The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities.

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia

Higgs-Stoponium Mixing Near the Stop-Antistop Threshold

Supersymmetric extensions of the standard model contain additional heavy neutral Higgs bosons that are coupled to heavy scalar top quarks (stops). This system exhibits interesting field theoretic phenomena when the Higgs mass is close to the stop-antistop production threshold. Existing work in the literature has examined the digluon-to-diphoton cross section near threshold and has focused on enhancements in the cross section that might arise either from the perturbative contributions to the Higgs-to-digluon and Higgs-to-diphoton form factors or from mixing of the Higgs boson with stoponium states. Near threshold, enhancements in the relevant amplitudes that go as inverse powers of the stop-antistop relative velocity require resummations of perturbation theory and/or nonperturbative treatments. We present a complete formulation of threshold effects at leading order in the stop-antistop relative velocity in terms of nonrelativistic effective field theory. We give detailed numerical calculations for the case in which the stop-antistop Green's function is modeled with a Coulomb-Schr\"odinger Green's function. We find several general effects that do not appear in a purely perturbative treatment. Higgs-stop-antistop mixing effects displace physical masses from the threshold region, thereby rendering the perturbative threshold enhancements inoperative. In the case of large Higgs-stop-antistop couplings, the displacement of a physical state above threshold substantially increases its width, owing to its decay width to a stop-antistop pair, and greatly reduces its contribution to the cross section.Comment: 45 pages, 13 figures, minor corrections, references added, figures 2--5 updated, version published in Phys. Rev.

Aphid reproductive investment in response to mortality risks

<p>Abstract</p> <p>Background</p> <p>Aphids are striking in their prodigious reproductive capacity and reliance on microbial endosymbionts, which provision their hosts with necessary amino acids and provide protection against parasites and heat stress. Perhaps as a result of this bacterial dependence, aphids have limited immune function that may leave them vulnerable to bacterial pathogens. An alternative, non-immunological response that may be available to infected aphids is to increase reproduction, thereby ameliorating fitness loss from infection. Such a response would reduce the need to mount a potentially energetically costly immune response, and would parallel that of other hosts that alter life-history traits when there is a risk of infection. Here we examined whether pea aphids (<it>Acyrthosiphon pisum</it>) respond to immunological challenges by increasing reproduction. As a comparison to the response to the internal cue of risk elicited by immunological challenge, we also exposed pea aphids to an external cue of risk - the aphid alarm pheromone (<it>E</it>)-<it>β</it>-farnesene (EBF), which is released in the presence of predators. For each challenge, we also examined whether the presence of symbionts modified the host response, as maintaining host fitness in the face of challenge would benefit both the host and its dependent bacteria.</p> <p>Results</p> <p>We found that aphids stabbed abdominally with a sterile needle had reduced fecundity relative to control aphids but that aphids stabbed with a needle bearing heat-killed bacteria had reproduction intermediate, and statistically indistinguishable, to the aphids stabbed with a sterile needle and the controls. Aphids with different species of facultative symbiotic bacteria had different reproductive patterns overall, but symbionts in general did not alter aphid reproduction in response to bacterial exposure. However, in response to exposure to alarm pheromone, aphids with <it>Hamiltonella defensa </it>or <it>Serratia symbiotica </it>symbiotic infections increased reproduction but those without a facultative symbiont or with <it>Regiella insecticola </it>did not.</p> <p>Conclusions</p> <p>Overall, our results suggest that pea aphids are able to increase their reproduction in response to specific cues and that symbiont presence sometimes moderates this response. Such increased reproduction in response to risk of death increases the fitness of both aphids and their vertically transmitted symbionts, and since these organisms have high reproductive capacity, slight increases in reproduction could lead to a very large numerical advantage later in the season. Thus both symbiotic partners can benefit by increasing host fecundity under dangerous conditions.</p

Improving three layer neural net convergence

The authors investigate the relationship between three layer feed forward back-propagation nets (using the terminology of Rumelhart et al., see Nature vol.323, p.533 et seq., 1986) and the committee net of (Nilsson, see Learning Machines, McGraw-Hill, 1956), and show that a simple modification to the algorithm of the latter makes them, in respect of their power to classify data sets, equivalent. Two algorithms may, however, be equivalent in power but differ greatly in their practicality. In the second part the authors conduct some experiments in order to determine whether the modified committee algorithm can compete with back-propagation in a variety of applications. It is found that the committee algorithm (a) is about ten times as fast in some applications and (b) is much less prone to getting trapped in local minima. The theoretical interest in the paper stems from the ease of analysing the committee algorithm together with the equivalence. The experimental interest is that this method of speeding up back-propagation may be used with other improvements to reduce training times in some application

Defect cluster recognition system for fabricated semiconductor wafers

The International Technology Roadmap for Semiconductors (ITRS) identifies production test data as an essential element in improving design and technology in the manufacturing process feedback loop. One of the observations made from the high-volume production test data is that dies that fail due to a systematic failure have a tendency to form certain unique patterns that manifest as defect clusters at the wafer level. Identifying and categorising such clusters is a crucial step towards manufacturing yield improvement and implementation of real-time statistical process control. Addressing the semiconductor industry&#039;s needs, this research proposes an automatic defect cluster recognition system for semiconductor wafers that achieves up to 95% accuracy (depending on the product type)

Spin relaxation in mesoscopic superconducting Al wires

We studied the diffusion and the relaxation of the polarized quasiparticle spins in superconductors. To that end, quasiparticles of polarized spins were injected through an interface of a mesoscopic superconducting Al wire in proximity contact with an overlaid ferromagnetic Co wire in the single-domain state. The superconductivity was observed to be suppressed near the spin-injecting interface, as evidenced by the occurrence of a finite voltage for a bias current below the onset of the superconducting transition. The spin diffusion length, estimated from finite voltages over a certain length of Al wire near the interface, was almost temperature independent in the temperature range sufficiently below the superconducting transition but grew as the transition temperature was approached. This temperature dependence suggests that the relaxation of the spin polarization in the superconducting state is governed by the condensation of quasiparticles to the paired state. The spin relaxation in the superconducting state turned out to be more effective than in the normal state.Comment: 9 pages, 8 figure

Molecular dynamics simulation of the transport of small molecules across a polymer membrane

The transport of small molecules through a polymer membrane is modeled using the computer simulation technique of molecular dynamics (MD). The transport coefficient is derived from a combination of the excess free energy and the diffusion constant. Both properties are derived from MD simulations, applied to helium and methane in polydimethylsiloxane (PDMS). The diffusional process appears to have the character of a jump diffusion for methane and less so for helium. Jumps are allowed by fluctuations of the size and shape of holes. Experimental diffusion constants are well reproduced. The excess free energies, determined by a particle insertion method, are lower by 5-7 kJ/mol than experimental values. It is shown that, as a result of a higher solubility, methane has a higher permeability constant than helium, despite its lower diffusion constant

Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice.

Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity

A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores

Background: Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes. Methods: The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months' treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease. Results: The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) -5 to 12], whereas the observed risk change was -28.8% (95% CI -42.0 to -11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of -12.4% (95% CI -17 to -7), which underestimated the observed risk change -21.8% (95% CI -34 to -6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [-24.0% (95% CI -30 to -17) and -22.6% (95% CI -23 to -16) for ESRD and the composite renal outcome, respectively]. Conclusion: A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies