Increased levels of circulating Annexin A5 in Familial Mediterranean fever

<p>Abstract</p> <p>Background</p> <p>Familial Mediterranean fever is a genetic autoinflammatory disease most commonly affecting the ethnic groups originating from around the Mediterranean Sea. Apoptosis plays an important role in down-regulation of the inflammatory response by reducing the lifespan of activated immunocompetent cells. Thus, increased apoptosis may be associated with pathogenesis of familial Mediterranean fever.</p> <p>Methods</p> <p>In the present study we determined the serum levels of apoptotic marker, Annexin A5, in familial Mediterranean fever patients, within an attack and attack-free, in comparison to healthy subjects and assessed the influence of colchicine treatment on this parameter. In addition, in all study subjects serum levels of C-reactive protein and interleukine-1β, and the total leukocyte count were also determined.</p> <p>Results</p> <p>Our results demonstrated that pathogenesis of familial Mediterranean fever is characterized by the increased levels of circulating Annexin A5, which is higher in patients within the attack and which associate with the increased levels of C-reactive protein and interleukine-1β and total leukocyte count.</p> <p>Conclusions</p> <p>The results obtained indicate elevated rates of apoptosis of subpopulations of leukocytes involved in autoinflammation and recurrent episodes of fever in familial Mediterranean fever. It was also revealed that regular colchicine treatment sufficiently decreases the rate of apoptosis in familial Mediterranean fever patients by affecting the intensity of autoinflammatory reactions.</p

Assessment of the teledial gas-cooled transmuter concept

The application of four gas-turbine, modular helium cooled reactors and an accelerator unit (GT/AD-MHR) has been proposed for burning transuranics recycled from LWR waste. The recycled LWR discharged transuranics encapsulated in TRISO coated particles are first loaded into the outer thermal spectrum zone of the GT/AD-MHR for burning in the critical mode for about three years. Previously burned fuel is in a central fast zone. In the fourth year, the same unit is configured as an accelerator-driven system, containing a centrally located spallation target. The three-year, thermal-zone burned fuel and the inner fast-zone fuel from the critical mode operation are used in this subcritical cycle, and remain in their respective zones. At the end of this one-year subcritical irradiation, the outer thermal-zone fuel is reconstituted and used as fast-zone fuel in another critical mode operation. As the fuel in the fast-zone has reached its end of life it is discharged, with very low transuranics content. The critical mode operation is staggered, and each GT/AD-MGR unit undergoes the subcritical burn in one out of four year. The physics performance of the GT/AD-MHR has been evaluated using independent deterministic and Monte Carlo codes and the results of the study are presented in the current paper. A companion paper discussing the verification of the codes is also presented at this meeting. Single-batch and three-batch fuel loading schemes for the GT/AD-MHR have been evaluated using the REBUS-3/DIF3D fuel cycle code, to determine the feasibility of achieving very high burnup without exceeding reactivity and power density limits. The reactor physics of the GT-MHR is complicated by the presence of the low-lying plutonium and Er-167 resonances (0.2--1.1 eV) and by the fact that the neutron spectrum has a low-energy peak about this energy range. This peak can change depending on the core state or material loading. The location of the peak and the direction of the spectral shift greatly affect both the resonance fission and capture rates and dictate the core or element criticality state and the magnitude and sign of reactivity coefficients. For these reasons, 23-energy-group, burnup-dependent microscopic cross sections are employed in the REBUS-3/DIF3D model used for evaluating the system. These cross sections were generated with the DRAGON codes using ENDF/B-VI data

Skeletal Muscle Acute and Chronic Metabolic Response to Essential Amino Acid Supplementation in Hypertriglyceridemic Older Adults

