Usp22 Deficiency Leads to Downregulation of PD-L1 and Pathological Activation of CD8+ T Cells and Causes Immunopathology in Response to Acute LCMV Infection.

Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22-deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Genetic Diversity and Fine-Scale Genetic Structure of Spodoptera litura Fabricius (Lepidoptera: Noctuidae) in Southern China Based on Microsatellite Markers.

Population genetic structure is strongly affected by dispersal events, especially for migratory species. The investigation of population structure is therefore conducive to increasing our understanding of species dispersal. Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) is an important tobacco pest in China causing serious damage to multiple crops. In this study, we explore its dispersal dynamics by clarifying the fine-scale population genetics using 545 S. litura samples collected from tobacco plantations at 24 locations (mainly in Baise, Hechi, and Hezhou, Southern China). We analyzed the genetic diversity, genetic structure, and gene flow of these populations using seven microsatellite loci. Our results revealed high genetic diversity and low population genetic structure among S. litura. The genetic distance was uncorrelated with geographical distance, indicating the complete randomness of dispersal among the local populations. Our results suggest that the movement scope of contemporary S. litura might be much higher than the local-level spatial scale, which will provide a theoretical basis for pest management.

A hybrid generative adversarial network for weakly-supervised cloud detection in multispectral images.

Cloud detection is a crucial step in the optical satellite image processing pipeline for Earth observation. Clouds in optical remote sensing images seriously affect the visibility of the background and greatly reduce the usability of images for land applications. Traditional methods based on thresholding, multi-temporal or multi-spectral information are often specific to a particular satellite sensor. Convolutional Neural Networks for cloud detection often require labeled cloud masks for training that are very time-consuming and expensive to obtain. To overcome these challenges, this paper presents a hybrid cloud detection method based on the synergistic combination of generative adversarial networks (GAN) and a physics-based cloud distortion model (CDM). The proposed weakly-supervised GAN-CDM method (available online https://github.com/Neooolee/GANCDM) only requires patch-level labels for training, and can produce cloud masks at pixel-level in both training and testing stages. GAN-CDM is trained on a new globally distributed Landsat 8 dataset (WHUL8-CDb, available online doi:https://doi.org/10.5281/zenodo.6420027) including image blocks and corresponding block-level labels. Experimental results show that the proposed GAN-CDM method trained on Landsat 8 image blocks achieves much higher cloud detection accuracy than baseline deep learning-based methods, not only in Landsat 8 images (L8 Biome dataset, 90.20% versus 72.09%) but also in Sentinel-2 images ("S2 Cloud Mask Catalogue" dataset, 92.54% versus 77.00%). This suggests that the proposed method provides accurate cloud detection in Landsat images, has good transferability to Sentinel-2 images, and can quickly be adapted for different optical satellite sensors.

The complete mitochondrial genome sequence of Aglossa dimidiata (Haworth, 1809) (Lepidoptera: Pyralidae).

The complete mitochondrial genome (mitogenome) of Aglossa dimidiata (Lepidoptera: Pyralidae) was sequenced using high-throughput sequencing. The mitogenome of A. dimidiata was 15,225 bp in length. It comprised 37 typical genes and one control region. All protein-coding genes (PCGs) were initiated with ATN, except for COX1 (TTG). All PCGs used TAN as stop codon, except for ND5 and ND4 terminated with incomplete T. Twenty-two tRNA genes ranged from 61 to 71 bp in size. The monophyly of family Pyralidae and the sister relationship between A. dimidiata and Orthopygia glanucinalis are both supported by maximum likelihood method using the nucleotide sequences of 13 PCGs.

Protein Signatures of NK Cell-Mediated Melanoma Killing Predict Response to Immunotherapies.

