Non-consensus GLI binding sites in Hedgehog target gene regulation

BACKGROUND: The GLI transcription factors, mediators of the hedgehog signal bind with high affinity to the consensus sequence GACCACCCA. The affinity of variant single substitutions in GLI binding sites has been measured systematically, but the affinities of the variant binding sites appears low compared to the frequency of occurrence of variant sites in known GLI target gene promoters. RESULTS: We quantified transcriptional activation by GLI using PTCH1 promoter based luciferase reporters containing all single substitutions of the GLI consensus binding site. As expected variants with very low affinity did not activate the reporter. Many lower affinity binding sequences are, however, functional in the presence of moderate GLI concentration. Using two natural non-consensus GLI site promoters we showed that substitution of the variant sequences by consensus leads to comparable activity. CONCLUSIONS: Variant GLI binding sites with relatively low affinity can within natural promoters lead to strong transcriptional activation. This may facilitate the identification of additional direct GLI target genes.(VLID)218887

Changes in Vitamin D Status in Overweight Middle-Aged Adults with or without Impaired Glucose Metabolism in Two Consecutive Nordic Summers

Background. Sun exposure is the main driver of vitamin D synthesis. High latitude, obesity, and type 2 diabetes mellitus (T2DM) are all risk factors for vitamin D deficiency. However, the seasonal variation in vitamin D concentrations (25[OH]D) in such populations before and after sun exposure during the summer is unknown. Therefore, we investigated 25[OH]D status before and after two consecutive summers in high latitude and its associations with body fat, sex, and glucose metabolism. Methods. 158 participants from Sweden (87 women, 71 men; mean age, 60 ± 5 y; body mass index ≥ 25 kg/m2) and 25[OH]D were measured and evaluated in relation to normal or impaired glucose tolerance, body composition, and dietary habits during summer season. Results. Eighty-four percent of the participants were categorized with low to deficient 25[OH]D values before summer (55.1 ± 21.7 nmol·L−1), with a significant increase after the summer season (66.3 ± 21.0 nmol·L−1; P<0.001). However, the values remained below the recommended range (76–250 nmol·L−1) in 66% of the participants. These findings were verified in a subgroup of the study population during the subsequent summer. Participants who reported use of vitamin D supplements had higher initial concentrations (64.2 ± 20.1 nmol·L−1) compared to nonusers (53.7 ± 21.7 nmol·L−1; P=0.04). Further, 25[OH]D values correlated negatively with fat mass (kg) prior to summer only in the female population (r=−0.29, P=0.008). Conclusions. In the present study, sun exposure had a beneficial but insufficient effect on 25[OH]D levels, and the same levels were documented in two consecutive summer seasons, confirming that vitamin D supplementation in both summer and winter should be considered in this population

Selective knockout of gold active sites

It has long been known that defects on a gold surface play an important role in electrocatalysis, but the precise mechanism has always been unclear. This work indicates that the defect sites provide partially filled d-orbitals that stabilize freeradical intermediates. Strong evidence for this hypothesis is that the sites can be selectively knocked out by treatment with OH• radicals generated by Fenton's reagent. The knockout effect is demonstrated using oxygen reduction, hydrogen reduction, and the redox electrochemistry of hydroquinone

Common Genetic Variation in the SERPINF1 Locus Determines Overall Adiposity, Obesity-Related Insulin Resistance, and Circulating Leptin Levels

OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels

Quantifying permafrost organic carbon remineralization after redeposition on the ocean floor, using δ13C and F14C.

Arctic permafrost is a critical global tipping element in a warming climate. Annually, the erosion of coastal permafrost discharges an estimated 5 to 14 Tg of organic carbon (OC) into the Arctic Ocean. Although this previously stored OC has the potential to be reintroduced into the atmosphere, thus accelerating human-induced climate change, little is known about the benthic remineralization processes of permafrost OC after erosion and redeposition on the ocean floor. Our research quantified fluxes of dissolved inorganic carbon (DIC) and analyzed its isotopic composition of nearshore sediments in the Canadian Beaufort Sea, specifically off Herschel Island. Our findings showed a DIC release of 0.217 mmo/m&amp;#178;/d, with an average signature of &amp;#948;13C = -22.44 &amp;#177; 72 &amp;#8240; and F14C = 0.548 &amp;#177; 0.007. Utilizing a model that combines two carbon isotopes, we estimate that approximately 38 &amp;#177; 10% of the released DIC is a result of subsurface degradation of redeposited permafrost OC, with an additional 15 &amp;#177; 12% originating from redeposited active layer OC. Additionally, isotopic endmember analysis was utilized on bacterial membrane lipids from live sedimentary bacteria to determine the relative utilization of OC sources in bacterial communities within shallow subsurface sediment (&lt;25 cm). Our results indicate that, on average, these communities obtain 73 &amp;#177; 10% of their OC from recent marine primary production, 11 &amp;#177; 6% from permafrost OC, and 16 &amp;#177; 11% from active layer OC. This study is the first direct quantitative assessment of the release of permafrost OC into the active carbon cycle after it has been redeposited on the ocean floor, as far as we know. The data suggest that the redeposited permafrost OC is easily accessible and utilized by subsurface bacteria. Considering the immense size and vulnerability of the eroding coastal permafrost OC pool, 27 to 53% of it contributing to benthic DIC fluxes could have a prolonged effect on the world's climate, worsening the climate emergency.</jats:p

