Breaking tolerance in transgenic mice expressing the human TSH receptor A-subunit: thyroiditis, epitope spreading and adjuvant as a 'double edged sword'.

Transgenic mice with the human thyrotropin-receptor (TSHR) A-subunit targeted to the thyroid are tolerant of the transgene. In transgenics that express low A-subunit levels (Lo-expressors), regulatory T cell (Treg) depletion using anti-CD25 before immunization with adenovirus encoding the A-subunit (A-sub-Ad) breaks tolerance, inducing extensive thyroid lymphocytic infiltration, thyroid damage and antibody spreading to other thyroid proteins. In contrast, no thyroiditis develops in Hi-expressor transgenics or wild-type mice. Our present goal was to determine if thyroiditis could be induced in Hi-expressor transgenics using a more potent immunization protocol: Treg depletion, priming with Complete Freund's Adjuvant (CFA) + A-subunit protein and further Treg depletions before two boosts with A-sub-Ad. As controls, anti-CD25 treated Hi- and Lo-expressors and wild-type mice were primed with CFA+ mouse thyroglobulin (Tg) or CFA alone before A-sub-Ad boosting. Thyroiditis developed after CFA+A-subunit protein or Tg and A-sub-Ad boosting in Lo-expressor transgenics but Hi- expressors (and wild-type mice) were resistant to thyroiditis induction. Importantly, in Lo-expressors, thyroiditis was associated with the development of antibodies to the mouse TSHR downstream of the A-subunit. Unexpectedly, we observed that the effect of bacterial products on the immune system is a "double-edged sword". On the one hand, priming with CFA (mycobacteria emulsified in oil) plus A-subunit protein broke tolerance to the A-subunit in Hi-expressor transgenics leading to high TSHR antibody levels. On the other hand, prior treatment with CFA in the absence of A-subunit protein inhibited responses to subsequent immunization with A-sub-Ad. Consequently, adjuvant activity arising in vivo after bacterial infections combined with a protein autoantigen can break self-tolerance but in the absence of the autoantigen, adjuvant activity can inhibit the induction of immunity to autoantigens (like the TSHR) displaying strong self-tolerance

Investigating the mechanism of acoustically activated uptake of drugs from Pluronic micelles

BACKGROUND: This paper examines the mechanism of ultrasonic enhanced drug delivery from Pluronic micelles. In previous publications by our group, fluorescently labeled Pluronic was shown to penetrate HL-60 cells with and without the action of ultrasound, while drug uptake was increased with the application of ultrasound. METHODS: In this study, the amount of uptake of two fluorescent probes, Lysosensor Green (a pH-sensitive probe) and Cell Tracker Orange CMTMR (a pH-independent probe), was measured in HL-60 and HeLa cells. RESULTS: The results of our experiments show that the increase in drug accumulation in the cells as a result of ultrasonication is not due to an increase in endocytosis due to ultrasonication. CONCLUSIONS: We hypothesize that sonoporation plays an important role in the acoustically activated drug delivery of chemotherapy drugs delivered from Pluronic micelles

Growing Scale-Free Networks with Tunable Clustering

We extend the standard scale-free network model to include a ``triad formation step''. We analyze the geometric properties of networks generated by this algorithm both analytically and by numerical calculations, and find that our model possesses the same characteristics as the standard scale-free networks like the power-law degree distribution and the small average geodesic length, but with the high-clustering at the same time. In our model, the clustering coefficient is also shown to be tunable simply by changing a control parameter - the average number of triad formation trials per time step.Comment: Accepted for publication in Phys. Rev.

A large conformational change of the translocation ATPase SecA

The ATPase SecA mediates the posttranslational translocation of a wide range of polypeptide substrates through the SecY channel in the cytoplasmic membrane of bacteria. We have determined the crystal structure of a monomeric form of Bacillus subtilis SecA at a 2.2-Å resolution. A comparison with the previously determined structures of SecA reveals a nucleotide-independent, large conformational change that opens a deep groove similar to that in other proteins that interact with diverse polypeptides. We propose that the open form of SecA represents an activated state

