Modulation of CP2 Family Transcriptional Activity by CRTR-1 and Sumoylation

CRTR-1 is a member of the CP2 family of transcription factors. Unlike other members of the family which are widely expressed, CRTR-1 expression shows specific spatio-temporal regulation. Gene targeting demonstrates that CRTR-1 plays a central role in the maturation and function of the salivary glands and the kidney. CRTR-1 has also recently been identified as a component of the complex transcriptional network that maintains pluripotency in embryonic stem (ES) cells. CRTR-1 was previously shown to be a repressor of transcription. We examine the activity of CRTR-1 in ES and other cells and show that CRTR-1 is generally an activator of transcription and that it modulates the activity of other family members, CP2, NF2d9 and altNF2d9, in a cell specific manner. We also demonstrate that CRTR-1 activity is regulated by sumoylation at a single major site, residue K30. These findings imply that functional redundancy with other family members may mask important roles for CRTR-1 in other tissues, including the blastocyst stage embryo and embryonic stem cells

The management of an endodontically abscessed tooth: patient health state utility, decision-tree and economic analysis

<p>Abstract</p> <p>Background</p> <p>A frequent encounter in clinical practice is the middle-aged adult patient complaining of a toothache caused by the spread of a carious infection into the tooth's endodontic complex. Decisions about the range of treatment options (conventional crown with a post and core technique (CC), a single tooth implant (STI), a conventional dental bridge (CDB), and a partial removable denture (RPD)) have to balance the prognosis, utility and cost. Little is know about the utility patients attach to the different treatment options for an endontically abscessed mandibular molar and maxillary incisor. We measured patients' dental-health-state utilities and ranking preferences of the treatment options for these dental problems.</p> <p>Methods</p> <p>Forty school teachers ranked their preferences for conventional crown with a post and core technique, a single tooth implant, a conventional dental bridge, and a partial removable denture using a standard gamble and willingness to pay. Data previously reported on treatment prognosis and direct "out-of-pocket" costs were used in a decision-tree and economic analysis</p> <p>Results</p> <p>The Standard Gamble utilities for the restoration of a mandibular 1st molar with either the conventional crown (CC), single-tooth-implant (STI), conventional dental bridge (CDB) or removable-partial-denture (RPD) were 74.47 [± 6.91], 78.60 [± 5.19], 76.22 [± 5.78], 64.80 [± 8.1] respectively (p < 0.05). Their respective Willingness-to-Pay ($CDN) were 1,782.05 [± 361.42], 1,871.79 [± 349.44], 1,605.13 [± 348.10], 1,351.28 [± 368.62] (p < 0.05).</p> <p>The standard gamble utilities for the restoration of a maxillary central incisor with a CC, STI, CDB and RPD were 88.50 [± 6.12], 90.68 [± 3.41], 89.78 [± 3.81] and 91.10 [± 3.57] respectively (p > 0.05). Their respective willingness-to-pay ($CDN) were: 1,782.05 [± 361.42], 1,871.79 [± 349.44], 1,605.13 [± 348.10] and 1,351.28 [± 368.62]. A statistical difference was found between the utility of treating a maxillary central incisor and mandibular 1st-molar (p < 0.05).</p> <p>The expected-utility-value for a 5-year prosthetic survival was highest for the CDB and the STI treatment of an abscessed mandibular molar (74.75 and 71.47 respectively) and maxillary incisor (86.24 and 84.91 respectively). This held up to a sensitivity analysis when the success of root canal therapy and the risk of damage to the adjacent tooth were varied. The RPD for both the molar and incisor was the favored treatment based on a cost-utility (3.85 and 2.74 CND$per year of tooth saved respectively) and cost-benefit analysis (0.92 to 0.60 CND$ of cost per $ of benefit, respectively) for a prosthetic clinical survival of 5-years.</p> <p>Conclusion</p> <p>The position of the abscessed tooth and the amount of insurance coverage influences the utility and rank assigned by patients to the different treatment options. STI and CDB have optimal EUVs for a 5-year survival outcome, and RPD has significantly lower cost providing the better cost:benefit ratio.</p

Ectodermal-Neural Cortex 1 Down-Regulates Nrf2 at the Translational Level

The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protecting cells from toxic and carcinogenic insults and in maintaining cellular redox homeostasis. Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effect of ENC1 on Nrf2 was not due to a change in the stability of Nrf2 because neither proteasomal nor lysosomal inhibitors had any effects. Overexpression of ENC1 did not result in a change in the level of Nrf2 mRNA, rather, it caused a decrease in the rate of Nrf2 protein synthesis. These results demonstrate that ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation, which adds another level of complexity in controlling the Nrf2 signaling pathway

