Methane oxidation and methylotroph population dynamics in groundwater mesocosms

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Kuloyo, O., Ruff, S. E., Cahill, A., Connors, L., Zorz, J. K., de Angelis, I. H., Nightingale, M., Mayer, B., & Strous, M. Methane oxidation and methylotroph population dynamics in groundwater mesocosms. Environmental Microbiology. (2020), doi:10.1111/1462-2920.14929.Extraction of natural gas from unconventional hydrocarbon reservoirs by hydraulic fracturing raises concerns about methane migration into groundwater. Microbial methane oxidation can be a significant methane sink. Here, we inoculated replicated, sand‐packed, continuous mesocosms with groundwater from a field methane release experiment. The mesocosms experienced thirty‐five weeks of dynamic methane, oxygen and nitrate concentrations. We determined concentrations and stable isotope signatures of methane, carbon dioxide and nitrate and monitored microbial community composition of suspended and attached biomass. Methane oxidation was strictly dependent on oxygen availability and led to enrichment of 13C in residual methane. Nitrate did not enhance methane oxidation under oxygen limitation. Methylotrophs persisted for weeks in the absence of methane, making them a powerful marker for active as well as past methane leaks. Thirty‐nine distinct populations of methylotrophic bacteria were observed. Methylotrophs mainly occurred attached to sediment particles. Abundances of methanotrophs and other methylotrophs were roughly similar across all samples, pointing at transfer of metabolites from the former to the latter. Two populations of Gracilibacteria (Candidate Phyla Radiation) displayed successive blooms, potentially triggered by a period of methane famine. This study will guide interpretation of future field studies and provides increased understanding of methylotroph ecophysiology.The authors acknowledge funding from the Alberta Innovates Technology Futures (AITF), and University of Calgary Eyes High Doctoral Scholarships (O.O.K., J.K.Z.) and AITF/Eyes High Postdoctoral Fellowships (S.E.R.), as well as the PROMOS Internship Abroad Scholarship by the German Academic Exchange Service (I.H.d.A.). Additional support was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC), Strategic Project Grant no. 463045‐14, the Campus Alberta Innovation Chair Program (M.S.), Alberta Innovates, The Canadian Foundation for Innovation (M.S.), the Alberta Small Equipment Grant Program (M.S.) and an NSERC Discovery Grant (M.S. and B.M.)

Anomalous excitonic phase diagram in band-gap-tuned Ta2Ni(Se,S)5

During a band-gap-tuned semimetal-to-semiconductor transition, Coulomb attraction between electrons and holes can cause spontaneously formed excitons near the zero-band-gap point, or the Lifshitz transition point. This has become an important route to realize bulk excitonic insulators -- an insulating ground state distinct from single-particle band insulators. How this route manifests from weak to strong coupling is not clear. In this work, using angle-resolved photoemission spectroscopy (ARPES) and high-resolution synchrotron x-ray diffraction (XRD), we investigate the broken symmetry state across the semimetal-to-semiconductor transition in a leading bulk excitonic insulator candidate system Ta2Ni(Se,S)5. A broken symmetry phase is found to be continuously suppressed from the semimetal side to the semiconductor side, contradicting the anticipated maximal excitonic instability around the Lifshitz transition. Bolstered by first-principles and model calculations, we find strong interband electron-phonon coupling to play a crucial role in the enhanced symmetry breaking on the semimetal side of the phase diagram. Our results not only provide insight into the longstanding debate of the nature of intertwined orders in Ta2NiSe5, but also establish a basis for exploring band-gap-tuned structural and electronic instabilities in strongly coupled systems.Comment: 27 pages, 4 + 9 figure

