlation between the original and augmented graphs, we introduce molecular fingerprint similarity and node similarity. Through these steps, Mix-Key determines the mixup ratio between the original graph and two isomers, thus generating more informative augmented molecular graphs. We extensively validate our approach on molecular datasets of different scales with several Graph Neural Network architectures. The results demonstrate that Mix-Key consistently outperforms other data augmentation methods in enhancing molecular property prediction on several datasets.

circTOP2A functions as a ceRNA to promote glioma progression by upregulating RPN2.

Competing endogenous RNA (ceRNA)-mediated signaling pathway dysregulation provides great insight into comprehensively understanding the molecular mechanism and combined targeted therapy for glioblastoma. circRNA is characterized by high stability, tissue/developmental stage-specific expression and abundance in brain and plays significant roles in the initiation and progression of cancer. Our previous published data have demonstrated that RPN2 was significantly upregulated in glioma and promoted tumor progression via the activation of the Wnt/ß-catenin pathway. Furthermore, we proved that miR-422a regulated the Wnt/ß-catenin signaling pathway by directly targeting RPN2. In this study, based on the glioblastoma microarray profiles, we identified the upstream circTOP2A, which completely bound to miR-422a and was co-expressed with the RPN2. circTOP2A was significantly overexpressed in glioma and conferred a poor prognosis. circTOP2A could regulate RPN2 expression by sponging miR-422a, verified by western blot, dual-luciferase reporter gene assay, and RNA pull-down assay. Functional assays including CCK8, transwell and FITC-annexin V were performed to explore the RPN2-mediated role of the circTOP2A effect on the glioma malignant phenotype. Additionally, TOP/FOP and immunofluorescence analysis were used to confirm that sh-circTOP2A could suppress the Wnt/ß-catenin pathway partly through RPN2. Finally, a tumor xenograft model was applied to validate the biological function of circTOP2A in vivo. Taken together, our findings reveal the critical role of circTOP2A in promoting glioma proliferation and invasion via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for glioma patients.

Analysis of the impact of fatty acid metabolism on immunotherapy for hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC), a malignancy with a very dismal prognosis, has drawn a lot of attention, particularly in East Asia, where morbidity and mortality are higher. Although new information about the role of fatty acids (FAs) in HCC is constantly being discovered, it is still vital to investigate how FA metabolism affects the prognosis, immune microenvironment, and responsiveness of HCC to immunotherapy as a whole. MATERIALS AND METHODS: To determine the significance of FA metabolism in HCC immunotherapy, we first evaluated HCC samples from the single-cell dataset GSE151530. The TCGA-LIHC cohort and GSE140901 were further studied to identify the impact of FA metabolism on prognosis, immune microenvironment, drug sensitivity, and immunotherapy response by developing a fatty acid prediction index (FPI). The heterogeneity and similarity of the involvement of FA metabolism in pan-cancer is also investigated. RESULTS: Combining single-cell and bulk analyses, we confirmed that FA metabolism regulates tumor malignancy, prognosis, immune microenvironment, drug sensitivity, and immunotherapy response in patients with HCC. Moreover, it can have a considerable impact on the physiological activities of hepatocellular cancer. In addition, we demonstrate that FA metabolism has a comparable or same role in many malignancies. CONCLUSIONS: Our investigation shows the crucial regulatory role of FA metabolism in HCC and suggests a potential therapeutic method for HCC patients, which may improve their survival.

Visualizing the Anomalous Catalysis in Two-Dimensional Confined Space.

Confined nanospaces provide a new platform to promote catalytic reactions. However, the mechanism of catalytic enhancement in the nanospace still requires insightful exploration due to the lack of direct visualization. Here, we report operando investigations on the etching and growth of graphene in a two-dimensional (2D) confined space between graphene and a Cu substrate. We observed that the graphene layer between the Cu and top graphene layer was surprisingly very active in etching (more than 10 times faster than the etching of the top graphene layer). More strikingly, at a relatively low temperature (∼530 °C), the etched carbon radicals dissociated from the bottom layer, in turn feeding the growth of the top graphene layer with a very high efficiency. Our findings reveal the in situ dynamics of the anomalous confined catalytic processes in 2D confined spaces and thus pave the way for the design of high-efficiency catalysts.

