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The highly dispersed ultrasmall palladium nanoparticles (Pd NPs) (1.7 nm) were successfully immobilized on a N-containing metal-organic framework (MOF, DUT-67-PZDC) using a co-reduction method, and it is used as an excellent catalyst for formic acid dehydrogenation (FAD). The optimized catalyst Pd/DUT-67-PZDC(10, 10 wt% Pd loading) shows 100% hydrogen (H 2 ) selectivity and formic acid (FA) conversion at 60 °C, and the commendable initial turnover frequency (TOF) values of 2572 h -1 with the sodium formate (SF) as an additive and 1059 h -1 even without SF, which is better than most reported MOF supported Pd monometallic heterogeneous catalysts. The activation energy (Ea) of FAD is 43.2 KJ/mol, which is lower than most heterogeneous catalysts. In addition, the optimized catalyst Pd/DUT-67-PZDC(10) maintained good stability over five consecutive runs, demonstrating only minimal decline in catalytic activity. The outstanding catalytic performance could be ascribed to the synergistic corporations of the unique structure of DUT-67-PZDC carrier with hierarchical pore characteristic, the metal-support interaction (MSI) between the active Pd NPs and DUT-67-PZDC, the highly dispersed Pd NPs with ultrafine size serve as the catalytic active site, as well as the N sites on the support could act as the proton buffers. This work provides a new paradigm for the efficient H 2 production of FAD by constructing highly active heterogeneous Pd-based catalysts using MOF supports., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human Na+-taurocholate cotransporting polypeptide (hNTCP) is predominantly expressed in hepatocytes, maintaining bile salt homeostasis and serving as a receptor for hepatitis B virus (HBV). hNTCP expression is downregulated during hepatocellular carcinoma (HCC) development. In this study, we investigated the molecular mechanisms underlying hNTCP dysregulation using HCC tissues and cell lines, and primary human hepatocytes (PHHs). Firstly, we observed a significant reduction of hNTCP in HCC tumors compared to adjacent and normal tissues. Additionally, h NTCP mRNA levels were markedly lower in HepG2 cells compared to PHHs, which was corroborated at the protein level by immunoblotting. Sanger sequencing confirmed identical sequences for h NTCP promoter, exons, and mRNA coding sequences between PHH and HepG2 cells, indicating no mutations or splicing alterations. We then assessed the epigenetic status of h NTCP . The h NTCP promoter, with low CG content, showed no significant methylation differences between PHH and HepG2 cells. Chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR) revealed a loss of activating histone posttranslational modification (PTM) H3K27ac near the h NTCP transcription start site (TSS) in HepG2 cells. This loss was also confirmed in HCC tumor cells compared to adjacent and background cells. Treating HepG2 cells with histone deacetylase inhibitors enhanced H3K27ac accumulation and glucocorticoid receptor (GR) binding at the h NTCP TSS, significantly increasing h NTCP mRNA and protein levels, and rendering the cells susceptible to HBV infection. In summary, histone PTM-related epigenetic mechanisms play a critical role in hNTCP dysregulation in liver cancer cells, providing insights into hepatocarcinogenesis and its impact on chronic HBV infection., Importance: HBV is a hepatotropic virus that infects human hepatocytes expressing the viral receptor hNTCP. Without effective antiviral therapy, chronic HBV infection poses a high risk of liver cancer. However, most liver cancer cell lines, including HepG2 and Huh7, do not support HBV infection due to the absence of hNTCP expression, and the mechanism underlying this defect remains unclear. This study demonstrates a significant reduction of hNTCP in hepatocellular carcinoma samples and HepG2 cells compared to normal liver tissues and primary human hepatocytes. Despite identical h NTCP genetic sequences, epigenetic analyses revealed a loss of the activating histone modification H3K27ac near the h NTCP transcription start site in cancer cells. Treatment with histone deacetylase inhibitors restored H3K27ac levels, reactivated h NTCP expression, and rendered HepG2 cells susceptible to HBV infection. These findings highlight the role of epigenetic modulation in h NTCP dysregulation, offering insights into hepatocarcinogenesis and its implications for chronic HBV infection., Competing Interests: The authors declare no conflict of interest.

Cone Beam Computed Tomography (CBCT) plays a vital role in clinical imaging. Traditional methods typically require hundreds of 2D X-ray projections to reconstruct a high-quality 3D CBCT image, leading to considerable radiation exposure. This has led to a growing interest in sparse-view CBCT reconstruction to reduce radiation doses. While recent advances, including deep learning and neural rendering algorithms, have made strides in this area, these methods either produce unsatisfactory results or suffer from time inefficiency of individual optimization. In this paper, we introduce a novel geometry-aware encoder-decoder framework to solve this problem. Our framework starts by encoding multi-view 2D features from various 2D X-ray projections with a 2D CNN encoder. Leveraging the geometry of CBCT scanning, it then back-projects the multi-view 2D features into the 3D space to formulate a comprehensive volumetric feature map, followed by a 3D CNN decoder to recover 3D CBCT image. Importantly, our approach respects the geometric relationship between 3D CBCT image and its 2D X-ray projections during feature back projection stage, and enjoys the prior knowledge learned from the data population. This ensures its adaptability in dealing with extremely sparse view inputs without individual training, such as scenarios with only 5 or 10 X-ray projections. Extensive evaluations on two simulated datasets and one real-world dataset demonstrate exceptional reconstruction quality and time efficiency of our method.

The aim of this study was to evaluate the effect of conjugated linoleic acid (CLA) on milk fat globule (MFG) size and the ruminal microbiome of goats. Twenty-four mid-lactation Saanen dairy goats weighing 49 ± 4.5 kg (168 ± 27 d in milk, 1.2 ± 0.1 kg milk/d, 2-3 years old) were randomly divided into four groups-a control (CON) group, which was fed a basal diet, and three CLA supplementation groups, in which 30 g CLA (low-dose group, L-CLA), 60 g CLA (medium-dose group, M-CLA), or 90 g CLA (high-dose group, H-CLA) was added to the basal diet daily. The experiment lasted for 21 days, during which time goat milk was collected for composition and MFG size analysis. On day 21 of feeding, ruminal fluid was collected from the CON and H-CLA groups for analysis of the changes in microorganismal abundance. The results showed that CLA supplementation did not affect milk production, milk protein, or lactose content in the dairy goats ( p > 0.05), but significantly reduced the milk fat content ( p < 0.01) compared with the CON group. The CLA supplementation significantly decreased the D [3,2] and D [4,3] of the MFGs in a dose-dependent manner ( p < 0.01). Moreover, dietary CLA inclusion increased the proportion of small-sized MFGs and decreased that of large-sized ones. The results of 16S rRNA gene sequencing showed that CLA-induced milk fat depression in dairy goats was accompanied by significant changes in the relative abundance of ruminal bacterial populations, most of which belonged to the Firmicutes and Bacteroidetes phyla. The relative abundance of Rikenellaceae&#95;RC9&#95;gut&#95;group and Prevolellaceae&#95;UCG-003 in Bacteroidetes and UCG-002 , Succiniclasticum , and norank&#95;f&#95;&#95;norank&#95;o&#95;&#95; Clostridia&#95;vadinBB60&#95; group in Firmicutes was significantly higher in the CON group than in the H-CLA group. In contrast, the relative abundance of norank&#95;f&#95;&#95; UCG-011 , norank&#95;f&#95; Eubacterium&#95;coprostanoligenes &#95;group, unclassified&#95;f&#95;&#95; Lachnospiraceae , and UCG-001 in Firmicutes and norank&#95;f&#95;&#95; Muribaculaceae in Bacteroidetes was significantly higher in the H-CLA group than in the CON group. Correlation analysis showed that the milk fat content was negatively correlated with the relative abundance of some bacteria, including members of Firmicutes and Bacteroidetes. Similarly, MFG size (D [3,2] and D [4,3] ) was negatively correlated with several members of Firmicutes and Bacteroidetes, including Lachnospiraceae , norank&#95;f&#95;&#95; UCG-011 , UCG-001 , norank&#95;f&#95;&#95; Eubacterium&#95;coprostanoligenes &#95;group (Firmicutes), and norank&#95;f&#95;&#95; Muribaculaceae (Bacteroidetes), while positively correlated with the relative abundance of some members of Firmicutes and Bacteroidetes, including Mycoplasma , Succiniclasticum , norank&#95;f&#95;&#95;norank&#95;o&#95;&#95; Clostridia&#95;vadinBB60&#95; group, UCG-002 (Firmicutes), and Rikenellaceae&#95;RC9&#95;gut&#95; group (Bacteroidetes). Overall, our data indicated that CLA treatment affected milk fat content and MFG size in dairy goats, and these effects were correlated with the relative abundance of ruminal bacterial populations. These results provide the first evidence to explain the mechanism underlying diet-induced MFG from the perspective of the ruminal microbiome in dairy goats.

Developing heterogeneous catalysts with exceptional catalytic activity over formic acid (HCOOH, FA) dehydrogenation is imperative to employ FA as an effective hydrogen (H 2 ) carrier. In this work, ultrasmall (1.4 nm) and well-dispersed PdIr nanoparticles (NPs) immobilized on amine-functionalized yolk-shell mesoporous silica nanospheres (YSMSNs) with radially oriented mesoporous channels have been synthesized by a co-reduction strategy. The optimized catalyst Pd 4 Ir 1 /YSMSNs-NH 2 (Pd/Ir molar ratio = 4:1) exhibited a remarkable turnover frequency (TOF) of 5818 h -1 and remarkable stability at 50 °C with the addition of sodium formate (SF), resulting in complete FA conversion and H 2 selectivity, exceeding most of the solid heterogeneous catalysts in previous reports under similar circumstances. Kinetic isotope effect (KIE) exploration indicates the cleavage of the CH bond is regarded as the rate-determining step (RDS) during the FA dehydrogenation process. Such excellent catalytic properties arise from the ultrafine and well-dispersed PdIr NPs supported on the nanosphere support YSMSNs-NH 2 , the electronic synergistic effect of PdIr alloy NPs, and the strong metal-support interaction (MSI) effect between the introduced PdIr NPs and YSMSNs-NH 2 support. This work offers a new paradigm for exploiting the highly effective silica-supported Pd-based heterogeneous catalysts over the dehydrogenation of FA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In milk, fat exists in the form of milk fat globules (MFGs). The average size (average fat globules of different particle sizes) is the most common parameter when describing MFG size. There are different views on whether there is a correlation between MFG size and milk fat content. Is the MFG size correlated with milk fat content in ruminants? To address this question, we conducted two experiments. In experiment Ⅰ, dairy cows (n = 40) and dairy goats (n = 30) were each divided into a normal group and a low-fat group according to the milk fat content. In experiment Ⅱ, dairy cows (n = 16) and dairy goats (n = 12) were each divided into a normal group and a conjugated linoleic acid (CLA)-induced low-fat group. The normal groups were fed a basal diet, and the CLA-induced low-fat groups were fed the basal diet + 300 g/d CLA (cows) or the basal diet + 90 g/d CLA (goats). In both experiments, we determined the correlation between MFG size and milk composition and MFG distribution. The results showed that in the normal and low-fat groups of cows and goats, MFG size was not correlated with milk fat, protein, or lactose content or fat-to-protein ratio. Additionally, there was no difference in the distribution of large, medium, and small MFGs (P > 0.05). However, in the CLA-induced low-fat groups, we found a correlation between MFG size and milk fat content and fat-to-protein ratio (R 2  > 0.3). Moreover, there was a significant change in the size distribution of MFGs. Therefore, in natural milk, MFG size was not correlated with milk fat content. Following CLA supplementation, MFG size was correlated with milk fat content. Our findings revealed that CLA and not milk fat affects MFG distribution and size., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning tool based on a deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and the cancer and tissue classification yields performance rates of 99.8 ± 0.2% and 95.0 ± 2.3%, respectively. A benchmark analysis suggests that the proposed model outperforms traditional generative models such as the variational autoencoder. In metastatic subtype classification, our generated samples show 97.6% predicting power compared to true metastatic samples. Additionally, we demonstrate MetGen's interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironments, such as immune responses and the metastasis process, which can potentially foster a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer.

Supercapacitors are widely used in many fields owing to their advantages, such as high power, good cycle performance, and fast charging speed. Among the many metal-oxide cathode materials reported for supercapacitors, NiMoO 4 is currently the most promising electrode material for high-specific-energy supercapacitors. We have employed a rational design approach to create a nanorod-like NiMoO 4 structure, which serves as a conductive scaffold for supercapacitors; the straightforward layout has led to outstanding results, with nanorod-shaped NiMoO 4 exhibiting a remarkable capacity of 424.8 F g -1 at 1 A g -1 and an impressive stability of 80.2% capacity preservation even after 3500 cycles, which surpasses those of the majority of previously reported NiMoO 4 materials. NiMoO 4 //AC supercapacitors demonstrate a remarkable energy density of 46.31 W h kg -1 and a power density of 0.75 kW kg -1 . This synthesis strategy provides a facile method for the fabrication of bimetallic oxide materials for high-performance supercapacitors., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Two-dimensional arrays of magnetically coupled nanomagnets provide a mesoscopic platform for exploring collective phenomena as well as realizing a broad range of spintronic devices. In particular, the magnetic coupling plays a critical role in determining the nature of the cooperative behavior and providing new functionalities in nanomagnet-based devices. Here, we create coupled Ising-like nanomagnets in which the coupling between adjacent nanomagnetic regions can be reversibly converted between parallel and antiparallel through solid-state ionic gating. This is achieved with the voltage-control of the magnetic anisotropy in a nanosized region where the symmetric exchange interaction favors parallel alignment and the antisymmetric exchange interaction, namely the Dzyaloshinskii-Moriya interaction, favors antiparallel alignment of the nanomagnet magnetizations. Applying this concept to a two-dimensional lattice, we demonstrate a voltage-controlled phase transition in artificial spin ices. Furthermore, we achieve an addressable control of the individual couplings and realize an electrically programmable Ising network, which opens up new avenues to design nanomagnet-based logic devices and neuromorphic computers., (© 2023. Springer Nature Limited.)

Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. In this study, we investigated the spatial single-cell molecular and cellular features of postmortem COVID-19 lung tissues using in situ sequencing (ISS). We detected 10 414 863 transcripts of 221 genes in whole-slide tissues and segmented them into 1 719 459 cells that were mapped to 18 major parenchymal and immune cell types, all of which were infected by SARS-CoV-2. Compared with the non-COVID-19 control, COVID-19 lungs exhibited reduced alveolar cells (ACs) and increased innate and adaptive immune cells. We also identified 19 differentially expressed genes in both infected and uninfected cells across the tissues, which reflected the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that were correlated with high cell densities (HIHD). The HIHD regions expressed high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2 and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration, which exhibited increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, mirroring the tissue damage and wound healing processes. Sparse nonnegative matrix factorization (SNMF) analysis of niche features identified seven signatures that captured structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A primarily progressed with increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B was marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions were marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations consisting mainly of myofibroblasts. Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-β-SMAD2/3 pathways in these cells, likely mediating the upregulation of COL1A1 and COL1A2 and excessive fibrosis in the lung tissues. Together, this study provides a spatial single-cell atlas of cellular and molecular signatures of fatal COVID-19 lungs, which reveals the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology., (© 2023 Wiley Periodicals LLC.)

As a result of their cell structures, elastomeric foams exhibit high compressibility and are frequently used as buffer cushions in energy absorption. Foam pads between two surfaces typically withstand uniaxial loads. In this paper, we considered the effects of porosity and cell size on the mechanical behavior of random elastomeric foams, and proposed a constitutive model based on an artificial neural network (ANN). Uniform cell size distribution was used to represent monodisperse foam. The constitutive relationship between Cauchy stress and the four input variables of axial stretch λ U , lateral stretch λ L , porosity φ, and cell size θ was given by con-ANN. The mechanical responses of 500 different foam structures (20% < φ < 60%, 0.1 mm < θ < 0.5 mm) under compression and tension loads (0.4 < λ U < 3) were simulated, and a dataset containing 100,000 samples was constructed. We also introduced a pre-ANN to predict lateral stretch to address the issue of missing lateral strain data in practical applications. By combining physical experience, we chose appropriate input forms and activation functions to improve ANN's extrapolation capability. The results showed that pre-ANN and con-ANN could provide reasonable predictions for λ U outside the dataset. We can obtain accurate lateral stretch and axial stress predictions from two ANNs. The porosity affects the stress and λ L , while the cell size only affects the stress during foam compression.

Significance: Double-helix point spread function (DH-PSF) microscopy has been developed for three-dimensional (3D) localization and imaging at super-resolution but usually in environments with no or weak scattering. To date, super-resolution imaging through turbid media has not been reported., Aim: We aim to explore the potential of DH-PSF microscopy in the imaging and localization of targets in scattering environments for improved 3D localization accuracy and imaging quality., Approach: The conventional DH-PSF method was modified to accommodate the scanning strategy combined with a deconvolution algorithm. The localization of a fluorescent microsphere is determined by the center of the corresponding double spot, and the image is reconstructed from the scanned data by deconvoluting the DH-PSF., Results: The resolution, i.e., the localization accuracy, was calibrated to 13 nm in the transverse plane and 51 nm in the axial direction. Penetration thickness could reach an optical thickness (OT) of 5. Proof-of-concept imaging and the 3D localization of fluorescent microspheres through an eggshell membrane and an inner epidermal membrane of an onion are presented to demonstrate the super-resolution and optical sectioning capabilities., Conclusions: Modified DH-PSF microscopy can image and localize targets buried in scattering media using super-resolution. Combining fluorescent dyes, nanoparticles, and quantum dots, among other fluorescent probes, the proposed method may provide a simple solution for visualizing deeper and clearer in/through scattering media, making in situ super-resolution microscopy possible for various demanding applications., (© 2023 The Authors.)

HBV cccDNA is the persistent form of viral genome, which exists in host cell nucleus as an episomal minichromosome decorated with histone and non-histone proteins. cccDNA is the authentic viral transcription template and resistant to current antivirals. Growing evidence shows that the transcriptional activity of cccDNA minichromosome undergoes epigenetic regulations, suggesting a new perspective for anti-cccDNA drug development through targeting histone modifications. In this study, we screened an epigenetic compound library in the cccDNA reporter cell line HepBHAe82, which produces the HA-tagged HBeAg in a cccDNA-dependent manner. Among the obtained hits, a bromodomain-containing protein 4 (BRD4) inhibitor MS436 exhibited marked inhibition of cccDNA transcription in both HBV stable cell line HepAD38 and HepG2-NTCP or primary human hepatocyte infection system under noncytotoxic concentrations. Chromatin immunoprecipitation (ChIP) assay demonstrated that MS436 dramatically reduced the enrichment of H3K27ac, an activating histone modification pattern, on cccDNA minichromosome. RNAseq differential analysis showed that MS436 does not drastically change host transcriptome or induce any known anti-HBV factors/pathways, indicating a direct antiviral effect of MS436 on cccDNA minichromosome. Interestingly, the MS436-mediated inhibition of cccDNA transcription is accompanied by cccDNA destabilization in HBV infection and a recombinant cccDNA system, indicating that BRD4 activity may also play a role in cccDNA maintenance. Furthermore, depletion of BRD4 by siRNA knockdown or PROTAC degrader resulted in cccDNA inhibition in HBV-infected HepG2-NTCP cells, further validating BRD4 as an antiviral target. Taken together, our study has demonstrated the practicability of HepBHAe82-based anti-HBV drug screening system and provided a proof-of-concept for targeting HBV cccDNA with epigenetic compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

NOC2 like nucleolar associated transcriptional repressor (NOC2L) was recently identified as a novel inhibitor of histone acetyltransferase (INHAT). NOC2L is found to have two INHAT function domains and regulates histone acetylation in a histone deacetylases (HDAC) independent manner, which is distinct from other INHATs. In this review, we summarize the biological function of NOC2L in histone acetylation regulation, P53-mediated transcription, ribosome RNA processing, certain development events and carcinogenesis. We propose that NOC2L may be explored as a potential biomarker and a therapeutic target in clinical practice., (© 2023. The Author(s).)

The all-area operating performance of the vehicles requires the development of diesel engines that can operate at high altitudes without significant performance deterioration. Prior to optimizing the efficiency and emissions of highland engines, there is a necessity to investigate the underlying causes of engine performance degradation. The purpose of this paper was to study the in-cylinder activities occurring in the combustion chamber of diesel engines at high altitudes, which can help explain the effect of altitude on engine efficiency and emissions of concern to the customer. Specifically, a turbocharged direct injection compression ignition engine was operated at a constant engine speed and load, but at different altitudes. The theoretical analyses based on experimental data suggested that the mismatch between air and diesel quantities caused by the high altitude atmosphere led to the engine combustion deterioration. Specifically, the lower gas density at high altitudes during fuel injection resulted in a reduction of the injection angle and an enhancement of the penetration capability. In addition, the rise in altitude extended the ignition delay, which increased the fuel fraction mixed with air in the premixed combustion stage and raised the pressure rise rate. Moreover, at high altitudes, the reduction in excess air ratio and increased possibility of wall impingement of the fuel droplets resulted in uneven mixture concentration distribution and reduced air utility. Accordingly, combustion deterioration occurred in the combustion chamber of the plateau engines, which reduced energy release during main mixing-controlled combustion, lowered combustion efficiency, increased exhaust energy, and raised engine-out incomplete combustion emissions. All these effects resulted in a decrease in engine thermal efficiency of ∼6.5% and an increase in soot emissions of ∼4.2 times from Hangzhou to Lhasa city for the engine and operating conditions investigated in this study. Consequently, engines operating in highland areas need to be optimized in terms of efficiency and emissions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

SARS-CoV-2 vaccines have contributed to the control of COVID-19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS-CoV-2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein-based pseudoviruses derived from wild type (WT) SARS-CoV-2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two-dose mRNA-1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA-1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA-1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA-based vaccine and the use of an mRNA-based vaccine 2 months after Ad26.COV2.S vaccination., (© 2022 Wiley Periodicals LLC.)