52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis

Objective: To compare the 52-week efficacy and safety of SB4 [an etanercept biosimilar] with reference etanercept (ETN) in patients with active RA. Methods: In a phase 3, randomized, double-blind, multicentre study, patients with moderate to severe RA despite MTX treatment were randomized to receive 50 mg/week of s.c. SB4 or ETN up to week 52. Efficacy assessments included ACR response rates, 28-joint DAS, Simplified and Clinical Disease Activity Indices and changes in the modified total Sharp score (mTSS). Safety and immunogenicity were also evaluated. Results: A total of 596 patients were randomized to receive either SB4 (n = 299) or ETN (n = 297) and 505 (84.7%) patients completed 52 weeks of the study. At week 52, the ACR20 response rates in the per-protocol set were comparable between SB4 (80.8%) and ETN (81.5%). All efficacy results were comparable between the two groups and they were maintained up to week 52. Radiographic progression was also comparable and the change from baseline in the mTSS was 0.45 for SB4 and 0.74 for ETN. The safety profile of SB4 was similar to that of ETN and the incidence of anti-drug antibody development up to week 52 was 1.0 and 13.2% in the SB4 and ETN groups, respectively. Conclusion: Efficacy including radiographic progression was comparable between SB4 and ETN up to week 52. SB4 was well tolerated and had a similar safety profile to that of ETN. Trial registration number: ClinicalTrials.gov NCT01895309, EudraCT 2012-005026-30

Continued Use of Exogenic Materials found on Mars as Planetary Research Tools

Exogenic materials (meteorites, micrometeorites and chemical tracers) are encountered both serendipitously and as campaign targets during Mars rover terrain traverse and reconnaissance. We advocate the continued study of these materials in-situ when encountered and permitted by extended and new Mars surface missions in the 2023–2032 decade.Whitepaper submitted to the Planetary Science and Astrobiology Decadal Survey 2023-2032. Additional co-authors: Sara Motaghian, Brandi L. Carrier, William H. Farrand, Marc D. Fries, Peter Grindrod, Andrew Langedam, Jérémie Lasue

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Osteoporosis in Men

Produženjem očekivanog trajanja života osteoporoza je postala rastući problem u većini razvijenih zemalja svijeta. U radu se raspravlja o učestalosti, patogenezi, dijagnostičkim kriterijima i mogućnostima liječenja osteoporoze u muškaraca. Svaki treći prijelom kuka događa se u muškaraca, a više od 11 % muškaraca starijih od 50 godina doživi ovaj prijelom. Dijagnoza idiopatske osteoporoze primjenjuje se za muškarce mlađe od 60 godina u kojih nema drugih mogućih uzroka bolesti. U njih je niska mineralna gustoća kosti (BMD) najvećim dijelom posljedica niske vršne koštane mase. U oko 30 % muškaraca nalazi se sekundarna osteoporoza, a involucijska osteoporoza nastaje u muškaraca starijih od 60 godina, kao rezultat smanjenja koncentracije testosterona i IGF-1. S obzirom na rezultate istraživanja koja su pokazala da vrijednost BMD-a u oba spola pruža slične informacije o riziku prijeloma, čini se da se postojeći kriteriji za dijagnozu osteoporoze u žena mogu iskoristiti i za muškarce. U liječenju, bisfosfonati i teriparatid dokazano i značajno povećavaju BMD u muškaraca. Primjena androgena pokazala se učinkovitom u muškaraca s hipogonadizmom, no opravdanost njihove primjene u eugonada još uvijek je predmet rasprava. Povećanjem znanja o metabolizmu kosti i koštanoj pregradnji u novije vrijeme otvorila su se vrata čitavom nizu molekula koje bi u budućnosti mogle postati temelj liječenja osteoporoze u muškaraca.With the prolongation of life expectancy, osteoporosis has become an increasing problem in the majority of developed countries worldwide. The paper discusses the frequency, pathogenesis, diagnostic criteria and treatment options for osteoporosis in men. Every third hip fracture occurs in men, and more than 11 % of the male population over the age of 50 years suffer the fracture. Diagnostic tests for idiopathic osteoporosis are performed in men under 60 years of age without other potential risk factors of developing the disease. In the majority of cases, their low bone mineral density (BMD) is caused by a low peak bone mass. Secondary osteoporosis occurs in about 30 % of men, and involutionary osteoporosis developed in men over 60 years of age results from their decreased testosterone and IGF-1 levels. The study results showing that BMD levels in both sexes provide similar fracture risk information suggest that the existing diagnostic criteria for female osteoporosis can also be employed in men. It has been proved that biphosphonate and teriparitide therapy significantly increase BMD levels in men. The administration of androgens has been shown to be effective in men with hypogonadism, although their validity for patients with eugonadism has not yet been discussed. An improved knowledge of the bone metabolism and bone remodelling has recently opened the door to an extensive series of molecules that may play a key role in the treatment of male osteoporosis in the future

