Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome.

BACKGROUND: The number of CD4(+)CD28(null) (CD28(null)) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28(null) T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28(null) T cells in ACS. METHODS AND RESULTS: We found that CD28(null) T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was attributable to a dramatic reduction in proapoptotic molecules Bim, Bax, and Fas in CD28(null) T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS. CONCLUSIONS: We show that CD28(null) T cells in ACS harbor marked defects in molecules that regulate T-cell apoptosis, which tips the balance in favor of antiapoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that the inhibition of proteasomal activity allows CD28(null) T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control the apoptosis sensitivity of CD28(null) T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients

Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

Complement activation is known to have deleterious effects on organ transplantation. On the other hand, the complement system is also known to have an important role in regulating immune responses. The balance between these two opposing effects is critical in the context of transplantation. Here, we report that female mice deficient in C1q (C1qa(−/−)) or C3 (C3(−/−)) reject male syngeneic grafts (HY incompatible) at an accelerated rate compared with WT mice. Intranasal HY peptide administration, which induces tolerance to syngeneic male grafts in WT mice, fails to induce tolerance in C1qa(−/−) or C3(−/−) mice. The rejection of the male grafts correlated with the presence of HY D(b)Uty-specific CD8(+) T cells. Consistent with this, peptide-treated C1qa(−/−) and C3(−/−) female mice rejecting male grafts exhibited more antigen-specific CD8(+)IFN-γ(+) and CD8(+)IL-10(+) cells compared with WT females. This suggests that accumulation of IFN-γ- and IL-10-producing T cells may play a key role in mediating the ongoing inflammatory process and graft rejection. Interestingly, within the tolerized male skin grafts of peptide-treated WT mice, IFN-γ, C1q and C3 mRNA levels were higher compared to control female grafts. These results suggest that C1q and C3 facilitate the induction of intranasal tolerance

Cell-Type Specific Changes in Glial Morphology and Glucocorticoid Expression During Stress and Aging in the Medial Prefrontal Cortex.

Repeated exposure to stressors is known to produce large-scale remodeling of neurons within the prefrontal cortex (PFC). Recent work suggests stress-related forms of structural plasticity can interact with aging to drive distinct patterns of pyramidal cell morphological changes. However, little is known about how other cellular components within PFC might be affected by these challenges. Here, we examined the effects of stress exposure and aging on medial prefrontal cortical glial subpopulations. Interestingly, we found no changes in glial morphology with stress exposure but a profound morphological change with aging. Furthermore, we found an upregulation of non-nuclear glucocorticoid receptors (GR) with aging, while nuclear levels remained largely unaffected. Both changes are selective for microglia, with no stress or aging effect found in astrocytes. Lastly, we show that the changes found within microglia inversely correlated with the density of dendritic spines on layer III pyramidal cells. These findings suggest microglia play a selective role in synaptic health within the aging brain

Decomposition of fractional quantum Hall states: New symmetries and approximations

We provide a detailed description of a new symmetry structure of the monomial (Slater) expansion coefficients of bosonic (fermionic) fractional quantum Hall states first obtained in Ref. 1, which we now extend to spin-singlet states. We show that the Haldane-Rezayi spin-singlet state can be obtained without exact diagonalization through a differential equation method that we conjecture to be generic to other FQH model states. The symmetry rules in Ref. 1 as well as the ones we obtain for the spin singlet states allow us to build approximations of FQH states that exhibit increasing overlap with the exact state (as a function of system size). We show that these overlaps reach unity in the thermodynamic limit even though our approximation omits more than half of the Hilbert space. We show that the product rule is valid for any FQH state which can be written as an expectation value of parafermionic operators.Comment: 22 pages, 8 figure

The Anatomy of Abelian and Non-Abelian Fractional Quantum Hall States

We deduce a new set of symmetries and relations between the coefficients of the expansion of Abelian and Non-Abelian Fractional Quantum Hall (FQH) states in free (bosonic or fermionic) many-body states. Our rules allow to build an approximation of a FQH model state with an overlap increasing with growing system size (that may sometimes reach unity!) while using a fraction of the original Hilbert space. We prove these symmetries by deriving a previously unknown recursion formula for all the coefficients of the Slater expansion of the Laughlin, Read Rezayi and many other states (all Jacks multiplied by Vandermonde determinants), which completely removes the current need for diagonalization procedures.Comment: modify comment in Ref. 1

On Poincare and logarithmic Sobolev inequalities for a class of singular Gibbs measures

