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Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

Abstract Recently, segmentation-based approaches have been proposed to tackle arbitrary-shaped text detection. The trade-off between speed and accuracy is still a challenge that hinders its deployment in practical applications. Previous methods adopt complex pipelines to improve accuracy while ignoring inference speed. Moreover, the performance of most efficient scene text detectors often suffers from weak feature extraction when equipping lightweight networks. In this paper, we propose a novel distillation method for efficient and accurate arbitrary-shaped text detection, termed kernel-mask knowledge distillation. Our approach equips a low computational-cost visual transformer module (VTM) and a feature adaptation layer to make full use of feature-based and response-based knowledge in distillation. More specifically, first, the text features are obtained by aggregating the multi-level information extracted in the respective backbones of the teacher and student networks. Second, the text features are respectively sent to the VTM to enhance the feature representation ability. Then, we distill the feature-based and response-based kernel knowledge of the teacher network to obtain an efficient and accurate arbitrary-shaped text detection model. Extensive experiments on publicly available datasets demonstrate the state-of-the-art performance of our method. It is worth noting that our method can achieve a competitive F-measure of 86.92% at 34.5 FPS on Total-text. Code is available at https://github.com/giganticpower/KKDnet .

Liver zonation across a murine ischemia/reperfusion injury model is characterised and the protective effect of celastrol against I/R injury by activating HIF1α signaling is presented, representing a novel strategy for resolving liver I/R

BackgroundThe role of copper in cancer treatment is multifaceted, with copper homeostasis-related genes associated with both breast cancer prognosis and chemotherapy resistance. Interestingly, both elimination and overload of copper have been reported to have therapeutic potential in cancer treatment. Despite these findings, the exact relationship between copper homeostasis and cancer development remains unclear, and further investigation is needed to clarify this complexity.MethodsThe pan-cancer gene expression and immune infiltration analysis were performed using the Cancer Genome Atlas Program (TCGA) dataset. The R software packages were employed to analyze the expression and mutation status of breast cancer samples. After constructing a prognosis model to separate breast cancer samples by LASSO-Cox regression, we examined the immune statement, survival status, drug sensitivity and metabolic characteristics of the high- and low-copper related genes scoring groups. We also studied the expression of the constructed genes using the human protein atlas database and analyzed their related pathways. Finally, copper staining was performed with the clinical sample to investigate the distribution of copper in breast cancer tissue and paracancerous tissue.ResultsPan-cancer analysis showed that copper-related genes are associated with breast cancer, and the immune infiltration profile of breast cancer samples is significantly different from that of other cancers. The essential copper-related genes of LASSO-Cox regression were ATP7B (ATPase Copper Transporting Beta) and DLAT (Dihydrolipoamide S-Acetyltransferase), whose associated genes were enriched in the cell cycle pathway. The low-copper related genes scoring group presented higher levels of immune activation, better probabilities of survival, enrichment in pathways related to pyruvate metabolism and apoptosis, and higher sensitivity to chemotherapy drugs. Immunohistochemistry staining showed high protein expression of ATP7B and DLAT in breast cancer samples. The copper staining showed copper distribution in breast cancer tissue.ConclusionThis study displayed the potential impacts of copper-related genes on the overall survival, immune infiltration, drug sensitivity and metabolic profile of breast cancer, which could predict patients’ survival and tumor statement. These findings may serve to support future research efforts aiming at improving the management of breast cancer.

Emerging evidence suggests that phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1), a specific phosphoethanolamine and phosphocholine phosphatase, is involved in energy metabolism. In this review, we describe the structure and regulation of PHOSPHO1, as well as current knowledge about the role of PHOSPHO1 and its related phospholipid metabolites in regulating energy metabolism. We also examine mechanistic evidence of PHOSPHO1- and phospholipid-mediated regulation of mitochondrial and lipid droplets functions in the context of metabolic homeostasis, which could be potentially targeted for treating metabolic disorders.

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.

