| 2851. |
|
|
| 2852. |
- Smirnova, Irina, et al.
(author)
-
Functional Role of Thr-312 and Thr-315 in the Proton-Transfer Pathway in ba3 Cytochrome c Oxidase from Thermus thermophilus
- 2010
-
In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 49:33, s. 7033-7039
-
Journal article (peer-reviewed)abstract
- Cytochrome ba3 from Thermus thermophilus is a member of the family of B-type heme-copper oxidases, which have a low degree of sequence homology to the well-studied mitochondrial-like A-type enzymes. Recently, it was suggested that the ba3 oxidase has only one pathway for the delivery of protons to the active site and that this pathway is spatially analogous to the K-pathway in the A-type oxidases [Chang, H.-Y., et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 16169−16173]. This suggested pathway includes two threonines at positions 312 and 315. In this study, we investigated the time-resolved reaction between fully reduced cytochrome ba3 and O2 in variants where Thr-312 and Thr-315 were modified. While in the A-type oxidases this reaction is essentially unchanged in variants with the K-pathway modified, in the Thr-312 → Ser variant in the ba3 oxidase both reactions associated with proton uptake from solution, the PR → F and F → O transitions, were slowed compared to those of wild-type ba3. The observed time constants were slowed 3-fold (for PR → F, from 60 to 170 μs in the wild type) and 30-fold (for F → O, from 1.1 to 40 ms). In the Thr-315 → Val variant, the F → O transition was 5-fold slower (5 ms) than for the wild-type oxidase, whereas the PR → F transition displayed an essentially unchanged time constant. However, the uptake of protons from solution was a factor of 2 slower and decoupled from the optical PR → F transition. Our results thus show that proton uptake is significantly and specifically inhibited in the two variants, strongly supporting the suggested involvement of T312 and T315 in the transfer of protons to the active site during O2 reduction in the ba3 oxidase.
|
|
| 2853. |
- Smith-Byrne, Karl, et al.
(author)
-
Circulating Isovalerylcarnitine and Lung Cancer Risk : evidence from Mendelian Randomization and Prediagnostic Blood Measurements
- 2022
-
In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 31:10, s. 1966-1974
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies.MATERIALS AND METHODS: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS).RESULTS: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes.CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers.IMPACT: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.
|
|
| 2854. |
- Smith, Felisa A, et al.
(author)
-
The evolution of maximum body size of terrestrial mammals
- 2010
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 330:6008, s. 1216-1219
-
Journal article (peer-reviewed)abstract
- The extinction of dinosaurs at the Cretaceous/Paleogene (K/Pg) boundary was the seminal event that opened the door for the subsequent diversification of terrestrial mammals. Our compilation of maximum body size at the ordinal level by sub-epoch shows a near-exponential increase after the K/Pg. On each continent, the maximum size of mammals leveled off after 40 million years ago and thereafter remained approximately constant. There was remarkable congruence in the rate, trajectory, and upper limit across continents, orders, and trophic guilds, despite differences in geological and climatic history, turnover of lineages, and ecological variation. Our analysis suggests that although the primary driver for the evolution of giant mammals was diversification to fill ecological niches, environmental temperature and land area may have ultimately constrained the maximum size achieved.
|
|
| 2855. |
- Smith, K., et al.
(author)
-
Climate change and the threat of novel marine predators in Antarctica
- 2017
-
In: Ecosphere. - : Wiley. - 2150-8925. ; 8:11
-
Journal article (peer-reviewed)abstract
- Historically low temperatures have severely limited skeleton-breaking predation on the Antarctic shelf, facilitating the evolution of a benthic fauna poorly defended against durophagy. Now, rapid warming of the Southern Ocean is restructuring Antarctic marine ecosystems as conditions become favorable for range expansions. Populations of the lithodid crab Paralomis birsteini currently inhabit some areas of the continental slope off Antarctica. They could potentially expand along the slope and upward to the outer continental shelf, where temperatures are no longer prohibitively low. We identified two sites inhabited by different densities of lithodids in the slope environment along the western Antarctic Peninsula. Analysis of the gut contents of P. birsteini trapped on the slope revealed them to be opportunistic invertivores. The abundances of three commonly eaten, eurybathic taxa—ophiuroids, echinoids, and gastropods—were negatively associated with P. birsteini off Marguerite Bay, where lithodid densities averaged 4280 ind/km2 at depths of 1100–1499 m (range 3440–5010 ind/km2), but not off Anvers Island, where lithodid densities were lower, averaging 2060 ind/km2 at these depths (range 660–3270 ind/km2). Higher abundances of lithodids appear to exert a negative effect on invertebrate distribution on the slope. Lateral or vertical range expansions of P. birsteini at sufficient densities could substantially reduce populations of their benthic prey off Antarctica, potentially exacerbating the direct impacts of rising temperatures on the distribution and diversity of the contemporary shelf benthos.
|
|
| 2856. |
- Soares, R.R.G., et al.