Engineering Interlayer Electron-Phonon Coupling in WS2/BN Heterostructures.

In van der Waals (vdW) heterostructures, the interlayer electron-phonon coupling (EPC) provides one unique channel to nonlocally engineer these elementary particles. However, limited by the stringent occurrence conditions, the efficient engineering of interlayer EPC remains elusive. Here we report a multitier engineering of interlayer EPC in WS2/boron nitride (BN) heterostructures, including isotope enrichments of BN substrates, temperature, and high-pressure tuning. The hyperfine isotope dependence of Raman intensities was unambiguously revealed. In combination with theoretical calculations, we anticipate that WS2/BN supercells could induce Brillouin-zone-folded phonons that contribute to the interlayer coupling, leading to a complex nature of broad Raman peaks. We further demonstrate the significance of a previously unexplored parameter, the interlayer spacing. By varying the temperature and high pressure, we effectively manipulated the strengths of EPC with on/off capabilities, indicating critical thresholds of the layer-layer spacing for activating and strengthening interlayer EPC. Our findings provide new opportunities to engineer vdW heterostructures with controlled interlayer coupling.

Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.

Multiplex ligation-dependent probe amplification identifies copy number changes in normal and undetectable karyotype MDS patients.

Chromosomal abnormalities play an important role in classification and prognostication of myelodysplastic syndrome (MDS) patients. However, more than 50% of low-risk MDS patients harbor a normal karyotype. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MDS patients. To characterize the subset of MDS with normal karyotype or failed chromosome banding analysis, we analyzed 144 patient samples with normal karyotype or undetectable through regular chromosome banding analysis, which were subjected to parallel comparison via fluorescence in situ hybridization (FISH) and MLPA. MLPA identifies copy number changes in 16.7% of 144 MDS patients, and we observed a significant difference in overall survival (OS) (median OS: undefined vs 27 months, p=0.0071) in patients with normal karyotype proved by MLPA versus aberrant karyotype cohort as determined by MLPA. Interestingly, patients with undetectable karyotype via regular chromosome banding indicated inferior outcome. Collectively, MDS patients with normal or undetectable karyotype via chromosome banding analysis can be further clarified by MLPA, providing more prognostic information that benefit for individualized therapy.

Bioinformatics analysis of microarray data reveals epithelial-mesenchymal-transition in pediatric ependymoma.

The objectives of this study were to explore the possible mechanisms of pediatric ependymoma using bioinformatics methods and provide potential genes and signaling pathways for pediatric ependymoma study. The data of GES74195 from Gene Expression Ominibus was analyzed by R language for pediatric ependymoma study. The differentially expressed genes were explored using gene set enrichment analysis, search tool for the retrieval of interacting genes, Cytoscape as well as other mainstream bioinformatics methods. Extracellular matrix-receptors interaction pathways and focal adhesion pathway were demonstrated as the key signaling pathway for pediatric ependymoma. The potential hub genes enriched in the two signaling pathways were regarded as final hub genes for this microarray analysis. The development and progression of pediatric ependymoma were associated with epithelial-mesenchymal-transition. Various potential hub genes and potential key signaling pathways in order to further explore their values in the diagnosis and treatment of this disease in the future.

Ultrafast Optical Modulation of Harmonic Generation in Two-Dimensional Materials.

The modulation of optical harmonic generation in two-dimensional (2D) materials is of paramount importance in nanophotonic and nano-optoelectronic devices for their applications in optical switching and communication. However, an effective route with ultrafast modulation speed, ultrahigh modulation depth, and broad operation wavelength range is awaiting a full exploration. Here, we report that an optical pump can dynamically modulate the third harmonic generation (THG) of a graphene monolayer with a relative modulation depth above 90% at a time scale of 2.5 ps for a broad frequency ranging from near-infrared to ultraviolet. Our observation, together with the real-time, time-dependent density functional theory (TDDFT) simulations, reveals that this modulation process stems from nonlinear dynamics of the photoexcited carriers in graphene. The superior performance of the nonlinear all-optical modulator based on 2D materials paves the way for its potential applications including nanolasers and optical communication circuits.

