AMPK Directly Inhibits NDPK Through a Phosphoserine Switch to Maintain Cellular Homeostasis

AMP-activated protein kinase (AMPK) is a key energy sensor that regulates metabolism to maintain cellular energy balance. AMPK activation has also been proposed to mimic benefits of caloric restriction and exercise. Therefore, identifying downstream AMPK targets could elucidate new mechanisms for maintaining cellular energy homeostasis. We identified the phosphotransferase nucleoside diphosphate kinase (NDPK), which maintains pools of nucleotides, as a direct AMPK target through the use of two-dimensional differential in-gel electrophoresis. Furthermore, we mapped the AMPK/NDPK phosphorylation site (serine 120) as a functionally potent enzymatic “off switch” both in vivo and in vitro. Because ATP is usually the most abundant cellular nucleotide, NDPK would normally consume ATP, whereas AMPK would inhibit NDPK to conserve energy. It is intriguing that serine 120 is mutated in advanced neuroblastoma, which suggests a mechanism by which NDPK in neuroblastoma can no longer be inhibited by AMPK-mediated phosphorylation. This novel placement of AMPK upstream and directly regulating NDPK activity has widespread implications for cellular energy/nucleotide balance, and we demonstrate in vivo that increased NDPK activity leads to susceptibility to energy deprivation–induced death

Colorectal cancer screening with fecal immunochemical testing or primary colonoscopy:An analysis of health equity based on a randomised trial

Background: We have addressed health equity attained by fecal immunochemical testing (FIT) and primary colonoscopy (PCOL), respectively, in the randomised controlled screening trial SCREESCO conducted in Sweden. Methods: We analysed data on the individuals recruited between March 2014, and March 2020, within the study registered with ClinicalTrials.gov, NCT02078804. Swedish population registry data on educational level, household income, country of birth, and marital status were linked to each 60-year-old man and woman who had been randomised to two rounds of FIT 2 years apart (n = 60,123) or once-only PCOL (n = 30,390). Furthermore, we geo-coded each study individual to his/her residential area and assessed neighbourhood-level data on deprivation, proportion of non-Western immigrants, population density, and average distance to healthcare center for colonoscopy. We estimated adjusted associations of each covariate with the colonoscopy attendance proportion out of all invited to respective arms; ie, the preferred outcome for addressing health equity. In the FIT arm, the test uptake and the colonoscopy uptake among the test positives were considered as the secondary outcomes. Findings: We found a marked socioeconomic gradient in the colonoscopy attendance proportion in the PCOL arm (adjusted odds ratio [95% credibility interval] between the groups categorised in the highest vs. lowest national quartile for household income: 2.20 [2.01-2.42]) in parallel with the gradient in the test uptake of the FIT x 2 screening (2.08 [1.96-2.20]). The corresponding gradient in the colonoscopy attendance proportion out of all invited to FIT was less pronounced (1.29 [1.16-1.42]), due to higher proportions of FIT positives in socioeconomically disadvantaged groups. Interpretation: The unintended risk of exacerbating inequalities in health by organised colorectal cancer screening may be higher with a PCOL strategy than a FIT strategy, despite parallel socioeconomic gradients in uptake

Combining EGM2008 and SRTM/DTM2006.0 residual terrain model data to improve quasigeoid computations in mountainous areas devoid of gravity data