Background: Postmenopausal osteoporosis (PMOP) is a disease with a high prevalence in postmenopausal women and is characterized by an imbalance in bone metabolism, reduced bone mass, and increased risk of fracture due to estrogen deficiency. Jiangu granules (JG) is a compound prescription used in traditional Chinese medicine to treat PMOP. However, its definitive mechanism in PMOP is unclear. This study used a 4D label-free quantitative proteomics method to explore the potential therapeutic mechanism of JG in an ovariectomy (OVX) rats' model. Materials and methods: A rat model of PMOP was established by removing the ovaries bilaterally. Nine 3-month-old specific-pathogen-free female SD rats. The nine rats were randomly divided into 3 groups ( n = 3 in each group): the sham-operated group (J), the ovariectomy group (NC), and the JG treatment (ZY) group. Proteins extracted from the bone tissue of the lumbar spine (L3, L4) of three groups of rats were analyzed by 4D label-free quantitative proteomics, and proteins differentially expressed after JG treatment and proteins differentially expressed after de-ovulation were intersected to identify proteins associated with the mechanism of PMOP by JG treatment. Result: There were 104 up-regulated and 153 down-regulated differentially expressed proteins (DEPs) in the J group vs. NC group, 107 up-regulated and 113 down-regulated DEPs in the J group vs. ZY group, and 15 up-regulated and 32 down-regulated DEPs in the NC group vs. ZY group. Six potential target proteins for JG regulation of osteoblast differentiation in OVX rats were identified by taking intersections of differential proteins in the J group vs. NC group and NC group vs. ZY group. Conclusion: JG may exert therapeutic effects by modulating the expression levels of target proteins associated with osteoblast differentiation to enhance osteoblast differentiation in OVX rats. These results further uncovered the target proteins and specific mechanisms of JG in treating PMOP, providing an experimental basis for the clinical application of JG in treating PMOP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Zhang, Xu, You, Zheng, Liu and Li.)

Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-β1 (TGF-β1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3β/β-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: During the COVID-19 pandemic, the protective and medical resources were limited, while a limited number of studies have concentrated on the influences of COVID-19 on the treatment of cancer patients. This survey aimed to explore the protective awareness about COVID-19, the incidence and factors influencing treatment delay, and expected treatment modality of cancer patients, so as to assist cancer patients., Methods: A current prospective, online survey was conducted through the WeChat platform on cancer outpatients at the Department of Peking University Third Hospital in China from March 4 to April 4, 2020., Results: A total of 141 patients completed the survey after excluding 35 patients with an incomplete questionnaire. Note that 100% of the patients wore masks and paid attention to hand hygiene during the hospital visits, 73.0% of the patients had a strong desire to treat cancer, and 41.8% experienced treatment delay. The rate of treatment delay among the patients treated in other departments was markedly higher than that in our department (64.7% vs. 38.7%, p = .042). The results of logistic regression analysis showed that the previous treatment department was independently correlated with treatment delay. Moreover, 51.8% of the patients preferred to receive chemotherapy in the day ward, 54.6% hoped to receive a strong contact with doctors, and 83.7% would like to receive online therapeutic consultation., Conclusion: The rate of treatment delay was remarkable, which may be related to previous treatment departments. Promotion of "active management of attending physician" and "telemedicine" may be highly advantageous for cancer patients during the COVID-19 pandemic., (© 2021 John Wiley & Sons Australia, Ltd.)

Summary: The number of instationary 13C-metabolic flux (INST-MFA) studies grows every year, making it more important than ever to ensure the clarity, standardization and reproducibility of each study. We proposed CeCaFLUX, the first user-friendly web server that derives metabolic flux distribution from instationary 13C-labeled data. Flux optimization and statistical analysis are achieved through an evolutionary optimization in a parallel manner. It can visualize the flux optimizing process in real-time and the ultimate flux outcome. It will also function as a database to enhance the consistency and to facilitate sharing of flux studies., Availability and Implementation: CeCaFLUX is freely available at https://www.cecaflux.net, the source code can be downloaded at https://github.com/zhzhd82/CeCaFLUX., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Silicosis is an irreversible occupational disease caused by silica particle exposure. Abundant evidences suggest that NLRP3-mediated inflammation acts an essential role in fibrogenesis and the pathogenesis of silicosis. In the current work, we firstly reported that (8R-12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of Chinese traditional medicinal plant Andrographis paniculata (Burm.f.) Nees, could reduce pulmonary inflammation and fibrosis by inhibiting NLRP3, and thereby ameliorate silicosis. ISA administration significantly alleviated lung injury, and attenuated inflammatory response, EMT, as well as collagen deposition in the lung of silica-induced mice. Further studies verified that ISA inhibited the expressions of NLRP3 inflammasome-related proteins NLRP3, ASC and caspase-1 in vivo and in vitro, leading to the attenuation of inflammation and EMT. Additionally, the molecular docking assay indicated that ISA possibly interacted with the residues of LYS26 and GLU47 of NLRP3, implying that ISA might directly bond to protein NLRP3. Of note, ISA revealed a lower cytotoxicity but more potent therapeutic effect than andrographolide (AD), the major active extract of A. paniculata, which has been traditionally used to treat inflammation-related diseases. Taken together, our study clarified a novel role of ISA in attenuating inflammation and fibrosis in silicosis, and indicated a bright future of ISA as a lead compound for developing therapeutic drug for silicosis., (Copyright © 2022. Published by Elsevier B.V.)