Despite impressive advances in melanoma-directed immunotherapies, resistance is common and many patients still succumb to metastatic disease. In this context, harnessing natural killer (NK) cells, which have thus far been sidelined in the development of melanoma immunotherapy, could provide therapeutic benefits for cancer treatment. To identify molecular determinants of NK cell-mediated melanoma killing (NKmK), we quantified NK-cell cytotoxicity against a panel of genetically diverse melanoma cell lines and observed highly heterogeneous susceptibility. Melanoma protein microarrays revealed a correlation between NKmK and the abundance and activity of a subset of proteins, including several metabolic factors. Oxidative phoshorylation, measured by oxygen consumption rate, negatively correlated with melanoma cell sensitivity toward NKmK, and proteins involved in mitochondrial metabolism and epithelial-mesenchymal transition were confirmed to regulate NKmK. Two- and three-dimensional killing assays and melanoma xenografts established that the PI3K/AKT/mTOR signaling axis controls NKmK via regulation of NK cell-relevant surface proteins. A "protein-killing-signature" based on the protein analysis predicted NKmK of additional melanoma cell lines and the response of patients with melanoma to anti-PD-1 checkpoint therapy. Collectively, these findings identify novel NK cell-related prognostic biomarkers and may contribute to improved and personalized melanoma-directed immunotherapies. SIGNIFICANCE: NK-cell cytotoxicity assays and protein microarrays reveal novel biomarkers of NK cell-mediated melanoma killing and enable development of signatures to predict melanoma patient responsiveness to immunotherapies.

SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome.

Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.

Digital mapping of zinc in urban topsoil using multisource geospatial data and random forest.

This study aimed to map the spatial patterns of Zn in urban topsoil by using multisource geospatial data and machine learning method. Geological map, digital elevation models, and Landsat images were used to extract data related to geology, relief, and land use types and a vegetation index. Urban functional types were derived from the fusion of Systeme Probatoire d'Observation de la Terre 5 images, points of interest, and real-time Tencent user data. A geodetector was adopted to select key environmental covariates. Random forest (RF) and geographically weighted regression (GWR) were employed to model and map Zn concentrations in urban topsoil. The results showed that urban functional type, geology, NDVI, elevation, slope, and aspect were key environmental covariates. Compared with land use types, urban functional types could better reflect the spatial variation in Zn. The RF and GWR models were established using the key environmental covariates, with leave-one-out cross-validated R values of 0.68 and 0.58 and root mean square errors of 0.51 and 0.57, respectively. The results indicated that digital mapping of Zn in urban topsoil by using multisource geospatial data and RF was feasible. RF might be more suitable to fit the stochastic characteristics of Zn in urban topsoils than GWR, which considers deterministic trends in modeling.

Nobiletin, a novel inhibitor, inhibits HBsAg production and hepatitis B virus replication.

Chronic hepatitis B virus (HBV) infection is a serious problem due to its extensive worldwide distribution and poor prognosis including cirrhosis and/or hepatocellular carcinoma. The hepatitis B surface antigen(HBsAg) is a vital serum marker in HBV infection and a major obstacle for effective and subsequently virus clearance. However, Current anti-HBV drugs, such as nucleos(t)ide analogs (NA) and PegIFN, do not meet ideal result of sustained HBsAg loss (defined as functional cure). Therefore, there is an urgent need to identify a new compound targeting HBsAg. In this study, nobiletin was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of nobiletin on HBV was determined in HepG2.2.15 and HepG2-NTCP cells. Furthermore, the antiviral capability of nobiletin was also verified in vivo. Unlike entecavir (ETV) therapy, which reduced HBV DNA but do not lead to an effective reduction in HBsAg, nobiletin significantly reduced the level of HBsAg as well as lowered HBV DNA in vivo and in vitro. Meanwhile, combination of nobiletin and ETV led to broad reductions of both HBV DNA and HBsAg level. This study may shed light on the development of a novel class of anti-HBV agents.

Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production.

BACKGROUND: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. METHODS: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. FINDINGS: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. INTERPRETATION: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.

Spatiotemporal evolution of urban agglomerations in four major bay areas of US, China and Japan from 1987 to 2017: Evidence from remote sensing images.