With the continuous development of communication technology, the wireless communication environment becomes more and more complex with various intentional and unintentional signals. Radio signals are modulated in different ways. The traditional radio modulation recognition technology cannot recognize the modulation modes accurately. Consequently, the communication system has embraced Deep Learning (DL) models as they can automatically recognize the modulation modes and have better accuracy. This paper systematically summarizes the related contents of radio Automatic Modulation Recognition (AMR) based on DL over the last seven years. First, we summarize the current research status of modulation recognition and the necessity of AMR research based on DL. Then, we review current radio AMR methods based on DL. In addition, we also propose a network model of AMR based on Convolutional Neural Network (CNN) and prove its effectiveness. Finally, we highlight existing challenges and research directions of radio AMR based on DL.

With the development of communication technology and the increasingly complex wireless communication channel environment, the requirements for radio modulation recognition are also increased to avoid interference and improve the efficiency of radio spectrum resources. To achieve high recognition accuracy with less computational overload, we propose a radio signal modulation recognition method based on deep learning, which uses a pruning strategy to reduce computational overload, based on the original model, CNN-LSTM-DNN (CLDNN), and the double-layer long short-term memory (LSTM). Effect factors are analyzed in terms of recognition accuracy by adjusting the parameters of each network layer. The results of the experiments show that the model not only has a greater precision improvement than some existing models, but also reduces the computational resources necessary.

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.

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.

Background and Aim: Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids. Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor (LXR), a nuclear receptor with anti-cholestasis activity, whereas the sulfated oxysterols antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Methods: Liver-specific STS transgenic mice were created and subject to the lithocholic acid (LCA)-induced model of cholestasis. Results: Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis. The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes, likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols. Conclusions: STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands. Keywords: Steroid sulfatase, Bile acid, Toxicity, Cholestasis, Liver X receptor

ABSTRACT 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. Polyomavirus and papillomavirus oncoproteins 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, we demonstrate that the upregulated APOBEC3B enzyme is strongly nuclear and partially localized to virus replication centers. Second, truncated T antigen (truncT) is sufficient for APOBEC3B upregulation, and the RB-interacting motif (LXCXE), but not the p53-binding domain, is required. Third, genetic knockdown of RB1 alone or in combination with RBL1 and/or RBL2 is insufficient to suppress truncT-mediated induction of APOBEC3B. Fourth, CDK4/6 inhibition by palbociclib is also insufficient to suppress truncT-mediated induction of APOBEC3B. Last, global gene expression analyses in a wide range of human cancers show significant associations between expression of APOBEC3B and other genes known to be regulated by the RB/E2F axis. These experiments combine to implicate the RB/E2F axis in promoting APOBEC3B transcription, yet they also suggest that the polyomavirus RB-binding motif has at least one additional function in addition to RB inactivation for triggering APOBEC3B upregulation in virus-infected cells. IMPORTANCE The APOBEC3B DNA cytosine deaminase is overexpressed in many different cancers and correlates 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 modulates the binding of E2F family transcription factors to promote APOBEC3B expression. This work strengthens the mechanistic linkage between active cell cycling, APOBEC3B overexpression, and cancer mutagenesis. Although this mutational 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 nonviral cancers, where genetic mechanisms often activate the RB/E2F axis and APOBEC3B mutagenesis contributes to tumor evolution.

Glycosphingolipids are ubiquitous molecules composed of a lipid and a carbohydrate moiety. Their main functions are as antigen/toxin receptors, in cell adhesion/recognition processes, or initiation/modulation of signal transduction pathways. Microbes take advantage of the different carbohydrate structures displayed on a specific cell surface for attachment during infection. For some viruses, such as the polyomaviruses, binding to gangliosides determines the internalization pathway into cells. For others, the interaction between microbe and carbohydrate can be a critical determinant for host susceptibility. In this review, we summarize the role of glycosphingolipids as receptors for members of the non-enveloped calici-, rota-, polyoma- and parvovirus families.