Background: Malignant pleural effusion is one of the common clinical manifestations of patients with lung adenocarcinoma. Patients with pleural effusion at the initial diagnosis of lung adenocarcinoma usually indicate poor prognosis. Epidermal growth factor receptor (EGFR) mutations mainly occur in patients with lung adenocarcinoma. Patients with different mutant subtypes have different prognosis. The clinical characteristics and prognostic factors of patients with EGFR mutated lung adenocarcinoma of different molecular subtypes combined with pleural effusion at initial diagnosis are still unclear. This study was designed to explore the clinical characteristics and prognostic factors of these patients in order to provide management recommendations for them., Methods: A retrospective analysis of the clinical characteristics, treatment, outcomes and progression-free survival (PFS) of first-line treatment in patients with EGFR mutated lung adenocarcinoma combined with pleural effusion at initial diagnosis admitted to Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital from January 2012 to June 2021 was performed. Pearson's chi-square test or Fisher's exact test were performed for comparison between groups. Kaplan-Meier method was performed for survival analysis and Cox proportional risk regression model was performed for multivariate analysis., Results: 76 patients met the inclusion criteria in this study. The incidences of EGFR classical mutations 19del, 21L858R and non-classical mutations were 46.0%, 38.2% and 15.8%, respectively among these patients. There was no significant difference between the three mutations in terms of gender, age, presence of dyspnea at presentation, whether other distant metastases were combined, site of pleural effusion, volume of pleural effusion, presence of other combined effusions, tumor-node-metastasis (TNM) stage, presence of other gene mutations, and treatment of pleural effusion (P>0.05). In patients with EGFR classical mutations 19del or 21L858R or non-classical mutations subtype, the proportion of chemotherapy in first-line regimens were 17.1%, 20.7% and 58.3%, respectively (P=0.001); and first-line disease control rates were 94.3%, 75.9% and 50%, respectively (P=0.003); pleural effusion control rates were 94.3%, 79.3% and 66.7%, respectively (P=0.04); PFS were 287 d, 327 d and 55 d, respectively (P=0.001). Univariate analysis showed that EGFR mutation subtype, control of pleural effusion, first-line treatment agents, and first-line treatment efficacy were significantly associated with PFS (P<0.05). Cox multifactorial analysis showed that only EGFR mutation subtype and first-line treatment efficacy were independent prognostic factors for PFS (P<0.05)., Conclusions: PFS was significantly better for classical mutations than for non-classical mutations in patients with EGFR mutated lung adenocarcinoma combined with pleural effusion at initial diagnosis. Improving the efficacy of first-line therapy is the key to improve the prognosis of these patients.

Background: Aerobic glycolysis is an emerging hallmark of cancer. Although some studies have constructed glycolysis-related prognostic models of colon adenocarcinoma (COAD) based on The Cancer Genome Atlas (TCGA) database, whether the COAD glycolysis-related prognostic model is appropriate for distinguishing the prognosis of rectal adenocarcinoma (READ) patients remains unknown. Exploring critical and specific glycolytic genes related to READ prognosis may help us discover new potential therapeutic targets for READ patients., Results: Three gene sets, HALLMARK&#95;GLYCOLYSIS, REACTOME&#95;GLYCOLYSIS and REACTOME&#95;REGULATION&#95;OF&#95;GLYCOLYSIS&#95;BY&#95;FRUCTOSE&#95;2&#95;6&#95;BISPHOSPHATE&#95;METABOLISM, were both significantly enriched in both COAD and READ through glycolysis-related gene set enrichment analysis (GSEA). We found that six genes (ANKZF1, STC2, SUCLG2P2, P4HA1, GPC1 and PCK1) were independent prognostic genes in COAD, while TSTA3 and PKP2 were independent prognostic genes in READ. Glycolysis-related prognostic model of COAD and READ was, respectively, constructed and assessed in COAD and READ. We found that the glycolysis-related prognostic model of COAD was not appropriate for READ, while glycolysis-related prognostic model of READ was more appropriate for READ than for COAD. PCA and t-SNE analysis confirmed that READ patients in two groups (high and low risk score groups) were distributed in discrete directions based on the glycolysis-related prognostic model of READ. We found that this model was an independent prognostic indicator through multivariate Cox analysis, and it still showed robust effectiveness in different age, gender, M stage, and TNM stage. A nomogram combining the risk model of READ with clinicopathological characteristics was established to provide oncologists with a practical tool to evaluate the rectal cancer outcomes. GO enrichment and KEGG analyses confirmed that differentially expressed genes (DEGs) were enriched in several glycolysis-related molecular functions or pathways based on glycolysis-related prognostic model of READ., Conclusions: We found that a glycolysis-related prognostic model of COAD was not appropriate for READ, and we established a novel glycolysis-related two-gene risk model to effectively predict the prognosis of rectal cancer patients., (© 2022. The Author(s).)

Since its selection as the method of the year in 2013, single-cell technologies have become mature enough to provide answers to complex research questions. With the growth of single-cell profiling technologies, there has also been a significant increase in data collected from single-cell profilings, resulting in computational challenges to process these massive and complicated datasets. To address these challenges, deep learning (DL) is positioned as a competitive alternative for single-cell analyses besides the traditional machine learning approaches. Here, we survey a total of 25 DL algorithms and their applicability for a specific step in the single cell RNA-seq processing pipeline. Specifically, we establish a unified mathematical representation of variational autoencoder, autoencoder, generative adversarial network and supervised DL models, compare the training strategies and loss functions for these models, and relate the loss functions of these models to specific objectives of the data processing step. Such a presentation will allow readers to choose suitable algorithms for their particular objective at each step in the pipeline. We envision that this survey will serve as an important information portal for learning the application of DL for scRNA-seq analysis and inspire innovative uses of DL to address a broader range of new challenges in emerging multi-omics and spatial single-cell sequencing., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Numerous single image super-resolution (SISR) algorithms have been proposed during the past years to reconstruct a high-resolution (HR) image from its low-resolution (LR) observation. However, how to fairly compare the performance of different SISR algorithms/results remains a challenging problem. So far, the lack of comprehensive human subjective study on large-scale real-world SISR datasets and accurate objective SISR quality assessment metrics makes it unreliable to truly understand the performance of different SISR algorithms. We in this paper make efforts to tackle these two issues. Firstly, we construct a real-world SISR quality dataset (i.e., RealSRQ) and conduct human subjective studies to compare the performance of the representative SISR algorithms. Secondly, we propose a new objective metric, i.e., KLTSRQA, based on the Karhunen-Loéve Transform (KLT) to evaluate the quality of SISR images in a no-reference (NR) manner. Experiments on our constructed RealSRQ and the latest synthetic SISR quality dataset (i.e., QADS) have demonstrated the superiority of our proposed KLTSRQA metric, achieving higher consistency with human subjective scores than relevant existing NR image quality assessment (NR-IQA) metrics. The dataset and the code will be made available at https://github.com/Zhentao-Liu/RealSRQ-KLTSRQA.

Just noticeable difference (JND) of natural images refers to the maximum pixel intensity change magnitude that typical human visual system (HVS) cannot perceive. Existing efforts on JND estimation mainly dedicate to modeling the diverse masking effects in either/both spatial or/and frequency domains, and then fusing them into an overall JND estimate. In this work, we turn to a dramatically different way to address this problem with a top-down design philosophy. Instead of explicitly formulating and fusing different masking effects in a bottom-up way, the proposed JND estimation model dedicates to first predicting a critical perceptual lossless (CPL) counterpart of the original image and then calculating the difference map between the original image and the predicted CPL image as the JND map. We conduct subjective experiments to determine the critical points of 500 images and find that the distribution of cumulative normalized KLT coefficient energy values over all 500 images at these critical points can be well characterized by a Weibull distribution. Given a testing image, its corresponding critical point is determined by a simple weighted average scheme where the weights are determined by a fitted Weibull distribution function. The performance of the proposed JND model is evaluated explicitly with direct JND prediction and implicitly with two applications including JND-guided noise injection and JND-guided image compression. Experimental results have demonstrated that our proposed JND model can achieve better performance than several latest JND models. In addition, we also compare the proposed JND model with existing visual difference predicator (VDP) metrics in terms of the capability in distortion detection and discrimination. The results indicate that our JND model also has a good performance in this task. The code of this work are available at https://github.com/Zhentao-Liu/KLT-JND.