As major urban agglomerations with strong urbanization, global bay areas are seldom detected and compared in detail regarding the spatiotemporal evolution of their urban expansion. In this work, a framework was applied for detecting and comparing the spatiotemporal evolution of urban agglomerations in four major bay areas: the San Francisco Bay Area and the New York Bay Area in the US, the Tokyo Bay Area in Japan, and the Guangdong-Hong Kong-Macau (GHM) Bay Area in China. Landsat images from 1987, 1997, 2007 and 2017 were employed to derive the four urban bay areas using the object-oriented support vector machine (O-SVM) classification method, and a multi-scale spatial analysis method was applied to detect the landscape characteristics and types of growth in the urban expansions. The results showed that: (1) the O-SVM classification method exhibited a high accuracy in urban area extraction, especially for classifying large-scale images; (2) the urban areas of the San Francisco Bay Area, the New York Bay Area, the Tokyo Bay Area and the GHM Bay Area from 1987 to 2017 expanded from 1686.82, 5315.93, 3765.09 and 605.71 km2 to 2714.7, 8359.18, 5351.06 and 7568.19 km2, respectively, with a corresponding annual average increase of 1.60%, 1.52%, 1.18% and 8.82%; (3) the GHM Bay Area had the largest expansion area and rate among the four bay areas; (4) both the San Francisco Bay Area and the New York Bay Area successively formed a multi-nuclei ribbon model, and the Tokyo Bay Area and the GHM Bay Area formed a multinuclear fan-shaped model and a triangle zonal expansion pattern, respectively; and (5) the spatial patterns of urban expansions in these bay areas shifted from outlying to edge-expansion and infilling, in which the Tokyo Bay Area and the New York Bay Area experienced the largest infilling growth, and the San Francisco Bay Area followed closely thereafter; all were ahead of the GHM Bay Area. These results will be helpful for the understanding and sustainable development of these bay areas.

PBK overexpression promotes metastasis of hepatocellular carcinoma via activating ETV4-uPAR signaling pathway.

Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A.

Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.

AGK2, A SIRT2 Inhibitor, Inhibits Hepatitis B Virus Replication In Vitro And In Vivo.

Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. We have reported that HBx (hepatitis B virus X protein)-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis. However, the potential anti-HBV effect of AGK2, a selective inhibitor of SIRT2, has not been reported. Here, the role of AGK2 on HBV replication was examined in the HepAD38 and HepG2-NTCP cell lines. The HBV genome was stably integrated in HepAD38 cell line which expresses HBV under the control of tetracycline. The HepG2-NTCP cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) receptor are susceptible to HBV infection. We found that AGK2 exhibited a robust anti-HBV activity with minimal hepatotoxicity. AGK2 inhibited the expression of HBV total and 3.5kb RNAs, DNA replicative intermediates and HBV core protein (HBc). Moreover, AGK2 treatment suppressed the secretion of the hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg). Importantly, AGK2 treatment inhibited serum HBV DNA, HBeAg and HBsAg levels as well as hepatic HBV DNA, RNA and HBc in the HBV transgenic mice. The results indicated that AGK2, as a SIRT2 inhibitor, might be a new therapeutic option for controlling HBV infection.

Association between SERT insertion/deletion polymorphism and the risk of irritable bowel syndrome: A meta-analysis based on 7039 subjects.

PURPOSE: We performed this study to better assess the relationship between serotonin transporter (SERT) insertion/deletion polymorphism and the risk of irritable bowel syndrome (IBS). METHODS: Eligible studies were searched in PubMed, Medline, Embase and CNKI. A total of 27 studies with 7039 participants were analyzed. RESULTS: Significant association with the risk of IBS was detected for the SERT insertion/deletion polymorphism in additive comparison (p < 0.0001). Further subgroup analyses according to ethnicity of participants revealed that the SERT insertion/deletion polymorphism was significantly associated with the risk of IBS in Asians (dominant model: p = 0.001; recessive model: p = 0.0003; allele model: p = 0.001) and Caucasians (dominant model: p = 0.04; additive model: p < 0.0001). When we stratified available data according to type of disease, we found that the SERT insertion/deletion polymorphism was significantly correlated with the risk of constipation predominant IBS (IBS-C) in recessive comparison (p = 0.04). However, no positive results were detected in the diarrhea predominant IBS (IBS-D) and mixture of diarrhea and constipation IBS (IBS-M) subgroups. CONCLUSIONS: Our findings indicated that the SERT insertion/deletion polymorphism may serve as a genetic biomarker of IBS in Asians and Caucasians.

Geo-detection of factors controlling spatial patterns of heavy metals in urban topsoil using multi-source data.

Heavy metal contamination has become a serious and widespread problem in urban environment. Understanding its controlling factors is vital for the identification, prevention, and remediation of pollution sources. This study aimed to identify the factors controlling heavy metal accumulation in urban topsoil using the geodetector method and multiple data sources. Environmental factors including geology, relief (elevation, slope, and aspect), and organism (land-use and vegetation) were extracted from a geological thematic map, digital elevation model, and time-series of Landsat images, respectively. Then, the power of determinant (q) was calculated using geodetector to measure the affinity between the environmental factors and arsenic (As) and lead (Pb). Geology was the dominant factor for As distribution in the this study area; it explained 38% of the spatial variation in As, and nonlinear enhancements were observed for the interactions between geology and elevation (q = 0.50) and slope (q = 0.49). Land-use and vegetation bi-enhanced each other and explained 39% of the spatial variation in Pb. These results indicated that geology and relief were the factors controlling the spatial distribution of As, and organism factors, especially anthropogenic activities, were the factors controlling the spatial distribution of Pb in the study area. As was derived from weathering transportation, and deposition processes of original bedrock and subsequent pedogenesis, and anthropogenic activity was the most likely source of Pb contamination in urban topsoil in Shenzhen. Moreover, geodetector provided evidence to explore the factors controlling spatial patterns of heavy metals in soils.