Functions and clinical significance of circular RNAs in glioma.

CircRNAs are a class of single-stranded RNA molecules with a covalently closed loop structure and have been characterized by high stability, abundance, conservation, and display tissue/developmental stage-specific expression, furthermore, based on the abundance in distinct body fluids or exosomes, circRNAs present novel biomarkers and targets for the diagnosis and prognosis of cancers. Recently, the regulatory mechanisms of biogenesis and molecular functions, including miRNAs and RBPs sponge, translation as well as transcriptional and splicing regulation, have been gradually uncovered, although various aspects remained to be elucidated in combination with deep-sequence and bioinformatics. Accumulating studies have indicated that circRNAs are more enriched in neuronal tissues partly due to the abundance of specific genes promoting circularization, suggesting dysregulation of circRNAs is closely related to diseases of the nervous system, including glioma. In this review, we elaborate on the biogenesis, functions, databases as well as novel advances especially involved in the molecular pathways, highlight its great value as diagnostic or therapeutic targets in glioma.

FTX contributes to cell proliferation and migration in lung adenocarcinoma via targeting miR-335-5p/NUCB2 axis.

BACKGROUND: Extensive studies revealed that long non-coding RNAs (lncRNAs) could act as a regulator in tumors, including lung adenocarcinoma (LUAD). LncRNA FTX transcript, XIST regulator (FTX) has been reported to regulate the biological behaviors of some cancers. Nevertheless, its functional role and molecular mechanism remain obscure in LUAD. Our current study concentrates on exploring the biological function of FTX in LUAD. METHODS: RT-qPCR was used to test the expression of FTX, miR-335-5p or NUCB2 in LUAD cells. The effect of FTX on LUAD progression was investigated by colony formation, EdU, flow cytometry, TUNEL, transwell and western blot assays. The interaction between microRNA-335-5p (miR-335-5p) and FTX or nucleobindin 2 (NUCB2) was confirmed by luciferase reporter assay. RESULTS: RT-qPCR showed that FTX expression was up-regulated in LUAD cell lines. Loss-of-function assay indicated that FTX accelerated cell proliferation, migration and invasion, while inhibited cell apoptosis in LUAD. Besides, miR-335-5p, lowly expressed in LUAD cells, was discovered to be sponged by FTX. Subsequently, NUCB2 was identified as a target gene of miR-335-5p. Additionally, it was confirmed that NUCB2 functioned as an oncogene in LUAD. Rescue assays indicated that LUAD progression inhibited by FTX knockdown could be restored by NUCB2 up-regulation. CONCLUSION: FTX played an oncogenic role in LUAD and contributed to cancer development via targeting miR-335-5p/NUCB2 axis.

Laser annealing towards high-performance monolayer MoS2 and WSe2 field effect transistors.

The transition metal dichalcogenides (TMDCs) have been intensively investigated as promising nanoelectronic and optoelectronic materials. However, the pervasive adsorbates on the surfaces of monolayer TMDCs, including oxygen and water molecules from the ambient environment, tend to degrade the device performance, thus hindering specific applications. In this work, we report the effect of laser irradiation on the transport and photoresponse of monolayer MoS2 and WSe2 devices, and this laser annealing process is demonstrated as a straightforward approach to remove physically adsorbed contaminants. Compared to vacuum pumping and in situ thermal annealing treatments, the field-effect transistors after laser annealing show a more than one order of magnitude higher on-state current, and no apparent degradation of device performance at low temperatures. The mobility of the monolayer WSe2 devices can be enhanced by three to four times, and for single-layered MoS2 devices with the commonly used SiO2 as the back-gate, the mobility increases by 20 times, reaching [Formula: see text]. The efficient cleaning effect of laser annealing is also supported by the reduction of channel and contact resistance revealed by a transmission line experiment. Further, an enhanced photocurrent, by a factor of ten, has been obtained in the laser annealed device. These findings pave the way for high-performance monolayer TMDC-based electronic and optoelectronic devices with a clean surface and intrinsic properties.