Quantification Of Fire Signatures For Practical Spacecraft Materials

The overall objective of this project is to measure the fire signatures of typical spacecraft materials in 1-g and determine how these signatures may be altered in a microgravity environment. During this project, we will also develop a test technique to obtain representative low-gravity signatures. The specific tasks that will be accomplished to achieve these objectives are to: (1) measure the time history of various fire signatures of typical spacecraft materials in 1-g at varying heating rates, temperatures, convective velocities, and oxygen concentrations, (2) conduct tests in the Zero-Gravity Facility at NASA John H. Glenn Research Center to investigate the manner that a microgravity environment alters the fire signature,(3) compare 0-g and 1-g time histories and determine if 0-g data exhibits the same dependence on the test parameters as experienced in 1-g (4) develop a 1-g test technique by which 0-g fire signatures can be measured. The proposed study seeks to investigate the differences in the identities and relative concentrations of the volatiles produced by pyrolyzing and/or smoldering materials between normal gravity and microgravity environments. Test materials will be representative of typical spacecraft materials and, where possible, will be tested in appropriate geometries. Wire insulation materials of Teflon, polyimide, silicone, and PVC will be evaluated using either cylindrical samples or actual wire insulation. Other materials such as polyurethane, polyimide, melamine, and silicone-based foams will be tested using cylindrical samples, in addition to fabric materials, such as Nomex. Electrical components, such as resistors, capacitors, circuit board will also be tested

Model-based analysis of biopharmaceutic experiments to improve mechanistic oral absorption modeling : an integrated in vitro in vivo extrapolation perspective using Ketoconazole as a model drug

Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro–in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo. However, this approach has not widely been applied within an integrated workflow. We present a stepwise modeling approach where relevant biopharmaceutics parameters for ketoconazole (KTZ) are determined and/or confirmed from the modeling of in vitro experiments before being directly used within a PBPK model. Modeling was applied to various in vitro experiments, namely: (a) aqueous solubility profiles to determine intrinsic solubility, salt limiting solubility factors and to verify pKa; (b) biorelevant solubility measurements to estimate bile-micelle partition coefficients; (c) fasted state simulated gastric fluid (FaSSGF) dissolution for formulation disintegration profiling; and (d) transfer experiments to estimate supersaturation and precipitation parameters. These parameters were then used within a PBPK model to predict the dissolved and total (i.e., including the precipitated fraction) concentrations of KTZ in the duodenum of a virtual population and compared against observed clinical data. The developed model well characterized the intraluminal dissolution, supersaturation, and precipitation behavior of KTZ. The mean simulated AUC0–t of the total and dissolved concentrations of KTZ were comparable to (within 2-fold of) the corresponding observed profile. Moreover, the developed PBPK model of KTZ successfully described the impact of supersaturation and precipitation on the systemic plasma concentration profiles of KTZ for 200, 300, and 400 mg doses. These results demonstrate that IVIV_E applied to biopharmaceutical experiments can be used to understand and build confidence in the quality of the input parameters and mechanistic models used for mechanistic oral absorption simulations in vivo, thereby improving the prediction performance of PBPK models. Moreover, this approach can inform the selection and design of in vitro experiments, potentially eliminating redundant experiments and thus helping to reduce the cost and time of drug product development