A global geopotential model, like EGM2008, is not capable of representing the high-frequency components of Earth?s gravity field. This is known as the omission error. In mountainous terrain, omission errors in EGM2008, even when expanded to degree 2,190, may reach amplitudes of10cm and more for height anomalies. The present paper proposes the utilisation of high-resolution residual terrain model (RTM) data for computing estimates of the omission error in rugged terrain. RTM elevations may be constructed as the difference between the SRTM (Shuttle Radar Topography Mission) elevation model and the DTM2006.0 spherical harmonic topographic expansion. Numerical tests, carried out in the German Alps with a precise gravimetric quasigeoid model (GCG05) and GPS/levelling data as references, demonstrate that RTM-based omission error estimatesimprove EGM2008 height anomaly differences by 10cm in many cases. The comparisons of EGM2008-only height anomalies and the GCG05 model showed 3.7 cm standard deviation after a bias-fit. Applying RTM omission error estimates to EGM2008 reduces the standard deviation to 1.9 cm which equates to a significant improvement rate of 47%. Using GPS/levelling data strongly corroborates thesefindings with an improvement rate of 49%. The proposed RTM approach may be of practical value to improve quasigeoid determination in mountainous areas without sufficient regional gravity data coverage, e.g., in parts of Asia, South America or Africa. As a further application, RTMomission error estimates will allow refined validation of global gravity field models like EGM2008 from GPS/levelling data

A critical analysis of building sustainability assessment methods for healthcare buildings

The healthcare building project contains different aspects from the most common projects. Designing a healthcare environment is based on a number of criteria related to the satisfaction and well-being of the professional working teams, patients and administrators. Mostly due to various design requirements, these buildings are rarely designed and operated in a sustainable way. Therefore, the sustainable development is a concept whose importance has grown significantly in the last decade in this sector. The worldwide economic crisis reinforces the growing environmental concerns as well as raising awareness among people to a necessary and inevitable shift in the values of their society. To support sustainable building design, several building sustainability assessment (BSA) methods are being developed worldwide. Since healthcare buildings are rather complex systems than other buildings, so specific methods were developed for them. These methods are aimed to support decision-making towards the introduction of the best sustainability practices during the design and operation phases of a healthcare environment. However, the comparison between the results of different methods is difficult, if not impossible, since they address different environmental, societal and economic criteria, and they emphasize different phases of the life cycle. Therefore, the aim of this study was to clarify the differences between the main BSA methods for healthcare buildings by analysing and categorizing them. Furthermore, the benefits of these methods in promoting a more sustainable environment will be analysed, and the current situation of them within the context of standardization of the concept sustainable construction will be discussed.The authors acknowledge the Portuguese Foundation for Science and Technology and POPH/FSE for the financial support for this study under the Reference SFRH/BD/77959/2011

Cross-sectional associations between air pollution and chronic bronchitis: an ESCAPE meta-analysis across five cohorts

BACKGROUND: This study aimed to assess associations of outdoor air pollution on prevalence of chronic bronchitis symptoms in adults in five cohort studies (Asthma-E3N, ECRHS, NSHD, SALIA, SAPALDIA) participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE) project. METHODS: Annual average particulate matter (PM10, PM2.5, PMabsorbance, PMcoarse), NO2, nitrogen oxides (NOx) and road traffic measures modelled from ESCAPE measurement campaigns 2008-2011 were assigned to home address at most recent assessments (1998-2011). Symptoms examined were chronic bronchitis (cough and phlegm for ≥3 months of the year for ≥2 years), chronic cough (with/without phlegm) and chronic phlegm (with/without cough). Cohort-specific cross-sectional multivariable logistic regression analyses were conducted using common confounder sets (age, sex, smoking, interview season, education), followed by meta-analysis. RESULTS: 15 279 and 10 537 participants respectively were included in the main NO2 and PM analyses at assessments in 1998-2011. Overall, there were no statistically significant associations with any air pollutant or traffic exposure. Sensitivity analyses including in asthmatics only, females only or using back-extrapolated NO2 and PM10 for assessments in 1985-2002 (ECRHS, NSHD, SALIA, SAPALDIA) did not alter conclusions. In never-smokers, all associations were positive, but reached statistical significance only for chronic phlegm with PMcoarse OR 1.31 (1.05 to 1.64) per 5 µg/m(3) increase and PM10 with similar effect size. Sensitivity analyses of older cohorts showed increased risk of chronic cough with PM2.5abs (black carbon) exposures. CONCLUSIONS: Results do not show consistent associations between chronic bronchitis symptoms and current traffic-related air pollution in adult European populations