BK polyomavirus (BKPyV) is an emerging pathogen whose reactivation causes severe disease in transplant patients. Unfortunately, there is no specific anti-BKPyV treatment available, and host cell components that affect the infection outcome are not well characterized. In this report, we examined the relationship between BKPyV productive infection and the activation of the cellular DNA damage response (DDR) in natural host cells. Our results showed that both the ataxia-telangiectasia mutated (ATM)- and ATM and Rad-3-related (ATR)-mediated DDR were activated during BKPyV infection, accompanied by the accumulation of polyploid cells. We assessed the involvement of ATM and ATR during infection using small interfering RNA (siRNA) knockdowns. ATM knockdown did not significantly affect viral gene expression, but reduced BKPyV DNA replication and infectious progeny production. ATR knockdown had a slightly more dramatic effect on viral T antigen (TAg) and its modified forms, DNA replication, and progeny production. ATM and ATR double knockdown had an additive effect on DNA replication and resulted in a severe reduction in viral titer. While ATM mainly led to the activation of pChk2 and ATR was primarily responsible for the activation of pChk1, knockdown of all three major phosphatidylinositol 3-kinase-like kinases (ATM, ATR, and DNA-PKcs) did not abolish the activation of γH2AX during BKPyV infection. Finally, in the absence of ATM or ATR, BKPyV infection caused severe DNA damage and aberrant TAg staining patterns. These results indicate that induction of the DDR by BKPyV is critical for productive infection, and that one of the functions of the DDR is to minimize the DNA damage which is generated during BKPyV infection.

ABSTRACT BK virus (BKV) is the causative agent for polyomavirus-associated nephropathy, a severe disease found in renal transplant patients due to reactivation of a persistent BKV infection. BKV replication relies on the interactions of BKV with many nuclear components, and subnuclear structures such as promyelocytic leukemia nuclear bodies (PML-NBs) are known to play regulatory roles during a number of DNA virus infections. In this study, we investigated the relationship between PML-NBs and BKV during infection of primary human renal proximal tubule epithelial (RPTE) cells. While the levels of the major PML-NB protein components remained unchanged, BKV infection of RPTE cells resulted in dramatic alterations in both the number and the size of PML-NBs. Furthermore, two normally constitutive components of PML-NBs, Sp100 and hDaxx, became dispersed from PML-NBs. To define the viral factors responsible for this reorganization, we examined the cellular localization of the BKV large tumor antigen (TAg) and viral DNA. TAg colocalized with PML-NBs during early infection, while a number of BKV chromosomes were adjacent to PML-NBs during late infection. We demonstrated that TAg alone was not sufficient to reorganize PML-NBs and that active viral DNA replication is required. Knockdown of PML protein did not dramatically affect BKV growth in culture. BKV infection, however, was able to rescue the growth of an ICP0-null herpes simplex virus 1 mutant whose growth defect was partially due to its inability to disrupt PML-NBs. We hypothesize that the antiviral functions of PML-NBs are inactivated through reorganization during normal BKV infection. IMPORTANCE BK virus (BKV) is a human pathogen that causes severe diseases, including polyomavirus-associated nephropathy in kidney transplant patients and hemorrhagic cystitis in bone marrow transplant recipients. How BKV replication is regulated and the effects of a lytic BKV infection on host cells at the molecular level are not well understood. Currently, there is no specific antiviral treatment for BKV-associated disease, and a better understanding of the complete life cycle of the virus is necessary. Here, we report the interplay between BKV and one of the regulatory structures in the host cell nucleus, promyelocytic leukemia nuclear bodies (PML-NBs). Our results show that BKV infection reorganizes PML-NBs as a strategy to inactivate the negative functions of PML-NBs.

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 dietinduced 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis. [ABSTRACT FROM AUTHOR]

The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estro gen/estrogen sulfate deliverymay represent a novel approach to manage metabolic syndrome. [ABSTRACT FROM AUTHOR]