Objective: The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors. Methods: We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as "clinicaltrials.gov". We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the publication time. Chi-square tests and binary logistic regression were used to identify the factors associated with improved SAEs reports. This study was registered on PROSPERO. Results: Of 1560 articles identified, 160 were eligible, with an RP of SAEs of 25.5% (41/160). In forty-one publications reporting SAEs, only 14.6% (6/41) described the pattern of SAEs in detail. In clinical trials sponsored by pharmaceutical companies, the RP of SAEs was significantly higher than that in those sponsored by investigators (57.6 versus 20.7%, p < 0.001). From 1993 to 2018, the RP of SAEs gradually increased (none (0/6) before 2000, 17.1% (12/70) from 2000 to 2009, and 34.5% (29/84) after 2009). The average RP of SAEs published in the New England Journal of Medicine (N Engl J Med), the Lancet, the Journal of the American Medical Association (JAMA), the Lancet Oncology (Lancet Oncol), and the Journal of Clinical Oncology (J Clin Oncol) was significantly higher than that published in other journals (31.9 versus 16.7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting. Conclusion: Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yao, Liu, Zhang, Li, Peng, Yu, Cao and Shen.)

A spectral polarization camera based on ghost imaging via sparsity constraints (GISC) is presented. The proposed imager modulates three-dimensional spatial and spectral information of the target into two-dimensional speckle patterns using a spatial random phase modulator and then acquires the speckle patterns at four linear polarization channels through a polarized CCD. The experimental results verify the feasibility of the system structure and reconstruction algorithm. The GISC spectral polarization camera, which has a simple structure and achieves compressive sampling during the imaging acquisition process, provides a simple scheme for obtaining multi-dimensional information of the light field.

Glioblastoma multiforme (GBM) is a devastating brain tumor and displays divergent clinical outcomes due to its high degree of heterogeneity. Reliable prognostic biomarkers are urgently needed for improving risk stratification and survival prediction. In this study, we analyzed genome-wide mRNA profiles in GBM patients derived from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify mRNA-based signatures for GBM prognosis with survival analysis. Univariate Cox regression model was used to evaluate the relationship between the expression of mRNA and the prognosis of patients with GBM. We established a risk score model that consisted of six mRNA (AACS, STEAP1, STEAP2, G6PC3, FKBP9, and LOXL1) by the LASSO regression method. The six-mRNA signature could divide patients into a high-risk and a low-risk group with significantly different survival rates in training and test sets. Multivariate Cox regression analysis confirmed that it was an independent prognostic factor in GBM patients, and it has a superior predictive power as compared with age, IDH mutation status, MGMT, and G-CIMP methylation status. By combining this signature and clinical risk factors, a nomogram can be established to predict 1-, 2-, and 3-year OS in GBM patients with relatively high accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Zhang, Hu, Cai, Lu, Liang, Qian, Wang and Jiang.)

Background: A precise map of the metabolic fluxome, the closest surrogate to the physiological phenotype, is becoming progressively more important in the metabolic engineering of photosynthetic organisms for biofuel and biomass production. For photosynthetic organisms, the state-of-the-art method for this purpose is instationary 13C fluxomics, which has arisen as a sibling of transcriptomics or proteomics. Instationary 13C data processing requires solving high-dimensional nonlinear differential equations and leads to large computational and time costs when its scope is expanded to a genome-scale metabolic network., Result: Here, we present a parallelized method to model instationary 13C labeling data. The elementary metabolite unit (EMU) framework is reorganized to allow treating individual mass isotopomers and breaking up of their networks into strongly connected components (SCCs). A variable domain parallel algorithm is introduced to process ordinary differential equations in a parallel way. 15-fold acceleration is achieved for constant-step-size modeling and ~ fivefold acceleration for adaptive-step-size modeling., Conclusion: This algorithm is universally applicable to isotope granules such as EMUs and cumomers and can substantially accelerate instationary 13C fluxomics modeling. It thus has great potential to be widely adopted in any instationary 13C fluxomics modeling., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Optical imaging through inhomogeneous media based on autocorrelations suffers from a limited field of view (FOV), since the optical memory effect (ME) of a scattering medium has its inherent angular extent. Here we successfully expand the angular ME range by exploiting a spatial filtering technique to select low-frequency components, mainly ballistic light and less scattered light, thereby increasing the FOV of the speckle autocorrelation imaging. Both a simulation and experimental verifications are presented. This technique, which is not limited to the discussed 4f structure, can provide a guideline for the design of an optical system to image through scattering media.

Afatinib is a pan-HER inhibitor approved for specific types of lung cancer. We explored antitumor activity, predictive biomarkers and the potential mechanisms underlying antitumor effect and acquired resistance of afatinib in gastric cancer (GC) in vitro and in vivo. Five human GC cell lines and eight patient-derived xenograft (PDX) models with clear molecular profiling were used to evaluate the antitumor activity and mechanisms of afatinib. The ErbB family and downstream PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways were evaluated before and after afatinib treatment. An afatinib-resistant PDX model was established to explore both the potential mechanisms of drug resistance and reversal strategies. We found that afatinib exerted a strong tumor suppression in EGFR/HER2 highly amplified (copy number >6) or overexpressed (IHC 3+) PDX models and a moderate tumor suppression in EGFR/HER2 moderately expressed (IHC 2+) PDX models. Afatinib selectively inhibited the proliferation of HER2 highly amplified GC cells in a dose-dependent manner in vitro. Afatinib also exerted its antitumor effect by inducing cell apoptosis and cell arrest at G1 phase. Diminished activation of the ErbB family and downstream PI3K/AKT/mTOR and MAPK pathways was also observed. Erythropoietin-producing hepatocellular receptor A2 (EPHA2) upregulation and phosphorylation might be involved in afatinib-acquired resistance, and EPHA2 blockade could restore afatinib sensitivity. GC patients with amplification (copy number >6) or overexpression (IHC 3+) of EGFR/HER2 were most likely to benefit from afatinib treatment and EPHA2 blockade reversed acquired resistance to afatinib treatment, which could provide solid evidences for future clinical trials., (© 2019 UICC.)

Ghost imaging (GI) is a novel imaging technique based on the second-order correlation of light fields. Due to limited number of samplings in practice, traditional GI methods often reconstruct objects with unsatisfactory quality. To improve the imaging results, many reconstruction methods have been developed, yet the reconstruction quality is still fundamentally restricted by the modulated light fields. In this paper, we propose to improve the imaging quality of GI by optimizing the light fields, which is realized via matrix optimization for a learned dictionary incorporating the sparsity prior of objects. A closed-form solution of the sampling matrix, which enables successive sampling, is derived. Through simulation and experimental results, it is shown that the proposed scheme leads to better imaging quality compared to the state-of-the-art optimization methods for light fields, especially at a low sampling rate.

