Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1low Monocytes

Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1(low) monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1(low) cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells

Discovering a taste for the unusual: exceptional models for preference mining

Exceptional preferences mining (EPM) is a crossover between two subfields of data mining: local pattern mining and preference learning. EPM can be seen as a local pattern mining task that finds subsets of observations where some preference relations between labels significantly deviate from the norm. It is a variant of subgroup discovery, with rankings of labels as the target concept. We employ several quality measures that highlight subgroups featuring exceptional preferences, where the focus of what constitutes exceptional' varies with the quality measure: two measures look for exceptional overall ranking behavior, one measure indicates whether a particular label stands out from the rest, and a fourth measure highlights subgroups with unusual pairwise label ranking behavior. We explore a few datasets and compare with existing techniques. The results confirm that the new task EPM can deliver interesting knowledge.This research has received funding from the ECSEL Joint Undertaking, the framework programme for research and innovation Horizon 2020 (2014-2020) under Grant Agreement Number 662189-MANTIS-2014-1

Yielding and irreversible deformation below the microscale: Surface effects and non-mean-field plastic avalanches

Nanoindentation techniques recently developed to measure the mechanical response of crystals under external loading conditions reveal new phenomena upon decreasing sample size below the microscale. At small length scales, material resistance to irreversible deformation depends on sample morphology. Here we study the mechanisms of yield and plastic flow in inherently small crystals under uniaxial compression. Discrete structural rearrangements emerge as series of abrupt discontinuities in stress-strain curves. We obtain the theoretical dependence of the yield stress on system size and geometry and elucidate the statistical properties of plastic deformation at such scales. Our results show that the absence of dislocation storage leads to crucial effects on the statistics of plastic events, ultimately affecting the universal scaling behavior observed at larger scales.Comment: Supporting Videos available at http://dx.plos.org/10.1371/journal.pone.002041

Cross-sectional study of the associations between circulating vitamin D concentrations and insulin resistance in children aged 9–10 years of South Asian, black African Caribbean and white European origins

Background Lower circulating vitamin D 25-hydroxyvitamin D (25(OH)D) concentrations are associated with higher type 2 diabetes risk in adults, although causality remains uncertain. However, associations between 25(OH)D and type 2 diabetes risk markers in children have been little studied, particularly in ethnic minority populations. We examined whether 25(OH)D concentrations were associated with insulin resistance in children and whether lower 25(OH)D concentrations in South Asians and black African Caribbeans could contribute to their higher insulin resistance. Methods Cross-sectional study of 4650 UK primary school children aged 9–10 years of predominantly South Asian, black African Caribbean and white European ethnicity. Children had fasting blood measurements of circulating 25(OH)D metabolite concentrations, insulin and glucose. Results Lower 25(OH)D concentrations were observed in girls, South Asians and black African Caribbeans. In analyses adjusted for age, sex, month, ethnic group and school, circulating 25(OH)D was inversely associated with fasting insulin (−0.38%, 95% CI −0.49% to −0.27%), homoeostasis model assessment (HOMA) insulin resistance (−0.39%, 95% CI −0.50% to −0.28%) and fasting glucose (−0.03%, 95% CI −0.05% to –0.02%) per nmol/L increase in 25(OH)D; associations did not differ between ethnic groups. Ethnic differences in fasting insulin and HOMA insulin resistance (higher among South Asian and black African Caribbeans) were reduced by >40% after adjustment for circulating 25(OH)D concentrations. Conclusion Circulating vitamin D was inversely associated with insulin resistance in all ethnic groups; higher insulin resistance in South Asian and black African children were partly explained by their lower vitamin D levels. Whether vitamin D supplementation can reduce emerging type 2 diabetes risk needs further evaluation

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Allocating the fixed cost:an approach based on data envelopment analysis and cooperative game

Allocating the fixed cost among a set of users in a fair way is an important issue both in management and economic research. Recently, Du et al. (Eur J Oper Res 235(1): 206–214, 2014) proposed a novel approach for allocating the fixed cost based on the game cross-efficiency method by taking the game relations among users in efficiency evaluation. This paper proves that the novel approach of Du et al. (Eur J Oper Res 235(1): 206–214, 2014) is equivalent to the efficiency maximization approach of Li et al. (Omega 41(1): 55–60, 2013), and may exist multiple optimal cost allocation plans. Taking into account the game relations in the allocation process, this paper proposes a cooperative game approach, and uses the nucleolus as a solution to the proposed cooperative game. The proposed approach in this paper is illustrated with a dataset from the prior literature and a real dataset of a steel and iron enterprise in China

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

Change from baseline in swollen (a) and tender (b) joint counts. *Error bars show upper SE for placebo and lower SE for namilumab. SE standard error, SJC swollen joint count, TJC tender joint count. (PDF 1292 kb

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure