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SUMMARY Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with the host lysine acetylases p300/CBP and the tumor suppressor RB. How these interactions influence cellular gene expression remains unclear. We find that e1a displaces RBs from E2F transcription factors and promotes p300 acetylation of RB1 K873/K874 to lock it into a repressing conformation that interacts with repressive chromatin-modifying enzymes. These repressing p300-e1a-RB1 complexes specifically interact with host genes that have unusually high p300 association within the gene body. The TGFβ-, TNF-, and interleukin-signaling pathway components are enriched among such p300-targeted genes. The p300-e1a-RB1 complex condenses chromatin in a manner dependent on HDAC activity, p300 lysine acetylase activity, the p300 bromodomain, and RB K873/K874 and e1a K239 acetylation to repress host genes that would otherwise inhibit productive virus infection. Thus, adenovirus employs e1a to repress host genes that interfere with viral replication.

Testing SARS-CoV-2 viral loads in wastewater has recently emerged as a method of tracking the prevalence of the virus and an early-warning tool for predicting outbreaks in the future. This study reports SARS-CoV-2 viral load in wastewater influents and treated effluents of 11 wastewater treatment plants (WWTPs), as well as untreated wastewater from 38 various locations, in the United Arab Emirates (UAE) in May and June 2020. Composite samples collected over twenty-four hours were thermally deactivated for safety, followed by viral concentration using ultrafiltration, RNA extraction using commercially available kits, and viral quantification using RT-qPCR. Furthermore, estimates of the prevalence of SARS-CoV-2 infection in different regions were simulated using Monte Carlo. Results showed that the viral load in wastewater influents from these WWTPs ranged from 7.50E+02 to over 3.40E+04 viral gene copies/L with some plants having no detectable viral RNA by RT-qPCR. The virus was also detected in 85% of untreated wastewater samples taken from different locations across the country, with viral loads in positive samples ranging between 2.86E+02 and over 2.90E+04 gene copies/L. It was also observed that the precautionary measures implemented by the UAE government correlated with a drop in the measured viral load in wastewater samples, which were in line with the reduction of COVID-19 cases reported in the population. Importantly, none of the 11 WWTPs’ effluents tested positive during the entire sampling period, indicating that the treatment technologies used in the UAE are efficient in degrading SARS-CoV-2, and confirming the safety of treated re-used water in the country. SARS-CoV-2 wastewater testing has the potential to aid in monitoring or predicting an outbreak location and can shed light on the extent viral spread at the community level.

Overcoming the cellular type I interferon (IFN) host defense response is critical for a virus to ensure successful infection. Investigating the effects of human adenovirus (HAdV) infection on global cellular histone posttranslational modification (hPTM), we discovered that virus infection-induced activation of IFN signaling triggers a global increase in the monoubiquitination of histone 2B (H2B) at lysine 120, which is a mark for transcriptionally active chromatin. This hPTM, catalyzed by the hBre1/RNF20 complex, is necessary for activation of the cellular IFN-stimulated gene (ISG) expression program in response to viruses. To establish effective infection, the HAdV E1A protein binds to and dissociates the hBre1 complex to block IFN-induced H2B monoubiquitination and associated ISG expression. Together, these data uncover a key role for H2B monoubiquitination in the type I IFN response and a viral mechanism of antagonizing this hPTM to evade the IFN response.

Diabetes mellitus is a multifactorial global health disorder that is rising at an alarming rate. Cardiovascular diseases, kidney damage and neuropathy are the main cause of high mortality rates among individuals with diabetes. One effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes is to target alpha-amylase and alpha-glucosidase, enzymes that catalyzes starch hydrolysis in the intestine. At present, approved inhibitors for these enzymes are restricted to acarbose, miglitol and voglibose. Although these inhibitors retard glucose absorption, undesirable gastrointestinal side effects impede their application. Therefore, research efforts continue to seek novel inhibitors with improved efficacy and minimal side effects. Natural products of plant origin have been a valuable source of therapeutic agents with lesser toxicity and side effects. The anti-diabetic potential through alpha-glucosidase inhibition of plant-derived molecules are summarized in this review. Eight molecules (Taxumariene F, Akebonoic acid, Morusin, Rhaponticin, Procyanidin A2, Alaternin, Mulberrofuran K and Psoralidin) were selected as promising drug candidates and their pharmacokinetic properties and toxicity were discussed where available. Supplementary Information The online version contains supplementary material available at 10.1007/s11101-021-09773-1.

We have determined distinct roles for different proteasome complexes in adenovirus (Ad) E1A-dependent transcription. We show that the 19S ATPase, S8, as a component of 19S ATPase proteins independent of 20S (APIS), binds specifically to the E1A transactivation domain, conserved region 3 (CR3). Recruitment of APIS to CR3 enhances the ability of E1A to stimulate transcription from viral early gene promoters during Ad infection of human cells. The ability of CR3 to stimulate transcription in yeast is similarly dependent on the functional integrity of yeast APIS components, Sug1 and Sug2. The 20S proteasome is also recruited to CR3 independently of APIS and the 26S proteasome. Chromatin immunoprecipitation reveals that E1A, S8 and the 20S proteasome are recruited to both Ad early region gene promoters and early region gene sequences during Ad infection, suggesting their requirement in both transcriptional initiation and elongation. We also demonstrate that E1A CR3 transactivation and degradation sequences functionally overlap and that proteasome inhibitors repress E1A transcription. Taken together, these data demonstrate distinct roles for APIS and the 20S proteasome in E1A-dependent transactivation.

Deregulation of the cell cycle is of paramount importance during adenovirus infection. Adenovirus normally infects quiescent cells and must initiate the cell cycle in order to propagate itself. The pRb family of proteins controls entry into the cell cycle by interacting with and repressing transcriptional activation by the E2F transcription factors. The viral E1A proteins indirectly activate E2F-dependent transcription and cell cycle entry, in part, by interacting with pRb and family members to free the E2Fs. We report here that an E1A 13S isoform can unexpectedly activate E2F-responsive gene expression independently of binding to the pRb family of proteins. We demonstrate that E1A binds to E2F/DP-1 complexes through a direct interaction with DP-1. E1A appears to utilize this binding to recruit itself to E2F-regulated promoters, and this allows the E1A 13S protein, but not the E1A 12S protein, to activate transcription independently of interaction with pRb. Importantly, expression of E1A 13S, but not E1A 12S, led to significant enhancement of E2F4 occupancy of E2F sites of two E2F-regulated promoters. These observations identify a novel mechanism by which adenovirus deregulates the cell cycle and suggest that E1A 13S may selectively activate a subset of E2F-regulated cellular genes during infection.

Unliganded thyroid hormone (TH) receptors (TRs) and other nuclear receptors (NRs) repress transcription of hormone-activated genes by recruiting corepressors (CoRs), such as NR CoR (N-CoR) and SMRT. Unliganded TRs also activate transcription of THrepressed genes. Some evidence suggests that these effects also involve TR͞CoR contacts; however, the precise reasons that CoRs activate transcription in these contexts are obscure. Unraveling these mechanisms is complicated by the fact that it is difficult to decipher direct vs. indirect effects of TR-coregulator contacts in mammalian cells. In this study, we used yeast, Saccharomyces cerevisiae, which lack endogenous NRs and NR coregulators, to determine how unliganded TRs can activate transcription. We previously showed that adenovirus 5 early-region 1A coactivates unliganded TRs in yeast, and that these effects are blocked by TH. We show here that human adenovirus type 5 early region 1A (