BACKGROUND: Supplementation with essential amino acids (EAAs) + arginine is a promising nutritional approach to decrease plasma triglyceride (TG) concentrations, which are an independent risk factor for ischemic heart disease. OBJECTIVE: The objective of this study was to examine the effects of 8 wk of EAA supplementation on skeletal muscle basal metabolite concentrations and changes in metabolic response to acute EAA intake, with an emphasis on mitochondrial metabolism, in adults with elevated TGs to better understand the mechanisms of lowering plasma TGs. METHODS: Older adults with elevated plasma TG concentrations were given 22 g EAAs to ingest acutely before and after an 8-wk EAA supplementation period. Skeletal muscle biopsy samples were collected before and after acute EAA intake, both pre- and postsupplementation (4 biopsy samples), and targeted metabolomic analyses of organic acids and acylcarnitines were conducted on the specimens. RESULTS: Acute EAA intake resulted in increased skeletal muscle acylcarnitine concentrations associated with oxidative catabolism of the supplement components, with the largest increases found in acylcarnitines of branched-chain amino acid oxidative catabolism, including isovaleryl-carnitine (2200%) and 2-methylbutyryl-carnitine (2400%). The chronic EAA supplementation resulted in a 19% decrease in plasma TGs along with accumulation of long-chain acylcarnitines myristoyl- (90%) and stearoyl- (120%) carnitine in skeletal muscle and increases in succinyl-carnitine (250%) and the late-stage tricarboxylic acid cycle intermediates fumarate (44%) and malate (110%). CONCLUSIONS: Supplementation with EAAs shows promise as an approach for moderate reduction in plasma TGs. Changes in skeletal muscle metabolites suggest incomplete fatty acid oxidation and increased anaplerosis, which suggests a potential bottleneck in fatty acid metabolism

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C \u3e 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer

Effects of Different Substituents on the Crystal Structures and Antimicrobial Activities of Six Ag(I) Quinoline Compounds

The syntheses and single crystal X-ray structures of [Ag(5-nitroquinoline)(2)]NO3 (1), [Ag(8-nitroquinoline)(2)]NO3 center dot H2O (2), [Ag(6-methoxy-8-nitroquinoline)(NO3)](n) (3), [Ag(3-quinolinecarbonitrile)(NO3)](n) (4), [Ag(3-quinolinecarbonitrile)(2)]NO3 (5), and [Ag(6-quinolinecarboxylic acid)(2)]NO3 (6) are described. As an alternative to solution chemistry, solid-state grinding could be used to prepare compounds 1 and 3, but the preparation of 4 and 5 in this way failed. The Ag(I) ions in the monomeric compounds 1, 2, 5, and 6 are coordinated to two ligands via the nitrogen atoms of the quinoline rings, thereby forming a distorted linear coordination geometry with Ag-N bond distances of 2.142(2)-2.336(2) angstrom and N-Ag-N bond angles of 163.62(13)degrees-172.25(13)degrees. The 1D coordination polymers 3 and 4 contain Ag(I) centers coordinating one ligand and two bridging nitrate groups, thereby forming a distorted trigonal planar coordination geometry with Ag-N bond distances of 2.2700(14) and 2.224(5) angstrom, Ag-O bond distances of 2.261(4)-2.536(5) angstrom, and N-Ag-O bond angles of 115.23(5)degrees-155.56(5)degrees. Hirshfeld surface analyses of compounds 1-6 are presented as d(norm) and curvedness maps. The d(norm) maps show different interaction sites around the Ag(I) ions, i.e., Ag center dot center dot center dot Ag interactions and possible O-H center dot center dot center dot O, C-H center dot center dot center dot O, C-H center dot center dot center dot N, and C-H center dot center dot center dot C hydrogen bonds. Curvedness maps are a good way of visualizing pi-pi tacking interactions between molecules. The antimicrobial activities of compounds 1, 2, and 6 were screened against 15 different multidrug-resistant strains of bacteria isolated from diabetic foot ulcers and compared to the antimicrobial activities of the clinically used silver sulfadiazine (SS). Compound 2 showed activity similar to SS against this set of test organisms, being active against all strains and having slightly better average silver efficiency than SS (5 vs 6 mu g Ag/mL). Against the standard nonresistant bacterial strains of Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, and Streptococcus pyogenes, compound 1 performed better than silver nitrate, with an average MIC of 6 mu g Ag/mL versus 18 mu g Ag/mL for the reference AgNO3. Electrospray ionization mass spectrometry (ESI-MS) analyses of compounds 3 and 6 in DMSO/MeOH confirm the two-coordinated Ag+ complexes in solution, and the results of the H-1 NMR titrations of DMSO solutions of 5-nitroquinoline and 8-nitroquinoline with AgNO3 in DMSO suggest that 5-nitroquinoline is more strongly coordinated to the silver ion

Clinicians’ Guide to Artificial Intelligence in Colon Capsule Endoscopy—Technology Made Simple

Artificial intelligence (AI) applications have become widely popular across the healthcare ecosystem. Colon capsule endoscopy (CCE) was adopted in the NHS England pilot project following the recent COVID pandemic’s impact. It demonstrated its capability to relieve the national backlog in endoscopy. As a result, AI-assisted colon capsule video analysis has become gastroenterology’s most active research area. However, with rapid AI advances, mastering these complex machine learning concepts remains challenging for healthcare professionals. This forms a barrier for clinicians to take on this new technology and embrace the new era of big data. This paper aims to bridge the knowledge gap between the current CCE system and the future, fully integrated AI system. The primary focus is on simplifying the technical terms and concepts in machine learning. This will hopefully address the general “fear of the unknown in AI” by helping healthcare professionals understand the basic principle of machine learning in capsule endoscopy and apply this knowledge in their future interactions and adaptation to AI technology. It also summarises the evidence of AI in CCE and its impact on diagnostic pathways. Finally, it discusses the unintended consequences of using AI, ethical challenges, potential flaws, and bias within clinical settings

Post COP26: does the 1.5°C climate target remain alive?

