Wrenkendall1749

The modulation of GLI2, an oncogenic transcription factor commonly upregulated in cancer, is in many cases not due to genetic defects, suggesting dysregulation through alternative mechanisms. The identity of these molecular events remains for the most part unknown. Here, we identified TFII-I as a novel repressor of GLI2 expression. Mapping experiments suggest that the INR region of the GLI2 promoter is necessary for GLI2 repression. ChIP studies showed that TFII-I binds to this INR. TFII-I knockdown decreased the binding of NELF-A, a component of the promoter-proximal pausing complex at this site, and enriched phosphorylated RNAPII serine 2 in the GLI2 gene body. Immunoprecipitation studies demonstrate TFII-I interaction with SPT5, another pausing complex component. TFII-I overexpression antagonized GLI2 induction by TGFβ, a known activator of GLI2 in cancer cells. TGFβ reduced endogenous TFII-I binding to the INR and increased RNAPII SerP2 in the gene body. We demonstrate that this regulatory mechanism is not exclusive of GLI2. TGFβ-induced genes CCR7, TGFβ1 and EGR3 showed similar decreased TFII-I and NELF-A INR binding and increased RNAPII SerP2 in the gene body post-TGFβ treatment. Together these results identify TFII-I as a novel repressor of a subset of TGFβ-responsive genes through the regulation of RNAPII pausing.Oligonucleotide-based therapeutics have become a reality, and are set to transform management of many diseases. Nevertheless, the modulatory activities of these molecules on immune responses remain incompletely defined. Here, we show that gene targeting 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) can have opposing activities on Toll-Like Receptors 7 and 8 (TLR7/8), leading to divergent suppression of TLR7 and activation of TLR8, in a sequence-dependent manner. Surprisingly, TLR8 potentiation by the gapmer ASOs was blunted by locked nucleic acid (LNA) and 2'-methoxyethyl (2'MOE) modifications. Through a screen of 192 2'OMe ASOs and sequence mutants, we characterized the structural and sequence determinants of these activities. Importantly, we identified core motifs preventing the immunosuppressive activities of 2'OMe ASOs on TLR7. Based on these observations, we designed oligonucleotides strongly potentiating TLR8 sensing of Resiquimod, which preserve TLR7 function, and promote strong activation of phagocytes and immune cells. We also provide proof-of-principle data that gene-targeting ASOs can be selected to synergize with TLR8 agonists currently under investigation as immunotherapies, and show that rational ASO selection can be used to prevent unintended immune suppression of TLR7. Taken together, our work characterizes the immumodulatory effects of ASOs to advance their therapeutic development.Background and aims Quality metrics were established to develop standards to help assess quality of care, yet variation in inflammatory bowel disease (IBD) clinical practice exists. We performed a systematic review to assess the overall quality of evidence cited in formulating IBD quality metrics. Methods A systematic search was performed on PubMed, MEDLINE, and EMBASE. All major national and international IBD societies were included. Quality metrics were assessed for evidence quality and categorized as category A (guideline based), category B (primarily retrospective and observational studies) or category C (expert opinion). Quality metrics were examined for the type of metric, the quality, measurability, review, existing conflicts of interest (COI), and patient participation of the metric. Statistical analysis was conducted in R. Results A total of 143 distinct, and an aggregate total of 217 quality metrics were included and analyzed. 68%, 3.2%, and 28.6% of IBD quality metrics were based on low, moderate, and high quality of evidence, respectively. The proportion of high quality evidence across societies was significantly different (P less then 0.01). Five organizations included patients in quality metric development, three reported external review, not all reported measurable outcomes or stated the presence of a COI. Finally, 43% of quality metrics were published more than 5 years ago. Conclusions Quality metrics are important to standardize practice. As more than two-thirds of the quality metrics in IBD are based on low quality evidence, further studies are needed to improve the overall quality of evidence supporting the development of quality measures.Understanding the thermodynamics of DNA motifs is important for prediction and design of probes and primers, but melt curve analyses are low-throughput and produce inaccurate results for motifs such as bulges and mismatches. HA130 molecular weight Here, we developed a new, accurate and high-throughput method for measuring DNA motif thermodynamics called TEEM (Toehold Exchange Energy Measurement). It is a refined framework of comparing two toehold exchange reactions, which are competitive strand displacement between oligonucleotides. In a single experiment, TEEM can measure over 1000 ΔG° values with standard error of roughly 0.05 kcal/mol.Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility, however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional (CV) and germ-free (GF) mice were orally exposed to the Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. RNA-Seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of AhR, PXR, and CAR were more readily up-regulated by PCBs in CV conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic and steroid metabolism pathways were up-regulated, whereas response to misfolded proteins-related pathways were down-regulated by PCBs. At the high PCB dose, NADP and arginine appear to interact with drug-metabolizing enzymes (i.e. Cyp1-3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the LINCS L1000 database, therapeutics targeting anti-inflammatory and ER stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics.Vertebrates interact directly with food items through their dentition, and these interactions with trophic resources could often feedback to influence tooth structure. Although dentitions are often considered to be a fixed phenotype, there is the potential for environmentally induced phenotypic plasticity in teeth to extensively influence their diversity. Here, we review the literature concerning phenotypic plasticity of vertebrate teeth. Even though only a few taxonomically disparate studies have focused on phenotypic plasticity in teeth, there are a number of ways teeth can change their size, shape, or patterns of replacement as a response to the environment. Elucidating the underlying physiological, developmental, and genetic mechanisms that generate phenotypic plasticity can clarify its potential role in the evolution of dental phenotypes.Spermine (Spm) regulates water balance involved in water channel proteins aquaporins (AQPs) in plants. An increase in endogenous Spm content via exogenous Spm application significantly improved cell membrane stability, photosynthesis, osmotic adjustment (OA), and water use efficiency (WUE) contributing to enhanced tolerance to water stress in white clover. Spm up-regulated TrTIP2-1, TrTIP2-2, and TrPIP2-7 expression and also increased the abundance of TIP2 and PIP2-7 proteins in white clover under water stress. Spm quickly activated intracellular Ca2+ signaling and Spm-induced TrTIP2-2 and TrPIP2-7 expression could be blocked by Ca2+ channels blockers and the inhibitor of CDPK in leaves of white clover. TrSAMS in relation to Spm biosynthesis was firstly cloned from white clover and the TrSAMS was located in nucleus. Transgenic Arabidopsis overexpressing the TrSAMS had significantly higher endogenous Spm content and improved cell membrane stability, photosynthesis, OA, WUE, and transcript levels of AtSIP1-1, AtSIP1-2, AtTIP2-1, AtTIP2-2, AtPIP1-2, AtPIP2-1, and AtNIP2-1 than wild type in response to water stress. Current findings indicates that Spm regulates water balance via enhancement in OA, WUE, and water transport related to Ca2+-dependent AQPs expression in plants under water stress.A number of important principles in effective risk communication established in the late 20th century can provide important scientific insight into patient response to the risks posed by COVID-19 [1-3]. Early risk communication scholars studied public perceptions of risk in response to environmental disasters, or infectious disease outbreaks. They found acceptability of risk, and any limitations and acceptability of response by experts was shaped by two key components hazard and outrage. The number of people who are exposed, infected and fall ill can be considered the hazard. How the public and patients perceive the risk and respond to messages regarding risk mitigation relates to outrage. Social and cultural factors, immediacy, uncertainty, familiarity, personal control, scientific uncertainty and trust in institutions and media all shape acceptability of response. These outrage factors influence the ever-changing public understanding of COVID-19 risk, as well as the public's acceptance of personal and societal mitigation strategies. Risk perceptions and acceptability of mitigation strategies are also largely shaped in the context of culture and society. In concert, hazard and outrage along with cultural and economic context shape adherence to, and overall acceptance of, personal mitigation strategies including wearing facemasks, and social distancing among the general public. The spread of misinformation on social media in the context of crisis communication provides both challenges and opportunities for experts and officials to effectively communicate and influence these outrage factors. Social media offers an opportunity for experts to quickly convey true information about hazards, but offers others the opportunity to counter this with the spread of misinformation and exacerbate outrage. We propose strategies for infectious diseases clinicians to apply risk communication principles and frameworks to improve patient care and public message development in response to COVID-19.N-terminal acetylation is one of the most common protein modifications in eukaryotes. The function of Naa50, the catalytic subunit of the evolutionarily conserved N-terminal acetyltransferase E complex, has not been reported in Arabidopsis. In this study, we found that a loss of Naa50 resulted in a pleiotropic phenotype that included dwarfism and sterility, premature leaf senescence, and a shortened primary root. Further analysis revealed that root cell patterning and various root cell properties were severely impaired in naa50 mutant plants. Moreover, defects in auxin distribution were observed due to the mislocalization of PIN auxin transporters. In contrast to its homologs in yeast and animals, Naa50 showed no co-immunoprecipitation with any subunit of the N-terminal acetyltransferase A complex. Moreover, plants lacking Naa50 displayed hypersensitive to abscisic acid and osmotic stress. Therefore, our results suggest that protein N-terminal acetylation catalyzed by Naa50 plays an essential role in Arabidopsis growth and osmotic stress responses.