Sulfotransferase (SULT)-mediated sulfation represents a critical mechanismin regulating the chemical and functional homeostasis of endogenous and exogenous molecules. The cholesterol sulfotransferase SULT2B1b catalyzes the sulfoconjugation of cholesterol to synthesize cholesterol sulfate (CS). In this study, we showed that the expression of SULT2B1b in the liver was induced in obese mice and during the transition from the fasted to the fed state, suggesting that the regulation of SULT2B1b is physiologically relevant. CS and SULT2B1b inhibited gluconeogenesis by targeting the gluconeogenic factor hepatocyte nuclear factor 4 (HNF4α) in both cell cultures and transgenic mice. Treatment of mice with CS or transgenic overexpression of the CS- generating enzyme SULT2B1b in the liver inhibited hepatic gluconeogenesis and alleviated metabolic abnormalities both in mice with diet-induced obesity (DIO) and in leptin-deficient (ob/ob) mice. Mechanistically, CS and SULT2B1b inhibited gluconeogenesis by suppressing the expression of acetyl coenzyme A (acetyl-CoA) synthetase (Acss), leading to decreased acetylation and nuclear exclusion of HNF4α. Our results also suggested that leptin is a potential effector of SULT2B1b in improving metabolic function. We conclude that SULT2B1b and its enzymatic by-product CS are important metabolic regulators that control glucose metabolism, suggesting CS as a potential therapeutic agent and SULT2B1b as a potential therapeutic target for metabolic disorders. [ABSTRACT FROM AUTHOR]

BK polyomavirus (BKPyV) is a widespread human pathogen that establishes a lifelong persistent infection and can cause severe disease in immunosuppressed patients. BKPyV is a nonenveloped DNA virus that must traffic through the endoplasmic reticulum (ER) for productive infection to occur; however, it is unknown how BKPyV exits the ER before nuclear entry. In this study, we elucidated the role of the ER-associated degradation (ERAD) pathway during BKPyV intracellular trafficking in renal proximal tubule epithelial (RPTE) cells, a natural host cell. Using proteasome and ERAD inhibitors, we showed that ERAD is required for productive entry. Altered trafficking and accumulation of uncoated viral intermediates were detected by fluorescence in situ hybridization and indirect immunofluorescence in the presence of an inhibitor. Additionally, we detected a change in localization of partially uncoated virus within the ER during proteasome inhibition, from a BiP-rich area to a calnexin-rich subregion, indicating that BKPyV accumulated in an ER subcompartment. Furthermore, inhibiting ERAD did not prevent entry of capsid protein VP1 into the cytosol from the ER. By comparing the cytosolic entry of the related polyomavirus simian virus 40 (SV40), we found that dependence on the ERAD pathway for cytosolic entry varied between the polyomaviruses and between different cell types, namely, immortalized CV-1 cells and primary RPTE cells. [ABSTRACT FROM AUTHOR]

Glycosphingolipids are ubiquitous molecules composed of a lipid and a carbohydrate moiety. Their main functions are as antigen/toxin receptors, in cell adhesion/recognition processes, or initiation/modulation of signal transduction pathways. Microbes take advantage of the different carbohydrate structures displayed on a specific cell surface for attachment during infection. For some viruses, such as the polyomaviruses, binding to gangliosides determines the internalization pathway into cells. For others, the interaction between microbe and carbohydrate can be a critical determinant for host susceptibility. In this review, we summarize the role of glycosphingolipids as receptors for members of the non-enveloped calici-, rota-, polyoma- and parvovirus families. [ABSTRACT FROM AUTHOR]

BK virus (BKV) is a nonenveloped, ubiquitous human polyomavirus that establishes a persistent infection in healthy individuals. It can be reactivated, however, in immunosuppressed patients and cause severe diseases, including polyomavirus nephropathy. The entry and disassembly mechanisms of BKV are not well defined. In this report, we characterized several early events during BKV infection in primary human renal proximal tubule epithelial (RPTE) cells, which are natural host cells for BKV. Our results demonstrate that BKV infection in RPTE cells involves an acidic environment relatively early during entry, followed by transport along the microtubule network to reach the endoplasmic reticulum (ER). A distinct disulfide bond isomerization and cleavage pattern of the major capsid protein VP1 was observed, which was also influenced by alterations in pH and disruption of trafficking to the ER. A dominant negative form of Derlin-1, an ER protein required for retro-translocation of certain misfolded proteins, inhibited BKV infection. Consistent with this, we detected an interaction between Derlin-1 and VP1. Finally, we show that proteasome function is also linked to BKV infection and capsid rearrangement. These results indicate that BKV early entry and disassembly are highly regulated processes involving multiple cellular components. [ABSTRACT FROM AUTHOR]

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 MutSa, 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 MutSa 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]