Unsupervised Simplification of Image Hierarchies via Evolution Analysis in Scale-Sets Framework.

Region-based hierarchical image representation is crucial in many computer vision applications. However, in practice, an image hierarchy is usually dense, and contains many less informative branches. It is expected that a hierarchy should be accurate and simplified, which is not only desirable for different applications, but also saves considerable computational load for the further analysis. To achieve this target, this paper proposes a novel approach for unsupervised simplification of region-based image hierarchies, which employs the global and local evolution analyses of a hierarchy. First, we introduce a global evolution analysis in the scale-sets framework, which provides clues for eliminating less informative branches. Moreover, a hybrid unsupervised simplification method is designed, utilizing the information from global and local evolution functions. A number of experiments on various images have shown that the proposed approach is effective and efficient in removing less informative nodes (averagely about 90% of the whole nodes), while preserving salient image details and retaining the accuracy.

miR-101 inhibits the G1-to-S phase transition of cervical cancer cells by targeting Fos.

OBJECTIVES: The chief objective of this study was to identify the miRNAs targeting Fos, a well-recognized proto-oncogene that is commonly overexpressed in cervical cancer, and its biological significance on the cellular behaviors of HeLa, a cervical cancer cell. MATERIALS AND METHODS: We initially analyzed the 3'untranslated region (3'UTR) of Fos and screened the potential miRNAs targeting Fos using 3 bioinformatical Web sites. Luciferase reporter assay, real-time polymerase chain reaction, and Western blotting were used to validate the binding of chosen miRNA (miR-101) on the 3'UTR of Fos and the downstream regulation on its mRNA and protein levels. Furthermore, flow cytometry along with the Fos rescue strategy was applied to analyze the modulation of cell cycle of HeLa cells by miR-101. RESULTS: Among these predicted candidate miRNAs, miR-101 was the miRNAs preferred by all the 3 used Web sites. The results of luciferase reporter assay, real-time polymerase chain reaction, and Western blotting demonstrated that miR-101 directly targeted on the 3'UTR of Fos and down-regulated the expression of Fos at mRNA and protein levels. Furthermore, cell cycle analysis showed that miR-101 arrests G1-to-S phase transition of HeLa cells, at least partially by targeting Fos. CONCLUSIONS: We concluded that by targeting the proto-oncogene Fos, miR-101 is involved in G1-to-S phase transition in cervical cancer cells in vitro and might provide a new approach for the pharmacological interference node in cervical cancer treatment.

Generalized groove density equation concerning bending-grating-related imaging properties.

Varied-line-spacing gratings are used in soft-x-ray monochromators and spectrometers because of their ability to correct various aberrations by varying the groove density. A curved grating blank in a Rowland circle mounting could eliminate primary aberrations. Bending a plane constant-groove-density grating into a desirable surface can eliminate higher-order aberrations as a result of the change in surface profile and groove density. This provides a simple means for improving the imaging properties. When used in a monochromator, the grating can be bent to different degrees to minimize aberrations at all wavelengths. General formulas concerning the transformations of groove function, groove density, and groove spacing are presented for the bending grating. Analytic results with a numerical example show the significant properties of the system.

Simplification of vector ray tracing by the groove function.

Tracing rays through arbitrary diffraction gratings (including holographic gratings of the second generation fabricated on a curved substrate) by the vector form is somewhat complicated. Vector ray tracing utilizes the local groove density, the calculation of which highly depends on how the grooves are generated. Characterizing a grating by its groove function, available for almost arbitrary gratings, is much simpler than doing so by its groove density, essentially being a vector. Applying the concept of Riemann geometry, we give an expression of the groove density by the groove function. The groove function description of a grating can thus be incorporated into vector ray tracing, which is beneficial especially at the design stage. A unified explicit grating ray-tracing formalism is given as well.