Long non-coding RNAs (lncRNAs) play important roles in tumor progression. Whereas the roles and underlying mechanisms of LINC00909 (a newly discovered lncRNA) are still unclear in glioma progression. In the present study, we identified that LINC00909 expression was significantly elevated in glioma tissues and cell lines. High LINC00909 expression was associated with advanced WHO grade, high Karnofsky Performance Score (KPS), and poor prognosis in patients with glioma. Function assays showed that LINC00909 depletion inhibited glioma cells proliferation, invasion in vitro and reduced tumor growth in vivo. In the mechanism, we found that LINC00909 could act as a ceRNA to interact with miR-194 and thereby up-regulate the expression of MUC1-C, thus promoting the proliferation and invasion of glioma cells. Collectively, these data demonstrated that LINC00909/miR-194/MUC1-C axis regulated glioma progression and might act as a novel therapeutic target., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ghost imaging LiDAR via sparsity constraints using push-broom scanning is proposed. It can image the stationary target scene continuously along the scanning direction by taking advantage of the relative movement between the platform and the target scene. Compared to conventional ghost imaging LiDAR that requires multiple speckle patterns staring the target, ghost imaging LiDAR via sparsity constraints using push-broom scanning not only simplifies the imaging system, but also reduces the sampling number. Numerical simulations and experiments have demonstrated its efficiency.

Background: Delanzomib, a novel proteasome inhibitor, has demonstrated promising efficacy and antitumor ability in human multiple myeloma cell lines and patient-derived cells. However, the potential therapeutic effects of delanzomib on breast cancer remain unknown. In this study, we show that delanzomib has antitumor effects and synergizes with doxorubicin (Dox) in human breast cancer cell lines., Methods: Cell proliferation assay and flow cytometry were used to evaluate cell viability and apoptosis in eight human breast cancer cell lines after treatment with delanzomib or Dox. Essential molecules of the p53, MAPK, and apoptosis signaling pathways were analyzed by Western blotting., Results: Delanzomib induced cell death and demonstrated synergism with Dox in all tested breast cancer cell lines. In addition, delanzomib enhanced the Dox-induced phosphorylation of p38/JNK and the expression of transcriptional target proteins of p53, such as p21, p27, NOXA, and PUMA., Conclusion: The combined regimen of the proteasome inhibitor delanzomib with Dox chemotherapy may become an effective strategy for breast cancer therapy., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: No approved targeted agents are available for esophageal squamous cell carcinoma (ESCC). Informative genomic analysis and mouse patient-derived xenografts (PDX) also called mouse avatar can greatly expedite drug discovery., Methods: Six ESCC cell lines and 7 out of 25 PDX models derived from 188 biopsies with clear molecular features were employed to evaluate the sensitivity of several EGFR blockers in vitro and in vivo, as well as the underlying antitumor mechanisms of the most promising EGFR-TKI afatinib. Mechanisms involved in acquired resistance of afatinib were explored based on established resistant cell lines and PDX models followed by an attempt to reverse resistance., Results: Compared with other EGFR blockers, the second-generation EGFR-TKI afatinib exerted superior antitumor effects in ESCC, and EGFR copy number gain (CNG) or overexpression was proposed to be predictive biomarkers. Afatinib played its antitumor effects by inhibiting EGFR downstream pathways, as well as inducing apoptosis and cell cycle arrest at G1. It was increased phosphorylation of Src family kinases (SFKs), rather than MET upregulation, that conferred to acquired resistance of afatinib. Dual blockade of EGFR and SFKs could overcome afatinib resistance and warrants validation in clinical practice., Conclusion: Both ESCC cell lines and PDXs with EGFR CNG or overexpression are potential candidates for afatinib, and concomitant EGFR/SFKs inhibition could reverse afatinib-acquired resistance caused by SFKs activation in ESCC.

A spectral camera based on ghost imaging via sparsity constraints (GISC) acquires a three-dimensional (3D) spatial-spectral data cube of the target through a two-dimensional (2D) detector in a single snapshot. However, the spectral and spatial resolution are interrelated because both of them are modulated by the same spatial random phase modulator. In this paper, we theoretically and experimentally demonstrate a system by equipping the GISC spectral camera with a flat-field grating to disperse the light fields before the spatial random phase modulator, hence consequently decoupling the spatial and spectral resolution. By theoretical derivation of the imaging process we obtain the spectral resolution 1nm and spatial resolution 50μm about the new system which are verified by the experiment. The new system can not only modulate the spatial and spectral resolution separately, but also provide a possibility of optimizing the light field fluctuations of different wavelengths according to the imaging scene.

c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC)., Methods: The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry. The antitumor activities of several targeted drugs were investigated in the PDX models. Furthermore, response biomarkers were explored., Results: Each PDX model had individual histopathological and molecular features, and recurrent alterations in the MAPK, ErbB, VEGF, mTOR, and cell cycle signaling pathways were major events in these PDX models. Several potential drug targets, such as EGFR, MET, and CCNE1, were selected and validated in this study. Volitinib demonstrated strong antitumor activity in PDX models with MET and phosphorylated MET (pMET) overexpression. The EGFR monoclonal antibodies BK011 and cetuximab inhibited tumor growth in a PDX model with EGFR amplification. Afatinib inhibited tumor growth in the PDX models with EGFR amplification, EGFR overexpression, or HER2 amplification. Apatinib was more sensitive in the PDX models with high microvessel density. The CDK1/2/9 inhibitor AZD5438 had superior anti-tumor activity in two models with higher copy number of CCNE1., Conclusions: PDX models with defined molecular signature are useful for preclinical studies with targeted drugs, and the results should be validated in larger studies with PDX models or in clinical trials.

This study was designed to investigate the significance of the effect of miR-34a on 5-fluorouracil (5-FU) sensitivity in vitro and in vivo . miR-34a expression in tumor tissues or serum was determined by quantitative polymerase chain reaction. CRC cell lines HCT116 and SW480 were used to evaluate cell viability, cell apoptosis, and the cell cycle using a cell proliferation assay, flow cytometry, and Western blotting, respectively. For the in vivo studies, xenografts derived from SW480 cells were established to assess the antitumor activity between miR-34a and 5-FU. Patients with high levels of miR-34a expression were found to benefit more from 5-FU-based chemotherapy than patients with low levels of miR-34a expression, regardless of disease stage. Ectopic expression of miR-34a alone or 5-FU alone was found to inhibit CRC cell growth in vitro and in vivo . Moreover, cell growth in vitro and in vivo was further inhibited when miR-34a combined with 5-FU through increasing the rate of cell apoptosis. The potential targets of miR-34a, including CREB1, Bcl-2, Notch 1, Sirt1, and E2F3, were predicted and preliminarily validated and merit further study., Conclusion: miR-34a might function as a predictor of fluorouracil chemosensitivity in CRC, and a combination strategy of miR-34a with fluorouracil was expected to be more beneficial for CRC patients., Competing Interests: None.

Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G 2 /M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

Background: Squamous cell carcinoma is the dominant type of esophageal cancer in China with many patients initially diagnosed at advanced stage. Patient-derived xenografts (PDX) models have been developed to be an important platform for preclinical research. This study aims to establish and characterize PDX models using biopsy tissue from advanced esophageal cancer patients to lay the foundation of preclinical application., Methods: Fresh endoscopic biopsy tissues were harvested from patients with advanced esophageal cancer and implanted subcutaneously into NOD/SCID mice. Then, the PDXs were serially passaged for up to four generations. Transplantation was analyzed and genomic characteristics of xenografts were profiled using next-generation sequencing., Results: Twenty-five PDX models were established (13.3%, 25/188). The latency period was 75.12 ± 19.87 days (50-120 days) for the first passage and it decreased with increasing passaging. Other than tumor stages, no differences were found between transplantations of xenografts and patient characteristics, irrespective of chemotherapy. Histopathological features and chemosensitivity of PDXs were in great accordance with primary patient tumors. Each PDX was assessed for molecular characteristics including copy number variations, somatic mutations, and signaling pathway abnormalities and these were similar to patient results., Conclusions: Our PDX models were established from real time biopsies and molecularly profiled. They might be promising for drug development and individualized therapy.

