Targeting the Ataxia Telangiectasia Mutated-null Phenotype in Chronic Lymphocytic Leukemia with Pro-oxidants

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumours with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia

Effect of a reduced fat and sugar maternal dietary intervention during lactation on the infant gut microbiome

PUBLISHED 17 August 2022Objective: A growing body of literature has shown that maternal diet during pregnancy is associated with infant gut bacterial composition. However, whether maternal diet during lactation affects the exclusively breastfed infant gut microbiome remains understudied. This study sets out to determine whether a two-week of a reduced fat and sugar maternal dietary intervention during lactation is associated with changes in the infant gut microbiome composition and function. Design: Stool samples were collected from four female and six male (n = 10) infants immediately before and after the intervention. Maternal baseline diet from healthy mothers aged 22–37 was assessed using 24-h dietary recall. During the 2-week dietary intervention, mothers were provided with meals and their dietary intake was calculated using FoodWorks 10 Software. Shotgun metagenomic sequencing was used to characterize the infant gut microbiome composition and function. Results: In all but one participant, maternal fat and sugar intake during the intervention were significantly lower than at baseline. The functional capacity of the infant gut microbiome was significantly altered by the intervention, with increased levels of genes associated with 28 bacterial metabolic pathways involved in biosynthesis of vitamins (p = 0.003), amino acids (p = 0.005), carbohydrates (p = 0.01), and fatty acids and lipids (p = 0.01). Although the dietary intervention did not affect the bacterial composition of the infant gut microbiome, relative difference in maternal fiber intake was positively associated with increased abundance of genes involved in biosynthesis of storage compounds (p = 0.016), such as cyanophycin. Relative difference in maternal protein intake was negatively associated with Veillonella parvula (p = 0.006), while positively associated with Klebsiella michiganensis (p = 0.047). Relative difference in maternal sugar intake was positively associated with Lactobacillus paracasei (p = 0.022). Relative difference in maternal fat intake was positively associated with genes involved in the biosynthesis of storage compounds (p = 0.015), fatty acid and lipid (p = 0.039), and metabolic regulator (p = 0.038) metabolic pathways. Conclusion: This pilot study demonstrates that a short-term maternal dietary intervention during lactation can significantly alter the functional potential, but not bacterial taxonomy, of the breastfed infant gut microbiome. While the overall diet itself was not able to change the composition of the infant gut microbiome, changes in intakes of maternal protein and sugar during lactation were correlated with changes in the relative abundances of certain bacterial species. Clinical trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12619000606189).Azhar S. Sindi, Lisa F. Stinson, Soo Sum Lean, Yit-Heng Chooi, Gabriela E. Leghi, Merryn J. Netting, Mary E. Wlodek, Beverly S. Muhlhausler, Donna T. Geddes and Matthew S. Payn

Ab initio atomistic thermodynamics and statistical mechanics of surface properties and functions

Previous and present "academic" research aiming at atomic scale understanding is mainly concerned with the study of individual molecular processes possibly underlying materials science applications. Appealing properties of an individual process are then frequently discussed in terms of their direct importance for the envisioned material function, or reciprocally, the function of materials is somehow believed to be understandable by essentially one prominent elementary process only. What is often overlooked in this approach is that in macroscopic systems of technological relevance typically a large number of distinct atomic scale processes take place. Which of them are decisive for observable system properties and functions is then not only determined by the detailed individual properties of each process alone, but in many, if not most cases also the interplay of all processes, i.e. how they act together, plays a crucial role. For a "predictive materials science modeling with microscopic understanding", a description that treats the statistical interplay of a large number of microscopically well-described elementary processes must therefore be applied. Modern electronic structure theory methods such as DFT have become a standard tool for the accurate description of individual molecular processes. Here, we discuss the present status of emerging methodologies which attempt to achieve a (hopefully seamless) match of DFT with concepts from statistical mechanics or thermodynamics, in order to also address the interplay of the various molecular processes. The new quality of, and the novel insights that can be gained by, such techniques is illustrated by how they allow the description of crystal surfaces in contact with realistic gas-phase environments.Comment: 24 pages including 17 figures, related publications can be found at http://www.fhi-berlin.mpg.de/th/paper.htm

The Intentional Use of Service Recovery Strategies to Influence Consumer Emotion, Cognition and Behaviour