Genome wide analyses uncover allele-specific RNA editing in human and mouse.

RNA editing is one of the most common RNA level modifications that potentially generate amino acid changes similar to those resulting from genomic nonsynonymous mutations. However, unlike DNA level allele-specific modifications such as DNA methylation, it is currently unknown whether RNA editing displays allele-specificity across tissues and species. Here, we analyzed allele-specific RNA editing in human tissues and from brain tissues of heterozygous mice generated by crosses between divergent mouse strains and found a high proportion of overlap of allele-specific RNA editing sites between different samples. We identified three allele-specific RNA editing sites cause amino acid changes in coding regions of human and mouse genes, whereas their associated SNPs yielded synonymous differences. In vitro cellular experiments confirmed that sequences differing at a synonymous SNP can have differences in a linked allele-specific RNA editing site with nonsynonymous implications. Further, we demonstrate that allele-specific RNA editing is influenced by differences in local RNA secondary structure generated by SNPs. Our study provides new insights towards a better comprehension of the molecular mechanism that link SNPs with human diseases and traits.

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary.

The timing of the diversification of placental mammals relative to the Cretaceous-Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms.

Adversarial attack on BC classification for scale-free networks.

Adversarial attacks have been alerting the artificial intelligence community recently since many machine learning algorithms were found vulnerable to malicious attacks. This paper studies adversarial attacks on Broido and Clauset classification for scale-free networks to test its robustness in terms of statistical measures. In addition to the well-known random link rewiring (RLR) attack, two heuristic attacks are formulated and simulated: degree-addition-based link rewiring (DALR) and degree-interval-based link rewiring (DILR). These three strategies are applied to attack a number of strong scale-free networks of various sizes generated from the Barabási-Albert model and the uncorrelated configuration model. It is found that both DALR and DILR are more effective than RLR in the sense that rewiring a smaller number of links can succeed in the same attack. However, DILR is as concealed as RLR in the sense that they both are introducing a relatively small change on several typical structural properties, such as the average shortest path-length, the average clustering coefficient, the average diagonal distance, and the Kolmogorov-Smirnov test of the degree distribution. The results of this paper suggest that to classify a network to be scale-free, one has to be very careful from the viewpoint of adversarial attack effects.

Dietary and serum selenium in coronary heart disease and all-cause mortality: An international perspective.

BACKGROUND AND OBJECTIVES: The objective of this study was to explore the associations of dietary selenium and serum selenium concentration with coronary heart disease (CHD) prevalence and all-cause mortality among participants in United States. METHODS AND STUDY DESIGN: Using data collected from the National Health and Nutrition Examination Survey (NHANES) 1999-2006, 17867 individuals were included. Logistic regression analyses were used to explore the associations between dietary selenium intake and serum selenium concentration and prevalent of CHD. Multivariable Cox regression was used to identify the association between dietary selenium intake and all-cause mortality. The nonlinear relationships were assessed using generalized additive models. RESULTS: A U-shaped association between dietary intake of selenium and all-cause mortality was observed. Compared with the lowest quartile, the second quartile of dietary intake of selenium was inversely associated with all-cause mortality (Hazard ratio [HR]: 0.802, 95% confidence interval [CI]: 0.658, 0.977, p=0.029). There was no evidence of association between dietary selenium intake and CHD risk (Odds ratio [OR]: 1.001, 95% CI: 0.999, 1.003, p=0.206). Furthermore, serum selenium concentration was negatively associated with CHD risk (OR: 0.989, 95% CI: 0.981, 0.997, p=0.006). Comparing with the lowest quartile, participants with the highest serum selenium concentration had a statistically significant decreased prevalence of CHD, with OR (95% CI) of 0.417 (0.259, 0.669) (p<0.001). The smoothing curve also showed a non-linear relationship between serum selenium and risk of CHD. CONCLUSIONS: This analysis suggested that a higher serum selenium concentration was associated with reduced risk of CHD, and that the relationship was non-linear. In addition, an appropriate dietary selenium intake might reduce all-cause mortality.