Dynamics in Liver Stiffness Measurements Predict Outcomes in Advanced Chronic Liver Disease

Background &amp; Aims:Liver stiffness measurements (LSMs) provide an opportunity to monitor liver disease progression and regression noninvasively. We aimed to determine the prognostic relevance of LSM dynamics over time for liver-related events and death in patients with chronic liver disease. Methods:Patients with chronic liver disease undergoing 2 or more reliable LSMs at least 180 days apart were included in this retrospective cohort study and stratified at baseline (BL) as nonadvanced chronic liver disease (non-ACLD, BL-LSM &lt; 10 kPa), compensated ACLD (cACLD; BL-LSM ≥ 10 kPa), and decompensated ACLD. Data on all consecutive LSMs and clinical outcomes were collected. Results: There were 2508 patients with 8561 reliable LSMs (3 per patient; interquartile range, 2–4) included: 1647 (65.7%) with non-ACLD, 757 (30.2%) with cACLD, and 104 (4.1%) with decompensated ACLD. Seven non-ACLD patients (0.4%) and 83 patients with cACLD (10.9%) developed hepatic decompensation (median follow-up, 71 months). A 20% increase in LSM at any time was associated with an approximately 50% increased risk of hepatic decompensation (hazard ratio, 1.58; 95% CI, 1.41–1.79; P &lt;.001) and liver-related death (hazard ratio, 1.45; 95% CI, 1.28–1.68; P &lt;.001) in patients with cACLD. LSM dynamics yielded a high accuracy to predict hepatic decompensation in the following 12 months (area under the receiver operating characteristics curve = 0.933). The performance of LSM dynamics was numerically better than dynamics in Fibrosis-4 score (0.873), Model for End-Stage Liver Disease (0.835), and single time-point LSM (BL-LSM: 0.846; second LSM: 0.880). Any LSM decrease to &lt;20 kPa identified patients with cACLD with a substantially lower risk of hepatic decompensation (hazard ratio, 0.13; 95% CI, 0.07–0.24). If reliable, LSM also confers prognostic information in decompensated ACLD. Conclusions: Repeating LSM enables an individual and updated risk assessment for decompensation and liver-related mortality in ACLD.</p

Metal-THINGS: On the metallicity and ionization of ULX sources in NGC 925

We present an analysis of the optical properties of three Ultra Luminous X-ray (ULX) sources identified in NGC 925. We use Integral field unit data from the George Mitchel spectrograph in the context of the Metal-THINGS survey. The optical properties for ULX-1 and ULX-3 are presented, while the spaxel associated with ULX-2 had a low S/N, which prevented its analysis. We also report the kinematics and dimensions of the optical nebula associated with each ULX using ancillary data from the PUMA Fabry-Perot spectrograph. A BPT analysis demonstrates that most spaxels in NGC 925 are dominated by star-forming regions, including those associated with ULX-1 and ULX-3. Using the resolved gas-phase metallicities, a negative metallicity gradient is found, consistent with previous results for spiral galaxies, while the ionization parameter tends to increase radially throughout the galaxy. Interestingly, ULX-1 shows a very low gas metallicity for its galactocentric distance, identified by two independent methods, while exhibiting a typical ionization. We find that such low gas metallicity is best explained in the context of the high-mass X-ray binary population, where the low-metallicity environment favours active Roche lobe overflows that can drive much higher accretion rates. An alternative scenario invoking accretion of a low-mass galaxy is not supported by the data in this region. Finally, ULX-3 shows both a high metallicity and ionization parameter, which is consistent with the progenitor being a highly-accreting neutron star within an evolved stellar population region.Comment: Accepted by Ap

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors

Downgrading Recent Estimates of Land Available for Biofuel Production

Recent estimates of additional land available for bioenergy production range from 320 to 1411 million ha. These estimates were generated from four scenarios regarding the types of land suitable for bioenergy production using coarse-resolution inputs of soil productivity, slope, climate, and land cover. In this paper, these maps of land availability were assessed using high-resolution satellite imagery. Samples from these maps were selected and crowdsourcing of Google Earth images was used to determine the type of land cover and the degree of human impact. Based on this sample, a set of rules was formulated to downward adjust the original estimates for each of the four scenarios that were previously used to generate the maps of land availability for bioenergy production. The adjusted land availability estimates range from 56 to 1035 million ha depending upon the scenario and the ruleset used when the sample is corrected for bias. Large forest areas not intended for biofuel production purposes were present in all scenarios. However, these numbers should not be considered as definitive estimates but should be used to highlight the uncertainty in attempting to quantify land availability for biofuel production when using coarse-resolution inputs with implications for further policy development