(author)
-
Partitioning in aqueous two-phase systems : Analysis of strengths, weaknesses, opportunities and threats
- 2015
-
In: Biotechnology Journal. - : Wiley. - 1860-6768 .- 1860-7314. ; 10:8, s. 1158-1169
-
Journal article (peer-reviewed)abstract
- For half a century aqueous two-phase systems (ATPSs) have been applied for the extraction and purification of biomolecules. In spite of their simplicity, selectivity, and relatively low cost they have not been significantly employed for industrial scale bioprocessing. Recently their ability to be readily scaled and interface easily in single-use, flexible biomanufacturing has led to industrial re-evaluation of ATPSs. The purpose of this review is to perform a SWOT analysis that includes a discussion of: (i) strengths of ATPS partitioning as an effective and simple platform for biomolecule purification; (ii) weaknesses of ATPS partitioning in regard to intrinsic problems and possible solutions; (iii) opportunities related to biotechnological challenges that ATPS partitioning may solve; and (iv) threats related to alternative techniques that may compete with ATPS in performance, economic benefits, scale up and reliability. This approach provides insight into the current status of ATPS as a bioprocessing technique and it can be concluded that most of the perceived weakness towards industrial implementation have now been largely overcome, thus paving the way for opportunities in fermentation feed clarification, integration in multi-stage operations and in single-step purification processes.
|
|
| 2857. |
- Soenen, Hilde, et al.
(author)
-
Laboratory investigation of bitumen based on round robin DSC and AFM tests
- 2014
-
In: Materials and Structures. - : Springer Science and Business Media LLC. - 1359-5997 .- 1871-6873. ; 47:7, s. 1205-1220
-
Journal article (peer-reviewed)abstract
- In the past years a wide discussion has been held among asphalt researchers regarding the existence and interpretation of observed microstructures on bitumen surfaces. To investigate this, the RILEM technical committee on nano bituminous materials 231-NBM has conducted a round robin study combining differential scanning calorimetry (DSC) and Atomic Force Microscopy (AFM). From this, methods for performing DSC and AFM tests on bitumen samples and determination of the influence of wax on the observed phases, taking into account thermal history, sample preparation and annealing procedure, are presented and critically discussed. DSC is used to measure various properties and phenomena that indicate physical changes such as glass transition temperature (T (g)) and phase transition such as melting and crystallization. In the case of existence of wax, either natural or synthetic, it can further indicate the melting point of wax, that could be used to determine wax content. The results from seven laboratories show that T (g) temperatures obtained from the heating scans are more repeatable and easier to obtain in comparison to the cooling scans. No significant difference was noted for T (g)'s obtained from the first and second heating scans. AFM is an imaging tool used to characterize the microstructures on a bituminous surface. Using AFM three phases in the materials with wax could be distinguished. The changes in the phases observed with AFM for increases in temperature were correlated with the DSC curve, and it could be established that the so called "Bee" structure disappeared around the melting peak in the DSC curve. Thus, this research has confirmed the relation between the microstructures on a bitumen surface and the wax content.
|
|
| 2858. |
|
|
| 2859. |
- Solomon, Scott D., et al.
(author)
-
Baseline Characteristics of Patients With HF With Mildly Reduced and Preserved Ejection Fraction : DELIVER Trial.
- 2022
-
In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:3, s. 184-197
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials. BACKGROUND: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF). METHODS: Adults with symptomatic HF and LVEF $>$40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo. RESULTS: A total of 6,263 patients were randomized (mean age: 72 +/- 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index $>$/=30 kg/m(2); and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 +/- 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF. CONCLUSIONS: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213]).
|
|
| 2860. |
- Solomon, Scott D., et al.
(author)
-
Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.
- 2022
-
In: The New England journal of medicine. ; 387:12, s. 1089-1098
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P$<$0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).
|
|
