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Deep learning has achieved remarkable results in various fields, such as image recognition and classification. However, in the recognition of radio modulation methods, deep learning for different modulation methods of radio signal recognition results are not satisfactory. In this paper, we propose to use densely connected convolutional networks combined with bidirectional recurrent neural networks to identify the radios of 11 different modulation methods. The final results show that our method is more accurate than the traditional convolution neural network in modulation recognition.

BK polyomavirus (PyV) infects the genitourinary tract of >90% of the adult population. Immunosuppression increases the risk of viral reactivation, making BKPyV a leading cause of graft failure in kidney transplant recipients. Polyomaviruses have a small double-stranded DNA (dsDNA) genome that requires host replication machinery to amplify the viral genome. Specifically, polyomaviruses promote S phase entry and delay S phase exit by activating the DNA damage response (DDR) pathway via an uncharacterized mechanism requiring viral replication. BKPyV infection elevates expression of MutSα, a mismatch repair (MMR) pathway protein complex that senses and repairs DNA mismatches and can activate the DDR. Thus, we investigated the role of the MMR pathway by silencing the MutSα component, Msh6, in BKPyV-infected primary cells. This resulted in severe DNA damage that correlated with weak DNA damage response activation and a failure to arrest the cell cycle to prevent mitotic entry during infection. Furthermore, silencing Msh6 expression resulted in significantly fewer infectious viral particles due to significantly lower levels of VP2, a minor capsid protein important for trafficking during subsequent infections. Since viral assembly occurs in the nucleus, our findings are consistent with a model in which entry into mitosis disrupts viral assembly due to nuclear envelope breakdown, which disperses VP2 throughout the cell, reducing its availability for encapsidation into viral particles. Thus, the MMR pathway may be required to activate the ATR (ATM-Rad3-related) pathway during infection to maintain a favorable environment for both viral replication and assembly. IMPORTANCE Since there are no therapeutics that target BKPyV reactivation in organ transplant patients, it is currently treated by decreasing immunosuppression to allow the natural immune system to fight the viral infection. Antivirals would significantly improve patient outcomes since reducing immunosuppression carries the risk of graft failure. PyVs activate the DDR, for which there are several promising inhibitors. However, a better understanding of how PyVs activate the DDR and what role the DDR plays during infection is needed. Here, we show that a component of the mismatch repair pathway is required for DDR activation during PyV infection. These findings show that the mismatch repair pathway is important for DDR activation during PyV infection and that inhibiting the DDR reduces viral titers by generating less infectious virions that lack the minor capsid protein VP2, which is important for viral trafficking.

Recovering the 3D human pose from a single image with 2D joints is a challenging task in computer vision applications. The sparse representation (SR) model has been successfully adopted in 3D pose estimation approaches. However, since existing available training 3D data are often collected in a constrained environment (i.e., indoor) with limited diversity of subjects and actions, most SR-based approaches would have a lower generalization to real-world scenarios that may contain more complex cases. To alleviate this issue, this paper proposes SDM3d, a novel shape decomposition using multiple geometric priors for 3D pose estimation. SDM3d makes a new attempt by separating a 3D pose into the global structure and body deformations that are encoded explicitly via different priors constraints. Furthermore, a joint learning strategy is designed to learn two over-complete dictionaries from training data to capture more geometric priors information. We have evaluated SDM3d on four well-recognized benchmarks, i.e., Human3.6M, HumanEva-I, CMU MoCap, and MPII. The experiment results show the effectiveness of SDM3d.

The most severe sequelae after rehabilitation from SARS are femoral head necrosis and pulmonary fibrosis. We performed a 15-year follow-up on the lung and bone conditions of SARS patients. We evaluated the recovery from lung damage and femoral head necrosis in an observational cohort study of SARS patients using pulmonary CT scans, hip joint MRI examinations, pulmonary function tests and hip joint function questionnaires. Eighty medical staff contracted SARS in 2003. Two patients died of SARS, and 78 were enrolled in this study from August 2003 to March 2018. Seventy-one patients completed the 15-year follow-up. The percentage of pulmonary lesions on CT scans diminished from 2003 (9.40 ± 7.83)% to 2004 (3.20 ± 4.78)% (P 1/FVC%, t = 2.21, P = 0.04) and mid-flow of maximum expiration (FEF25%–75%, t = 2.76, P = 0.01). The volume of femoral head necrosis decreased significantly from 2003 (38.83 ± 21.01)% to 2005 (30.38 ± 20.23)% (P = 0.000 2), then declined slowly from 2005 to 2013 (28.99 ± 20.59)% and plateaued until 2018 (25.52 ± 15.51)%. Pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. Femoral head necrosis induced by large doses of steroid pulse therapy in SARS patients was not progressive and was partially reversible.