Service recovery strategies have been identified as a critical factor in the success of. service organizations. This study develops a conceptual frame work to investigate how specific service recovery strategies influence the emotional, cognitive and negative behavioural responses of . consumers., as well as how emotion and cognition influence negative behavior. Understanding the impact of specific service recovery strategies will allow service providers' to more deliberately and intentionally engage in strategies that result in positive organizational outcomes. This study was conducted using a 2 x 2 between-subjects quasi-experimental design. The results suggest that service recovery has a significant impact on emotion, cognition and negative behavior. Similarly, satisfaction, negative emotion and positive emotion all influence negative behavior but distributive justice has no effect

Nuclear Alpha-Particle Condensates

The $\alpha$-particle condensate in nuclei is a novel state described by a product state of $\alpha$'s, all with their c.o.m. in the lowest 0S orbit. We demonstrate that a typical $\alpha$-particle condensate is the Hoyle state ($E_{x}=7.65$ MeV, $0^+_2$ state in $^{12}$C), which plays a crucial role for the synthesis of $^{12}$C in the universe. The influence of antisymmentrization in the Hoyle state on the bosonic character of the $\alpha$ particle is discussed in detail. It is shown to be weak. The bosonic aspects in the Hoyle state, therefore, are predominant. It is conjectured that $\alpha$-particle condensate states also exist in heavier $n\alpha$ nuclei, like $^{16}$O, $^{20}$Ne, etc. For instance the $0^+_6$ state of $^{16}$O at $E_{x}=15.1$ MeV is identified from a theoretical analysis as being a strong candidate of a $4\alpha$ condensate. The calculated small width (34 keV) of $0^+_6$, consistent with data, lends credit to the existence of heavier Hoyle-analogue states. In non-self-conjugated nuclei such as $^{11}$B and $^{13}$C, we discuss candidates for the product states of clusters, composed of $\alpha$'s, triton's, and neutrons etc. The relationship of $\alpha$-particle condensation in finite nuclei to quartetting in symmetric nuclear matter is investigated with the help of an in-medium modified four-nucleon equation. A nonlinear order parameter equation for quartet condensation is derived and solved for $\alpha$ particle condensation in infinite nuclear matter. The strong qualitative difference with the pairing case is pointed out.Comment: 71 pages, 41 figures, review article, to be published in "Cluster in Nuclei (Lecture Notes in Physics) - Vol.2 -", ed. by C. Beck, (Springer-Verlag, Berlin, 2011

Magnetic Field Generation in Stars

Enormous progress has been made on observing stellar magnetism in stars from the main sequence through to compact objects. Recent data have thrown into sharper relief the vexed question of the origin of stellar magnetic fields, which remains one of the main unanswered questions in astrophysics. In this chapter we review recent work in this area of research. In particular, we look at the fossil field hypothesis which links magnetism in compact stars to magnetism in main sequence and pre-main sequence stars and we consider why its feasibility has now been questioned particularly in the context of highly magnetic white dwarfs. We also review the fossil versus dynamo debate in the context of neutron stars and the roles played by key physical processes such as buoyancy, helicity, and superfluid turbulence,in the generation and stability of neutron star fields. Independent information on the internal magnetic field of neutron stars will come from future gravitational wave detections. Thus we maybe at the dawn of a new era of exciting discoveries in compact star magnetism driven by the opening of a new, non-electromagnetic observational window. We also review recent advances in the theory and computation of magnetohydrodynamic turbulence as it applies to stellar magnetism and dynamo theory. These advances offer insight into the action of stellar dynamos as well as processes whichcontrol the diffusive magnetic flux transport in stars.Comment: 41 pages, 7 figures. Invited review chapter on on magnetic field generation in stars to appear in Space Science Reviews, Springe

A century of sea level measurements at Newlyn, SW England

The Newlyn Tidal Observatory is the most important sea level station in the UK. It commenced operations in 1915 as part of the Second Geodetic Levelling of England and Wales, and the mean sea level determined from the tide gauge during the first six years (May 1915-April 1921) defined Ordnance Datum Newlyn (ODN) which became the national height datum for the whole of Great Britain. The 100 years of sea level data now available have contributed significantly to many studies in oceanography, geology and climate change. This paper marks the centenary of this important station by reviewing the sea level (and, more recently, detailed land level) measurements and Newlyn’s contributions to UK cartography, geodesy and sea-level science in general. Recommendations are made on how sea and land level measurements at Newlyn might be enhanced in the future