This note, mostly expository, is devoted to Poincar{\'e} and log-Sobolev inequalities for a class of Boltzmann-Gibbs measures with singular interaction. Such measures allow to model one-dimensional particles with confinement and singular pair interaction. The functional inequalities come from convexity. We prove and characterize optimality in the case of quadratic confinement via a factorization of the measure. This optimality phenomenon holds for all beta Hermite ensembles including the Gaussian unitary ensemble, a famous exactly solvable model of random matrix theory. We further explore exact solvability by reviewing the relation to Dyson-Ornstein-Uhlenbeck diffusion dynamics admitting the Hermite-Lassalle orthogonal polynomials as a complete set of eigenfunctions. We also discuss the consequence of the log-Sobolev inequality in terms of concentration of measure for Lipschitz functions such as maxima and linear statistics.Comment: Minor improvements. To appear in Geometric Aspects of Functional Analysis -- Israel Seminar (GAFA) 2017-2019", Lecture Notes in Mathematics 225

Denial-of-service resilience in peer-to-peer file sharing systems

Peer-to-peer (p2p) file sharing systems are characterized by highly replicated content distributed among nodes with enormous aggregate resources for storage and communication. These properties alone are not sufficient, however, to render p2p networks immune to denial-of-service (DoS) attack. In this paper, we study, by means of analytical modeling and simulation, the resilience of p2p file sharing systems against DoS attacks, in which malicious nodes respond to queries with erroneous responses. We consider the filetargeted attacks in current use in the Internet, and we introduce a new class of p2p-network-targeted attacks. In file-targeted attacks, the attacker puts a large number of corrupted versions of a single file on the network. We demonstrate that the effectiveness of these attacks is highly dependent on the clients’ behavior. For the attacks to succeed over the long term, clients must be unwilling to share files, slow in removing corrupted files from their machines, and quick to give up downloading when the system is under attack. In network-targeted attacks, attackers respond to queries for any file with erroneous information. Our results indicate that these attacks are highly scalable: increasing the number of malicious nodes yields a hyperexponential decrease in system goodput, and a moderate number of attackers suffices to cause a near-collapse of the entire system. The key factors inducing this vulnerability are (i) hierarchical topologies with misbehaving “supernodes,” (ii) high path-length networks in which attackers have increased opportunity to falsify control information, and (iii) power-law networks in which attackers insert themselves into high-degree points in the graph. Finally, we consider the effects of client counter-strategies such as randomized reply selection, redundant and parallel download, and reputation systems. Some counter-strategies (e.g., randomized reply selection) provide considerable immunity to attack (reducing the scaling from hyperexponential to linear), yet significantly hurt performance in the absence of an attack. Other counter-strategies yield little benefit (or penalty). In particular, reputation systems show little impact unless they operate with near perfection

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study

Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 10−8) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case–control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and α-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD.Robert P. & Judith N. Goldberg FoundationWilliam N. & Bernice E. Bumpus FoundationHoward Hughes Medical Institute (Collaborative Innovation Award)National Science Foundation (U.S.) (R01-NS036711

739 observed NEAs and new 2-4m survey statistics within the EURONEAR network

We report follow-up observations of 477 program Near-Earth Asteroids (NEAs) using nine telescopes of the EURONEAR network having apertures between 0.3 and 4.2 m. Adding these NEAs to our previous results we now count 739 program NEAs followed-up by the EURONEAR network since 2006. The targets were selected using EURONEAR planning tools focusing on high priority objects. Analyzing the resulting orbital improvements suggests astrometric follow-up is most important days to weeks after discovery, with recovery at a new opposition also valuable. Additionally we observed 40 survey fields spanning three nights covering 11 sq. degrees near opposition, using the Wide Field Camera on the 2.5m Isaac Newton Telescope (INT), resulting in 104 discovered main belt asteroids (MBAs) and another 626 unknown one-night objects. These fields, plus program NEA fields from the INT and from the wide field MOSAIC II camera on the Blanco 4m telescope, generated around 12,000 observations of 2,000 minor planets (mostly MBAs) observed in 34 square degrees. We identify Near Earth Object (NEO) candidates among the unknown (single night) objects using three selection criteria. Testing these criteria on the (known) program NEAs shows the best selection methods are our epsilon-miu model which checks solar elongation and sky motion and the MPC's NEO rating tool. Our new data show that on average 0.5 NEO candidates per square degree should be observable in a 2m-class survey (in agreement with past results), while an average of 2.7 NEO candidates per square degree should be observable in a 4m-class survey (although our Blanco statistics were affected by clouds). At opposition just over 100 MBAs (1.6 unknown to every 1 known) per square degree are detectable to R=22 in a 2m survey based on the INT data, while our two best ecliptic Blanco fields away from opposition lead to 135 MBAs (2 unknown to every 1 known) to R=23.Comment: Published in Planetary and Space Sciences (Sep 2013