In this study, we investigated the structural characterization and antidiabetic effects of Lactobacillus H31 exopolysaccharide (EPS) H31-2 from pickled cabbage. The BLAST result indicated that Lactobacillus H31 was closely related to Lactobacillus plantarum S1S2L2. In the spectrum of Fourier-transform infrared spectroscopy (FT-IR), 3370 cm−1 was the characteristic band of polysaccharide. A structural analysis showed that the monosaccharides of EPS H31-2 included d -mannose (Man) and d -glucose (Glc). The molecular weight of EPS H31-2 was around 10.75 kDa. All these results suggested EPS H31-2 was a novel polysaccharide. The inhibition ratios of crude EPS H31 and the pure fraction H31-2 of pancreatic α-amylase were 89.1 ± 2.59% and 69.2 ± 8.95%, respectively. In addition, the supernatant glucose concentration of insulin-resistant HepG2 cells decreased by treatment with 10−8 M of EPS H31-2, which meant EPS H31-2 could promote the glucose uptake of insulin-resistant HepG2 cell. Furthermore, EPS H31-2 upregulated the expression of the GLUT-4, Akt-2, and AMPK, which play important roles in glycometabolism. These results suggested that Lactobacillus plantarum EPS H31-2 could effectively inhibit the activity of pancreas α-amylase and has potential applications in the prevention and alleviation of diabetes mellitus.

Understanding the underlying mechanism of HBV maturation and subviral particle production is critical to control HBV infection and develop new antiviral strategies. Here, we demonstrate that deoxycholic acid (DCA) plays a central role in HBV production. HBV infection increased DCA levels, whereas elimination of DCA-producing microbiome decreased HBV viral load. DCA can bind to HBs antigen via LXXLL motif at TM1 and TM2 region to regulate HBs-HBc interaction and the production of mature HBV. Plasma DCA levels from patients undergoing antiviral therapy were significantly higher in those with positive HBV viral load. These results suggest that intestinal DCA-producing microbiome can affect the efficiency of antiviral therapy and provide a potential novel strategy for HBV antiviral therapy.One Sentence SummaryWe demonstrate that DCA-promoted HBs-HBc interaction and contributes to HBV maturation.

The soft rot disease caused by Rhizopus stolonifer is an important disease in cherry tomato fruit. In this study, the effect of iturin A on soft rot of cherry tomato and its influence on the storage quality of cherry tomato fruit were investigated. The results showed that 512 μg/mL of iturin A could effectively inhibit the incidence of soft rot of cherry tomato fruit. It was found that iturin A could induce the activity of resistance-related enzymes including phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), peroxidase (POD), glucanase (GLU), and chitinase (CHI), and active oxygen-related enzymes including ascorbate peroxidases (APX), superoxide dismutases (SOD), catalases (CAT), and glutathione reductase (GR) of cherry tomato fruit. In addition, iturin A treatment could slow down the weight loss of cherry tomato and soften the fruit. These results indicated that iturin A could retard the decay and improve the quality of cherry tomato fruit by both the inhibition growth of R. stolonifera and the inducing the resistance.