Changing climate both increases and decreases European river floods

Climate change has led to concerns about increasing river floods resulting from the greater water-holding capacity of a warmer atmosphere. These concerns are reinforced by evidence of increasing economic losses associated with flooding in many parts of the world, including Europe. Any changes in river floods would have lasting implications for the design of flood protection measures and flood risk zoning. However, existing studies have been unable to identify a consistent continental-scale climatic-change signal in flood discharge observations in Europe, because of the limited spatial coverage and number of hydrometric stations. Here we demonstrate clear regional patterns of both increases and decreases in observed river flood discharges in the past five decades in Europe, which are manifestations of a changing climate. Our results—arising from the most complete database of European flooding so far—suggest that: increasing autumn and winter rainfall has resulted in increasing floods in northwestern Europe; decreasing precipitation and increasing evaporation have led to decreasing floods in medium and large catchments in southern Europe; and decreasing snow cover and snowmelt, resulting from warmer temperatures, have led to decreasing floods in eastern Europe. Regional flood discharge trends in Europe range from an increase of about 11 per cent per decade to a decrease of 23 per cent. Notwithstanding the spatial and temporal heterogeneity of the observational record, the flood changes identified here are broadly consistent with climate model projections for the next century, suggesting that climate-driven changes are already happening and supporting calls for the consideration of climate change in flood risk management

Cortical Surround Interactions and Perceptual Salience via Natural Scene Statistics

Spatial context in images induces perceptual phenomena associated with salience and modulates the responses of neurons in primary visual cortex (V1). However, the computational and ecological principles underlying contextual effects are incompletely understood. We introduce a model of natural images that includes grouping and segmentation of neighboring features based on their joint statistics, and we interpret the firing rates of V1 neurons as performing optimal recognition in this model. We show that this leads to a substantial generalization of divisive normalization, a computation that is ubiquitous in many neural areas and systems. A main novelty in our model is that the influence of the context on a target stimulus is determined by their degree of statistical dependence. We optimized the parameters of the model on natural image patches, and then simulated neural and perceptual responses on stimuli used in classical experiments. The model reproduces some rich and complex response patterns observed in V1, such as the contrast dependence, orientation tuning and spatial asymmetry of surround suppression, while also allowing for surround facilitation under conditions of weak stimulation. It also mimics the perceptual salience produced by simple displays, and leads to readily testable predictions. Our results provide a principled account of orientation-based contextual modulation in early vision and its sensitivity to the homogeneity and spatial arrangement of inputs, and lends statistical support to the theory that V1 computes visual salience

Wnt signaling in triple-negative breast cancer

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease

Molecular and physiological basis of Saccharomyces cerevisiae tolerance to adverse lignocellulose-based process conditions

Lignocellulose-based biorefineries have been gaining increasing attention to substitute current petroleum-based refineries. Biomass processing requires a pretreatment step to break lignocellulosic biomass recalcitrant structure, which results in the release of a broad range of microbial inhibitors, mainly weak acids, furans, and phenolic compounds. Saccharomyces cerevisiae is the most commonly used organism for ethanol production; however, it can be severely distressed by these lignocellulose-derived inhibitors, in addition to other challenging conditions, such as pentose sugar utilization and the high temperatures required for an efficient simultaneous saccharification and fermentation step. Therefore, a better understanding of the yeast response and adaptation towards the presence of these multiple stresses is of crucial importance to design strategies to improve yeast robustness and bioconversion capacity from lignocellulosic biomass. This review includes an overview of the main inhibitors derived from diverse raw material resultants from different biomass pretreatments, and describes the main mechanisms of yeast response to their presence, as well as to the presence of stresses imposed by xylose utilization and high-temperature conditions, with a special emphasis on the synergistic effect of multiple inhibitors/stressors. Furthermore, successful cases of tolerance improvement of S. cerevisiae are highlighted, in particular those associated with other process-related physiologically relevant conditions. Decoding the overall yeast response mechanisms will pave the way for the integrated development of sustainable yeast cell--based biorefineries.This study was supported by the Portuguese Foundation for Science and Technology (FCT) by the strategic funding of UID/BIO/04469/2013 unit, MIT Portugal Program (Ph.D. grant PD/BD/128247/ 2016 to Joana T. Cunha), Ph.D. grant SFRH/BD/130739/2017 to Carlos E. Costa, COMPETE 2020 (POCI-01-0145-FEDER-006684), BioTecNorte operation (NORTE-01-0145-FEDER-000004), YeasTempTation (ERA-IB-2-6/0001/2014), and MultiBiorefinery project (POCI-01-0145-FEDER-016403). Funding by the Institute for Bioengineering and Biosciences (IBB) from FCT (UID/BIO/04565/2013) and from Programa Operacional Regional de Lisboa 2020 (Project N. 007317) was also receiveinfo:eu-repo/semantics/publishedVersio

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. Copyright (C) 2021 World Health Organization; licensee Elsevier