Background: HER2 status is significant to trastuzumab therapy; however, it is difficult to determine HER2 status accurately with few pieces of biopsies from advanced gastric cancer (AGC) due to highly heterogeneity and invasive behaviour, which will be investigated in this study., Methods: Fifty-six patients with AGC were included in this study. Primary tumour tissues and matched plasmas before medication from 36 patients were retrospectively collected, and the other 20 patients with primary tumour tissues and paired plasmas were prospectively collected. HER2 expression and amplification in 56 tumour tissues were determined by immunohistochemistry (IHC) and dual in situ hybridisation (DISH), and HER2 copy number in 135 circulating tumour DNAs (ctDNAs) was judged by next-generation sequencing., Results: For tumour tissues, HER2 amplification by DISH was most commonly found in patients with HER2 score 3+by IHC. For plasmas, HER2 amplification defined as HER2 copy number >2.22 was identified in 26 of 56 patients. There was a high concordance of HER2 amplification between ctDNA and tumour tissues, suggesting that ctDNA could function as an alternative to screen HER2-targeted population. Moreover, the changes of HER2 copy number in ctDNA could efficiently monitor trastuzumab efficacy, the power of which was superior to commonly used markers carcinoembryonic antigen (CEA) and CA199, suggesting its potential role in clinical practice., Conclusion: ctDNA for HER2 analysis was strongly recommended to serve as a surrogate to screen trastuzumab-suitable population and monitor trastuzumab efficacy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models., Methods: GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed., Results: Gimatecan inhibited the proliferation of GC cells in vitro in a dose- and time-dependent manner by inducing apoptosis, and gimatecan had greater inhibitory effects than irinotecan. In addition, both gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2)., Conclusions: For the first time, we have shown that the antitumor activity of gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that gimatecan might be an alternative to irinotecan in the treatment of GC.

Background: Individual studies of the association between N-acetyltransferase 1 (NAT1)*10 allele and bladder cancer susceptibility have shown inconclusive results. To derive a more precise estimation of any such relationship, we performed this systemic review and updated meta-analysis based on 17 publications., Methods: A total of 17 studies were investigated with 4,322 bladder cancer cases and 4,944 controls. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Subgroup analyses were conducted based on ethnicity, sex, source of controls and detecting methods. Then trial sequential analysis was performed to evaluate whether the evidence of the results was sufficient and reduce the risk of type I error., Results: There was no association between NAT1*10 allele and bladder cancer risk in a random-effects model (OR = 0.96, 95% CI, 0.84-1.10) or in a fixed-effects model (OR = 0.95, 95% CI, 0.87-1.03). In addition, no significantly increased risk of bladder cancer was found in any other subgroup analysis. Then, trial sequential analyses demonstrated that the results of our study need to be further verified., Conclusions: Despite its limitations, the results of the present meta-analysis suggested that there was no association between NAT1*10 allele and bladder cancer risk. More importantly, our findings need to be further validated regarding whether being without the NAT1*10 allele could in the future be shown to be a potential marker for the risk of bladder cancer.

Gastric cancer (GC) remains the second tumor caused death threat worldwide, and personalized medicine for GC is far from expectation. Finding novel, recurrently mutated genes through next-generation sequencing (NGS) is a powerful and productive approach. However, previous genomic data for GC are based on surgical resected samples while a large proportion of advanced gastric cancer (AGC) patients have already missed the chance for operation. The aim of this study is to assess frequent genomic alteration in AGC via biopsy samples. Here we performed targeted genomic sequencing of 78 AGC patients' tumor biopsies along with matched lymphocyte samples based on a 118 cancer related gene panel. In total, we observed 301 somatic nonsynonymous genomic alterations in 92 different genes, as well as 37 copy number gain events among 15 different genes (fold change 2-12), and validated the fold changes of ERBB2 copy number gains with IHC and FISH test showed an accuracy of 81.8%. Previously reported driver genes for gastric cancer ( TP53, KMT2D, KMT2B, EGFR, PIK3CA, GNAQ , and ARID1A ), and several unreported mutations ( TGFBR2, RNF213, NF1, NSD1 , and LRP2 ) showed high non-silent mutation prevalence (7.7%-34.6%). When comparing intestinal-type gastric cancer (IGC) with diffuse-type gastric cancer (DGC), TP53 and GNAQ appear to be more frequently mutated in IGC ( P =0.028 and P =0.023, respectively), whereas LRP2, BRCA2 and FGFR3 mutations are not observed in IGC, but have 12.8%, 7.7% and 7.7% mutation rates, respectively, in DGC patients. Patients with one or more mutations in adherens junction pathway ( CREBBP, EP300, CDH1, CTNNB1, EGFR, MET, TGFBR2 and ERBB2 ) or TGF-β signaling pathway ( CREBBP, EP300, MYST4, KRAS and TGFBR2 ) showed significantly better overall survival ( P =0.007 and P =0.014, respectively), consistent with The Cancer Genome Atlas (TCGA) cohort data. Importantly, 57 (73.1%) patients harbored at least one genomic alteration with potential treatments, making NGS-based drug target screening a viable option for AGC patients. Our study established a comprehensive genomic portrait of AGC, and identified several mutation signatures highly associated with clinical features, survival outcomes, which may be used to design future personalized treatments., Competing Interests: None.

Background: Cell cycle dysregulation is common in human malignancies, and CDK4/6 inhibitors targeting cell cycle have potential antitumor activity. SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway. However, the role of SHR6390 in esophageal squamous cell carcinoma (ESCC) remains unknown, which will be investigated in our study., Methods: Eca 109, Eca 9706, and KYSE-510 ESCC cell lines were chosen for further analysis. The effect of SHR6390 on cell viability, cell cycle and cell apoptosis, the status of kinases in Cyclin D1-CDK4/6-Rb pathway were determined by MTS assay, flow cytometry, and western blotting, respectively. Cell-derived and patient-derived xenografts were established to investigate the effects of drugs in vivo., Results: SHR6390 could suppress cell proliferation in vitro cell lines and inhibit tumor growth in vivo PDX models with different drug susceptibility. The effective treatment of SHR6390 induced the inhibition of phosphorylated Rb and cell cycle arrest at G1 phase both in cell lines and in xenografts. SHR6390 combined with paclitaxel or cisplatin offered synergistic inhibitory effects in cell-derived xenografts especially in Eca 9706 xenografts which showed relative lower sensitivity of SHR6390 single. Moreover, low expression of CDK6 and/or high expression of Cyclin D1 might be associated with high sensitivity of SHR6390, which would be validated in the future., Conclusions: CDK4/6 inhibitor-SHR6390 exerted potential antitumor activity against ESCC cell lines and xenografts, and evaluation of CDK6 and Cyclin D1 expressions might be helpful to select patients beneficial from SHR6390, which provided evidences for future clinical trials.