In this paper, we aim to reconstruct a full 3D human shape from a single image. Previous vertex-level and parameter regression approaches reconstruct 3D human shape based on a pre-defined adjacency matrix to encode positive relations between nodes. The deep topological relations for the surface of the 3D human body are not carefully exploited. Moreover, the performance of most existing approaches often suffer from domain gap when handling more occlusion cases in real-world scenes. In this work, we propose a Deep Mesh Relation Capturing Graph Convolution Network, DC-GNet, with a shape completion task for 3D human shape reconstruction. Firstly, we propose to capture deep relations within mesh vertices, where an adaptive matrix encoding both positive and negative relations is introduced. Secondly, we propose a shape completion task to learn prior about various kinds of occlusion cases. Our approach encodes mesh structure from more subtle relations between nodes in a more distant region. Furthermore, our shape completion module alleviates the performance degradation issue in the outdoor scene. Extensive experiments on several benchmarks show that our approach outperforms the previous 3D human pose and shape estimation approaches., Accepted by ACM MM'21 (oral)

Capturing and annotating 3D point cloud data are very time-consuming and expensive. The unsupervised method is an effective solution to learn point cloud representations without data annotation. Most existing unsupervised methods take into account the importance of both local structure features and global features and combine them to learn object representations. However, they rarely consider that different local structures contribute differently for object representation. In this paper, we argue that the discriminative local structures are significant for object representation. Therefore, we propose a discriminability enhancement scheme to mine discriminative local structure features and further enhance their discriminability. Our unsupervised method can learn powerful representations of point clouds by fusing discriminative local structure features and global features. Experimental results show that our method can achieve superior performance on downstream classification tasks.

Under the strong supervision information of a large number of training samples with ground-truth labels, the point cloud classification techniques have achieved great success. However, in real tasks, it is difficult to get strong supervision information like fully ground-truth labels due to the high cost of the data labeling process. Thus, it is desirable to work with weak supervision. This paper presents a semi-supervised learning framework based on consistency constraints on the point cloud to solve the classification task. The key to the framework mainly includes consistency constraints and pseudo-label generation. The former uses consistency constraints to encourage the model to output consistent predictions on the original and the perturbed point cloud, which avoids overfitting due to limited labeled data. The latter generates high-quality pseudo-labels for unlabeled point clouds to strengthen the discriminative supervision of the model. By fully mining the labeled and unlabeled point clouds, the generalization ability of the model is improved. On the 3D point cloud benchmark ModelNet40 [19], with only 10% labeled data, our proposed approach performs comparable results to the supervised approaches.

Since a point cloud might contain large quantities of points in practical scenarios, it is desirable to perform downsampling before point cloud analysis. Classic downsampling strategies, such as farthest point sampling (FPS), tend to sample points regardless of subsequent tasks, which inevitably hampers the effectiveness of sampling results. Moreover, raw point clouds obtained from 3D sensors are usually noisy and unevenly distributed. As a consequence, the downsampling process might be affected seriously. In this paper, we propose a density-adaptive downsampling network (DA-Net) for point cloud classification task. The entire process of DA-Net is conducted in an end-to-end way, ensuring that the sampling operation is differentiable and optimal for downstream applications. One key process of DA-Net is density-adaptive K nearest neighboring (DAKNN), which is proposed to alleviate the adverse effects brought by density variation of point clouds. Another key process is the local adjustment (LA) of initial sampled points, which can further equip our model with noise immunity. Consequently, our network can enhance the effectiveness of sampled points and further improve the task performance. In point cloud classification task, our approach achieves significantly better results over existing downsampling alternatives. Extensive experiments are presented to demonstrate the advantages of our DA-Net.

3D human pose estimation from 2D joints of an image is a worthwhile and challenging research topic. Since a specific 2D pose could be projected from various 3D poses, the ambiguity becomes a difficult obstacle when recovering 3D pose from 2D. Many supervised learning solutions have been proposed in recent years, however, most of them require an abundant of well-annotated training samples to get satisfied estimation performance. In this paper, an unsupervised approach that built upon sparse representation (SR) is presented and its two enhancement schemes are provided. As the first scheme, the reweighting one improves the sparsity of the SR model which leads to a more accurate solution. Furthermore, based on the resulting minimization residual of the loss function in 2D, the discrepancy between the estimated 3D pose and the target 3D pose is used to adjust the estimated 3D pose to reach a better accuracy. Comprehensive experiments have been conducted on four well-recognized benchmarks for evaluation. Significant and consistent improvements over existing SR models are observed in our experiments. Furthermore, the proposed approach even outperforms many supervised learning works.