One of the COP26 aims was to keep 1.5°C within reach by asking countries to come forward with ambitious year 2030 emission reductions targets to further pursue the necessary action to meet the Paris climate targets. We assess the mean global temperature rise given the updated year 2030 emission pledges in the context of future emission pathways considered by the international scientific community. Overall, we find current pledges are not consistent with a likely meeting of 1.5°C this century without overshoot. Meeting the 1.5°C goal in 2100 post overshoot given the pledges remains feasible, but urgent action is required to ensure pledges are met and policies are in place for the very deep and rapid emission reductions that are required post 2030

High temperature fusion reactor design

Fusion energy may have unique advantages over other systems as a source for high temperature process heat. A conceptual design of a blanket for a 7 m tokamak reactor has been developed that is capable of producing 1100/sup 0/C process heat at a pressure of approximately 10 atmospheres. The design is based on the use of a falling bed of MgO spheres as the high temperature heat transfer system. By preheating the spheres with energy taken from the low temperature tritium breeding part of the blanket, 1086 MW of energy can be generated at 1100/sup 0/C from a system that produces 3000 MW of total energy while sustaining a tritium breeding ratio of 1.07. The tritium breeding is accomplished using Li/sub 2/O modules both in front of (6 cm thick) and behind (50 cm thick) the high temperature ducts. Steam is used as the first wall and front tritium breeding module coolant while helium is used in the rear tritium breeding region. The system produces 600 MW of net electricity for use on the grid

Changes in climate extremes, fresh water availability and vulnerability to food insecurity projected at 1.5°C and 2°C global warming with a higher-resolution global climate model

This is the final version. Available on open access from the Royal Society via the DOI in this recordData accessibility: This article has no additional data.We projected changes in weather extremes, hydrological impacts and vulnerability to food insecurity at global warming of 1.5°C and 2°C relative to pre-industrial, using a new global atmospheric general circulation model HadGEM3A-GA3.0 driven by patterns of sea-surface temperatures and sea ice from selected members of the 5th Coupled Model Intercomparison Project (CMIP5) ensemble, forced with the RCP8.5 concentration scenario. To provide more detailed representations of climate processes and impacts, the spatial resolution was N216 (approx. 60 km grid length in mid-latitudes), a higher resolution than the CMIP5 models. We used a set of impacts-relevant indices and a global land surface model to examine the projected changes in weather extremes and their implications for freshwater availability and vulnerability to food insecurity. Uncertainties in regional climate responses are assessed, examining ranges of outcomes in impacts to inform risk assessments. Despite some degree of inconsistency between components of the study due to the need to correct for systematic biases in some aspects, the outcomes from different ensemble members could be compared for several different indicators. The projections for weather extremes indices and biophysical impacts quantities support expectations that the magnitude of change is generally larger for 2°C global warming than 1.5°C. Hot extremes become even hotter, with increases being more intense than seen in CMIP5 projections. Precipitation-related extremes show more geographical variation with some increases and some decreases in both heavy precipitation and drought. There are substantial regional uncertainties in hydrological impacts at local scales due to different climate models producing different outcomes. Nevertheless, hydrological impacts generally point towards wetter conditions on average, with increased mean river flows, longer heavy rainfall events, particularly in South and East Asia with the most extreme projections suggesting more than a doubling of flows in the Ganges at 2°C global warming. Some areas are projected to experience shorter meteorological drought events and less severe low flows, although longer droughts and/or decreases in low flows are projected in many other areas, particularly southern Africa and South America. Flows in the Amazon are projected to decline by up to 25%. Increases in either heavy rainfall or drought events imply increased vulnerability to food insecurity, but if global warming is limited to 1.5°C, this vulnerability is projected to remain smaller than at 2°C global warming in approximately 76% of developing countries. At 2°C, four countries are projected to reach unprecedented levels of vulnerability to food insecurity. This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.European Union FP7Joint UK BEIS/Defra Met Office Hadley Centre Climate Programm