The effect of thymopentin add-on in hepatitis B e antigen positive chronic hepatitis B after virus suppression by peginterferon plus entecavir therapy.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) was positively correlated with serological hepatitis B surface antigen (HBsAg) levels in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. We evaluated whether Thymopentin (TP5) and interferon (IFN-a) had a synergic effect on HBV cccDNA and the effect of TP5 addition therapy on HBsAg clearance in CHB patients. Real-time PCR experiments were performed to test cccDNA in HepG2.2.15 cells. 45 HBeAg-positive CHB patients had been distributed into two groups randomly. Treatment group: 23 patients were treated with a 24-week TP5 on the basis of the treatment entecavir (ETV) and peginterferon alfa-2a (PegIFN alpha-2a). Control group: 22 patients were treated with ETV and PegIFNa-2a. The study period was 72 weeks. In HepG2.2.15 cells, TP5 5ug/ml and 10ug/ml respectively combined with IFN-a 2ku/ml could potently inhibit cccDNA level at 72 hours (P<0.05). In clinical study, mean HBsAg levels in two groups are not significantly different at different time points (p=0.112). However, changes of mean HBsAg levels in TP5 add-on group at different time points are significantly different (p<0.05). Patients with HBsAg levels <1500IU/ml in control group had higher HBsAg levels compared with patients with HBsAg levels <1500IU/ml in TP5 add-on group (P=0.019). The latter had the most pronounced HBsAg reduction. TP5 and IFN had a synergic effect on inhibiting cccDNA levels in HepG2.2.15 cells; Patients in treatment group showed no extra side effects compared with the control group. 24 weeks TP5 add-on treatment was safe and had a tendency to accelerate the decline of HBsAg when HBV-DNA was undetectable.

Tumor-induced mortality in adult primary supratentorial glioblastoma multiforme with different age subgroups.

AIM: To assess the independent determinants of tumor-induced mortality in different age subgroups after considering competing risk (CR). METHODS: Data were extracted from the SEER database. The independent determinants of tumor-induced mortality were defined by CR analysis and validated by conditional inference trees. A CR nomogram was created based on the proportional subdistribution hazard model. RESULTS: The different age subgroups had their own independent determinants of tumor-induced mortality. Using these variables, a CR nomogram was built with good discrimination and calibration. CONCLUSION: When conducting population-based cohort studies, a CR analysis is recommended for cancers with short survival and high mortality. A CR nomogram represents the first attempt at a predictive model for quantifying tumor-induced mortality.

Correlation Between Liver Stiffness Measured by Shear Wave Elastography and Child-Pugh Classification.

OBJECTIVES: To explore the association between liver stiffness and the Child-Pugh classification of liver function by shear wave elastography (SWE). METHODS: A total of 116 patients with liver cirrhosis were divided into 3 groups according to the Child-Pugh classification prospectively. Conventional ultrasound imaging and SWE were performed for all patients. The associations of liver stiffness measured by SWE with ultrasound measurements, serum biochemical indicators, and the Child-Pugh classification were analyzed. Receiver operating characteristic curves were analyzed and compared to determine the ability of liver stiffness to diagnose cirrhosis. RESULTS: Liver stiffness measured by SWE increased with an increasing Child-Pugh classification, internal diameter of the hepatic portal and splenic veins, spleen thickness, spleen length, total bilirubin level, and prothrombin time, which were positively correlated with the Child-Pugh classification (all P < .05). The albumin level and liver stiffness showed higher areas under the curve in comparison with other parameters for evaluating the Child-Pugh classification. Albumin and cholinesterase levels were negatively correlated with the Child-Pugh classification (P < .05). All of these indicators were significantly different between each pair of groups (all P < .05), except for the internal diameter of the hepatic portal vein, prothrombin time, and total bilirubin, and cholinesterase levels between groups B and C (P > 0.05) and the thickness and length of spleen and internal diameter of the splenic vein between groups A and B (P > 0.05). There were no differences among the groups for alanine aminotransferase, aspartate aminotransferase, and globulin levels. CONCLUSIONS: Liver stiffness measured by SWE was correlated with the Child-Pugh classification, and it may be able to help evaluate liver function in patients with cirrhosis.