The inhibitory effect of Bacillomycin D, a cyclic lipopeptide, on Rhizopus stolonifer colonization of cherry tomato was studied, and its possible mechanism of action was explored. Bacillomycin D showed a direct inhibitory effect on R. stolonifer spore germination and mycelial growth in vitro. It conferred both a direct inhibitory effect on R. stolonifer growth in cherry tomato in vivo and induced host resistance in cherry tomato. Moreover, Bacillomycin D treatment significantly increased the activities of plant defense-related enzymes, including chitinase (CHI), β-1,3-glucanase (GLU), phenylalanine ammonia-lyase (PAL), and peroxidase (POD). Real-time PCR (RT-PCR) showed that defense-related genes involved in the salicylic acid defense signaling pathway and genes encoding pathogenesis-related proteins were up-regulated in Bacillomycin D treatment. Furthermore, Bacillomycin D-C16 resulted in direct inhibition and a remarkable induced resistance to R. stolonifer which was higher than as induced by Bacillomycin D-C14. Together, the data indicated that Bacillomycin D can control the growth of R. stolonifer through both the direct inhibition of the fungus and the activation of defense-related genes and enzymes in cherry tomato.

To ensure the real-time and accuracy of the human tracking system, it is necessary to predict the position of the target at the next moment according to the current trajectory of the target. This paper presents an accurate detection, extraction and tracking algorithm for human motion targets in video sequences. The algorithm uses the inter-frame difference threshold (TIFD) method to quickly and accurately detect and extract the target. The Buchberger algorithm is used to predict the area which may be in the next moment of the target, and the search scope of the target is reduced. Making full use of the results of running target detection can improve the target’s matching efficiency and tracking speed. At the same time, the corresponding experimental results are given. The results show that the method is more practical and can meet the basic requirements of human motion analysis.

Estimating 3D human pose from an annotated or detected 2D pose in a single RGB image is a challenging problem. A successful way to address this problem is the example-based approach. The existing example-based approaches often calculate a global pose error to search a single match 3D pose from the source library. This way fails to capture the local deformations of human pose and highly dependent on a large training set. To alleviate these issues, we propose a simple example-based approach with locality similarity preserving to estimate 3D human pose. Specifically, first of all, we split an annotated or detected 2D pose into 2D body parts with kinematic priors. Then, to recover the 3D pose from these 2D body parts, we recombine a 3D pose by using 3D body parts that are split from the 3D pose candidates. Note that joints in the combined 3D parts are refined by a weighted searching strategy during the inference. Moreover, to increase the search speed, we propose a candidate selecting mechanism to narrow the original source data. We evaluate our approach on three well-design benchmarks, including Human3.6M, HumanEva-I, and MPII. The extensive experimental results show the effectiveness of our approach. Specifically, our approach achieves better performance than compared approaches while using fewer training samples.

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.

Endometriosis is a frequent gynecologic disease in the world. CircRNAs can exert a crucial role in various diseases. Nevertheless, little is known about its roles in endometriosis. We investigated the involvement of circ_0061140 in endometriosis. Tissues from endometriosis women displayed an increased expression of circ_0061140. Then, we found loss of circ_0061140 significantly repressed ectopic endometrial cell proliferation, migration and invasion. Meanwhile,miR-140-3pcan demonstrate an important role in several cancers.Here, we reported miR-140-3p was reduced in ectopic endometrial cells and it acted as a target of circ_0061140. Moreover, miR-140-3p was able to reverse the effect of circ_0061140 on ectopic endometrial cells. Furthermore, Notch2 was predicted as a putative target of miR-140-3p. A positive correlation between circ_0061140 and Notch2 was indicated. miR-140-3p and Notch2 were operated as downstream effectors in the circ_0061140 mediated signaling in endometriosis. Decrease of circ_0061140 could depress endometriosis progression through modulating miR-140-3p and Notch2.

Purpose: To characterize the quality of life and mental health status of patients with uveitis and investigate predictors of psychological problems. Methods: A total of 245 patients and 105 controls were enrolled in this cross-sectional study. Quality of life, psychological status, socio-demographic and clinical data were obtained from questionnaires and medical records. Multivariate regression analyses and Receiver Operating Characteristic (ROC) were applied to obtain the model predicting psychological problems of patients. Results: Of 245 patients, 16.7% and 26.5% (PP= .029,PPP= .012, respectively), with an AUC of 0.78. Conclusions: Economic hardship, ocular complications, and poor self-reported visual function are predictors of mental problems in patients with uveitis.