Network dynamics of ongoing social relationships

Many recent large-scale studies of interaction networks have focused on networks of accumulated contacts. In this paper we explore social networks of ongoing relationships with an emphasis on dynamical aspects. We find a distribution of response times (times between consecutive contacts of different direction between two actors) that has a power-law shape over a large range. We also argue that the distribution of relationship duration (the time between the first and last contacts between actors) is exponentially decaying. Methods to reanalyze the data to compensate for the finite sampling time are proposed. We find that the degree distribution for networks of ongoing contacts fits better to a power-law than the degree distribution of the network of accumulated contacts do. We see that the clustering and assortative mixing coefficients are of the same order for networks of ongoing and accumulated contacts, and that the structural fluctuations of the former are rather large.Comment: to appear in Europhys. Let

Increased Expression of Tissue Factor and Receptor for Advanced Glycation End Products in Peripheral Blood Mononuclear Cells of Patients With Type 2 Diabetes Mellitus with Vascular Complications

The aim of the study was to determine the correlation between the expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in patients with longstanding uncontrolled type 2 diabetes (T2D). TF and RAGE mRNAs as well as TF antigen and activity were investigated in 21 T2D patients with and without vascular complications. mRNA expression was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) in nonstimulated and advanced glycation end product (AGE) albumin–stimulated peripheral blood mononuclear cells (PBMCs). TF antigen expression was determined by enzyme-linked immunosorbent assay (ELISA) and TF activity by a modified prothrombin time assay. Basal RAGE mRNA expression was 0.2 ± 0.06 in patients with complications and 0.05 ± 0.06 patients without complications (P = .004). Stimulation did not cause any further increase in either group. TF mRNA was 0.58 ± 0.29 in patients with complications and 0.21 ± 0.18 in patients without complications (P = .003). Stimulation resulted in a nonsignificant increase in both groups. Basal TF activity (U/106 PBMCs) was 18.4 ± 13.2 in patients with complications and 6.96 ± 5.2 in patients without complications (P = .003). It increased 3-fold in both groups after stimulation (P = .001). TF antigen (pg/106 PBMCs) was 33.7 ± 28.6 in patients with complications, 10.4 ± 7.8 in patients without complications (P = .02). Stimulation tripled TF antigen in both groups of patients (P = .001). The RAGE/TF axis is up-regulated inT2Dpatients with vascular complications as compared to patients without complications. This suggests a role for this axis in the pathogenesis of vascular complications in T2D

Networking Effects on Cooperation in Evolutionary Snowdrift Game

The effects of networking on the extent of cooperation emerging in a competitive setting are studied. The evolutionary snowdrift game, which represents a realistic alternative to the well-known Prisoner's Dilemma, is studied in the Watts-Strogatz network that spans the regular, small-world, and random networks through random re-wiring. Over a wide range of payoffs, a re-wired network is found to suppress cooperation when compared with a well-mixed or fully connected system. Two extinction payoffs, that characterize the emergence of a homogeneous steady state, are identified. It is found that, unlike in the Prisoner's Dilemma, the standard deviation of the degree distribution is the dominant network property that governs the extinction payoffs.Comment: Changed conten

Controlling cluster synchronization by adapting the topology

We suggest an adaptive control scheme for the control of zero-lag and cluster synchronization in delay-coupled networks. Based on the speed-gradient method, our scheme adapts the topology of a network such that the target state is realized. It is robust towards different initial condition as well as changes in the coupling parameters. The emerging topology is characterized by a delicate interplay of excitatory and inhibitory links leading to the stabilization of the desired cluster state. As a crucial parameter determining this interplay we identify the delay time. Furthermore, we show how to construct networks such that they exhibit not only a given cluster state but also with a given oscillation frequency. We apply our method to coupled Stuart-Landau oscillators, a paradigmatic normal form that naturally arises in an expansion of systems close to a Hopf bifurcation. The successful and robust control of this generic model opens up possible applications in a wide range of systems in physics, chemistry, technology, and life science

Human behavior in Prisoner's Dilemma experiments suppresses network reciprocity

During the last few years, much research has been devoted to strategic interactions on complex networks. In this context, the Prisoner's Dilemma has become a paradigmatic model, and it has been established that imitative evolutionary dynamics lead to very different outcomes depending on the details of the network. We here report that when one takes into account the real behavior of people observed in the experiments, both at the mean-field level and on utterly different networks the observed level of cooperation is the same. We thus show that when human subjects interact in an heterogeneous mix including cooperators, defectors and moody conditional cooperators, the structure of the population does not promote or inhibit cooperation with respect to a well mixed population.Comment: 5 Pages including 4 figures. Submitted for publicatio