Steroid sulfatase (STS), a desulfating enzyme that converts steroid sulfates to hormonally active steroids, plays an important role in the homeostasis of sex hormones. STS is expressed in the adipose tissue of both male and female mice, but the role of STS in the development and function of adipose tissue remains largely unknown. In this report, we show that the adipose expression of Sts was induced in the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes. Transgenic overexpression of the human STS in the adipose tissue of male mice exacerbated the HFD-induced metabolic phenotypes, including increased body weight gain and fat mass, and worsened insulin sensitivity, glucose tolerance, and energy expenditure, which were accounted for by adipocyte hypertrophy, increased adipose inflammation, and dysregulation of adipogenesis. The metabolic harm of the STS transgene appeared to have resulted from increased androgen activity in the adipose tissue, and castration abolished most of the phenotypes. Interestingly, the transgenic effects were sex specific, because the HFD-fed female STS transgenic mice exhibited improved metabolic functions, which were associated with attenuated adipose inflammation. The metabolic benefit of the STS transgene in female mice was accounted for by increased estrogenic activity in the adipose tissue, whereas such benefit was abolished upon ovariectomy. Our results revealed an essential role of the adipose STS in energy homeostasis in sex- and sex hormone-dependent manner. The adipose STS may represent a therapeutic target for the management of obesity and type 2 diabetes.

Brown adipose tissue (BAT) metabolism influences glucose homeostasis and metabolic health in mice and humans. Sympathetic stimulation of β-adrenergic receptors in response to cold induces proliferation, differentiation, and UCP1 expression in pre-adipocytes and mature brown adipocytes. Here we show that spleen tyrosine kinase (SYK) is upregulated during brown adipocyte differentiation and activated by β-adrenergic stimulation. Deletion or inhibition of SYK, a kinase known for its essential roles in the immune system, blocks brown and white pre-adipocyte proliferation and differentiation in vitro, and results in diminished expression of Ucp1 and other genes regulating brown adipocyte function in response to β-adrenergic stimulation. Adipocyte-specific SYK deletion in mice reduces BAT mass and BAT that developed consisted of SYK-expressing brown adipocytes that had escaped homozygous Syk deletion. SYK inhibition in vivo represses β-agonist-induced thermogenesis and oxygen consumption. These results establish SYK as an essential mediator of brown fat formation and function., Spleen protein tyrosine kinase (Syk) has so far been mainly studied in haematopoietic and immune cells. Here, the authors show that Syk also has a role in brown adipose tissue, where it regulates the formation of brown adipocytes and their thermogenic activation in response to β-adrenergic stimulation.

Estrogen sulfotransferase catalyzes the sulfoconjugation and deactivation of estrogens. Previously, we showed that loss of Est in male ob/ob mice, but not in female ob/ob mice, exacerbated the diabetic phenotype, but the underlying mechanism was unclear. In this study, we show that transgenic reconstitution of Est in the adipose tissue, but not in the liver, attenuated diabetic phenotype in Est-deficient ob/ob mice (obe mice). Mechanistically, adipose reconstitution of Est in obe mice (oae mice) resulted in reduced local and systemic inflammation, improved insulin sensitivity, and increased energy expenditure. At the molecular level, adipose induction of lipocalin-2 (Lcn2) in oae males may have contributed to the inhibition of inflammation because the level of Lcn2 was negatively associated with tumor necrosis factor (Tnf) α expression, and treatment of differentiated adipocytes with Lcn2 antagonized Tnfα-responsive inhibition of insulin signaling. The metabolic benefit of adipose reconstitution of Est was sex specific, because adipose reconstitution of Est in obe females had little effect. Interestingly, despite their improved metabolic functions, obe male mice with reconstituted Est in their adipose tissue failed to ameliorate the impairment of the structure and function of the pancreatic islets. In summary, our study uncovers a crucial adipose- and male-specific role of Est in maintaining the whole-body energy homeostasis.

Background & Aims Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men, which is thought to be due to compromised liver function to break down estrogens. The goal of this study is to determine whether the inflammatory induction of steroid sulfatase (STS), which converts inactive estrogen sulfates to active estrogens, may have contributed to the estrogen excess in chronic liver disease. Methods We performed bioinformatic analysis, real-time PCR, immunohistochemistry, and UPLC/MS-MS to analyze hepatic STS expression and serum estrogen levels in patients with chronic liver diseases. The crosstalk between NF-κB pathway and STS-regulated estrogen signaling was investigated by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay and gene knockdown experiments in human hepatocytes. Results Hepatic STS was induced in patients with chronic inflammatory liver diseases, which was accompanied by increased circulating estrogen levels. The human STS gene, but not the mouse Sts gene, was induced by inflammatory stimuli in hepatic cells. Mechanistically, STS was established as a novel NF-κB target gene, whose induction facilitated the conversion of inactive estrogen sulfates to active estrogens, and consequently attenuated the inflammatory response. In contrast, genetic or pharmacological inhibition of STS or a direct blockade of estrogen signaling sensitized liver cells to the transcriptional activation of NF-κB and inflammatory response, possibly through the inhibition of IκB kinase activation. Conclusions Our results suggest a negative feedback loop in chronic inflammatory liver diseases, in which the inflammatory activation of NF-κB induces STS gene expression. The induced STS facilitates the conversion of inactive estrogen sulfates to active estrogens, which in return attenuates the NF-κB-mediated inflammation.

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APOBEC3B is a single-stranded DNA cytosine deaminase with beneficial innate antiviral functions. However, misregulated APOBEC3B can also be detrimental by inflicting APOBEC signature C-to-T and C-to-G mutations in genomic DNA of multiple cancer types. Polyomaviruses and papillomaviruses use dominant oncoproteins to induce APOBEC3B overexpression, perhaps to their own benefit, but little is known about the cellular mechanisms hijacked by these viruses to do so. Here we investigate the molecular mechanism of APOBEC3B upregulation by the polyomavirus large T-antigen. First, truncated T-antigen (truncT) is sufficient for APOBEC3B upregulation and the RB interacting motif (LXCXE), but not the TP53 inhibition domain, is required. Second, upregulated APOBEC3B is strongly nuclear and partially localized to virus replication centers. Third, genetic knockdown of RB1 alone or in combination with RBL1 and/or RBL2 is insufficient to suppress truncT-mediated induction ofAPOBEC3B. Fourth, CDK4/6 inhibition by palbociclib is also insufficient to suppress truncT-mediated induction ofAPOBEC3B. Fifth, global gene expression analyses in a wide range of human cancers show significant associations between expression ofAPOBEC3Band other genes known to be regulated by the RB/E2F axis. These experiments combine to implicate the RB/E2F axis in promotingAPOBEC3Btranscription, yet they also suggest that the polyomavirus RB binding motif has in addition to RB inactivation at least one additional function for triggeringAPOBEC3Bupregulation in virus-infected cells.IMPORTANCEThe APOBEC3B DNA cytosine deaminase is overexpresssed in many different cancers and correlated with elevated frequencies of C-to-T and C-to-G mutations in 5’-TC motifs, oncogene activation, acquired drug resistance, and poor clinical outcomes. The mechanisms responsible for APOBEC3B overexpression are not fully understood. Here, we show that the polyomavirus truncated T-antigen (truncT) triggers APOBEC3B overexpression through its RB-interacting motif, LXCXE, which in turn likely enables one or more E2F family transcription factors to promoteAPOBEC3Bexpression. This work strengthens the mechanistic linkage between active cell cycling, APOBEC3B overexpression, and cancer mutagenesis. Although this mechanism damages cellular genomes, viruses may leverage it to promote evolution, immune escape, and pathogenesis. The cellular portion of the mechanism may also be relevant to non-viral cancers, where genetic mechanisms often activate the RB/E2F axis and APOBEC3B mutagenesis contributes to tumor evolution.

Sulfonation and desulfation are two opposing processes that represent an important layer of regulation of estrogenic activity via ligand supplies. Enzymatic activities of families of enzymes, known as sulfotransferases and sulfatases, lead to structural and functional changes of the steroids, thyroids, xenobiotics, and neurotransmitters. Estrogen sulfotransferase (EST) and steroid sulfatase (STS) represent negative and positive regulation of the estrogen activity, respectively. This is because EST-mediated sulfation deactivates estrogens, whereas STS-mediated desulfation converts the inactive estrogen sulfates to active estrogens. In addition to the known functions of estrogens, EST and STS in reproductive processes, regulation of estrogens and other signal molecules especially at the local tissue levels has gained increased attention in the context of metabolic disease in recent years. EST expression is detectable in the subcutaneous adipose tissue in both obese women and men, and the expression of EST is markedly induced in the livers of rodent models of obesity and type 2 diabetes. STS was found to be upregulated in patients with chronic inflammatory liver diseases. Interestingly, the tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity. EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Adipogenesis is also differentially regulated by EST in murine and human adipocytes. This chapter focuses on the recent progress in our understanding of the expression and regulation EST and STS in the context of metabolic homeostasis.

Polyomaviruses are a family of small DNA viruses that are associated with a number of severe human diseases, particularly in immunocompromised individuals. The detailed virus-host interactions during lytic polyomavirus infection are not fully understood. Here, we report the first nuclear proteomic study with BK polyomavirus (BKPyV) in a primary renal proximal tubule epithelial cell culture system using stable isotope labeling by amino acids in cell culture (SILAC) proteomic profiling coupled with liquid chromatography-tandem mass spectrometry. We demonstrated the feasibility of SILAC labeling in these primary cells and subsequently performed reciprocal labeling-infection experiments to identify proteins that are altered by BKPyV infection. Our analyses revealed specific proteins that are significantly up- or down-regulated in the infected nuclear proteome. The genes encoding many of these proteins were not identified in a previous microarray study, suggesting that differential regulation of these proteins may be independent of transcriptional control. Western blotting experiments verified the SILAC proteomic findings. Finally, pathway and network analyses indicated that the host cell DNA damage response signaling and DNA repair pathways are among the cellular processes most affected at the protein level during polyomavirus infection. Our study provides a comprehensive view of the host nuclear proteomic changes during polyomavirus lytic infection and suggests potential novel host factors required for a productive polyomavirus infection.

Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2−/− mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST−/− males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST−/− mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. Background: EST regulates estrogen homeostasis by sulfonating and deactivating estrogens. Results: Liver ischemia and reperfusion (I/R) induced the expression of EST and comprised estrogen activity in an Nrf2-dependent manner. EST ablation gender-specifically affected I/R sensitivity. Conclusion: EST is an oxidative stress responsive gene that affects liver I/R injury. Significance: Inhibition of EST, at least in females, represents an effective approach to manage hepatic I/R injury.

BK polyomavirus (BKPyV) reactivation is associated with severe human disease in kidney and bone marrow transplant patients. The interplay between viral and host factors that regulates the productive infection process remains poorly understood. We have previously reported that the cellular DNA damage response (DDR) is activated upon lytic BKPyV infection and that its activation is required for optimal viral replication in primary kidney epithelial cells. In this report, we set out to determine what viral components are responsible for activating the two major phosphatidylinositol 3-kinase-like kinases (PI3KKs) involved in the DDR: ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3-related (ATR) kinase. Using a combination of UV treatment, lentivirus transduction, and mutant virus infection experiments, our results demonstrate that neither the input virus nor the expression of large T antigen (TAg) alone is sufficient to trigger the activation of ATM or ATR in our primary culture model. Instead, our data suggest that the activation of both the ATM- and ATR-mediated DDR pathways is linked to viral DNA replication. Intriguingly, a TAg mutant virus that is unable to activate the DDR causes substantial host DNA damage. Our study provides insight into how DDRs are activated by polyomaviruses in primary cells with intact cell cycle checkpoints and how the activation might be linked to the maintenance of host genome stability. IMPORTANCE Polyomaviruses are opportunistic pathogens that are associated with several human diseases under immunosuppressed conditions. BK polyomavirus (BKPyV) affects mostly kidney and bone marrow transplant patients. The detailed replication mechanism of these viruses remains to be determined. We have previously reported that BKPyV activates the host DNA damage response (DDR), a response normally used by the host cell to combat genotoxic stress, to aid its own replication. In this study, we identified that the trigger for DDR activation is viral replication. Furthermore, we show that the virus is able to cause host DNA damage in the absence of viral replication and DDR activation. These results suggest an intricate relationship between viral replication, DDR activation, and host genome instability.