On the continuity of the integrated density of states in the disorder

Recently, Hislop and Marx studied the dependence of the integrated density of states on the underlying probability distribution for a class of discrete random Schr\"odinger operators, and established a quantitative form of continuity in weak* topology. We develop an alternative approach to the problem, based on Ky Fan inequalities, and establish a sharp version of the estimate of Hislop and Marx. We also consider a corresponding problem for continual random Schr\"odinger operators on $\R^d$.Comment: 9 pages, generalization of continuous case to any dimension (Theorem 2, part 1), expanded introduction, added references, fixed a few typo

Comfortable Accessible Urban Environment when Designing an Object on the Example of a Children's Educational Center

В настоящей статье приведено исследование комфортной доступной среды для дальнейшего проектирования детского образовательного центра. Рассмотрены цели, задачи и методика исследования детского образовательного центра. Были рассмотрены основные принципы формирования комфортной среды и проведена параллель на проектируемый объект детского центра. При рассмотрении вопросов были выдвинуты выводы и заключения по проделанному исследованию.In this article, a study is given of a comfortable accessible environment for the further design of a children's educational center. The goals, tasks and methods of research of the children's educational center are considered. The main principles of creating a comfortable environment were considered and a parallel was made to the projected facility of the children's center. When examining issues, conclusions and conclusions were made on the research done

IA-CCF: Individual accountability for permissioned ledgers

Permissioned ledger systems allow a consortium of members that do not trust one another to execute transactions safely on a set of replicas. Such systems typically use Byzantine fault tolerance (BFT) protocols to distribute trust, which only ensures safety when fewer than 1/3 of the replicas misbehave. Providing guarantees beyond this threshold is a challenge: current systems assume that the ledger is corrupt and fail to identify misbehaving replicas or hold the members that operate them accountable—instead all members share the blame. We describe IA-CCF, a new permissioned ledger system that provides individual accountability. It can assign blame to the individual members that operate misbehaving replicas regardless of the number of misbehaving replicas or members. IA-CCF achieves this by signing and logging BFT protocol messages in the ledger, and by using Merkle trees to provide clients with succinct, universally-verifiable receipts as evidence of successful transaction execution. Anyone can audit the ledger against a set of receipts to discover inconsistencies and identify replicas that signed contradictory statements. IACCF also supports changes to consortium membership and replicas by tracking signing keys using a sub-ledger of governance transactions. IA-CCF provides strong disincentives to misbehavior with low overhead: it executes 47,000 tx/s while providing clients with receipts in two network round trips

HIV Envelope gp120 Activates LFA-1 on CD4 T-Lymphocytes and Increases Cell Susceptibility to LFA-1-Targeting Leukotoxin (LtxA)

The cellular adhesion molecule LFA-1 and its ICAM-1 ligand play an important role in promoting HIV-1 infectivity and transmission. These molecules are present on the envelope of HIV-1 virions and are integral components of the HIV virological synapse. However, cellular activation is required to convert LFA-1 to the active conformation that has high affinity binding for ICAM-1. This study evaluates whether such activation can be induced by HIV itself. The data show that HIV-1 gp120 was sufficient to trigger LFA-1 activation in fully quiescent naïve CD4 T cells in a CD4-dependent manner, and these CD4 T cells became more susceptible to killing by LtxA, a bacterial leukotoxin that preferentially targets leukocytes expressing high levels of the active LFA-1. Moreover, virus p24-expressing CD4 T cells in the peripheral blood of HIV-infected subjects were found to have higher levels of surface LFA-1, and LtxA treatment led to significant reduction of the viral DNA burden. These results demonstrate for the first time the ability of HIV to directly induce LFA-1 activation on CD4 T cells. Although LFA-1 activation may enhance HIV infectivity and transmission, it also renders the cells more susceptible to an LFA-1-targeting bacterial toxin, which may be harnessed as a novel therapeutic strategy to deplete virus reservoir in HIV-infected individuals

Different Pattern of Immunoglobulin Gene Usage by HIV-1 Compared to Non-HIV-1 Antibodies Derived from the Same Infected Subject

A biased usage of immunoglobulin (Ig) genes is observed in human anti-HIV-1 monoclonal antibodies (mAbs) resulting probably from compensation to reduced usage of the VH3 family genes, while the other alternative suggests that this bias usage is due to antigen requirements. If the antigen structure is responsible for the preferential usage of particular Ig genes, it may have certain implications for HIV vaccine development by the targeting of particular Ig gene-encoded B cell receptors to induce neutralizing anti-HIV-1 antibodies. To address this issue, we have produced HIV-1 specific and non-HIV-1 mAbs from an infected individual and analyzed the Ig gene usage. Green-fluorescence labeled virus-like particles (VLP) expressing HIV-1 envelope (Env) proteins of JRFL and BaL and control VLPs (without Env) were used to select single B cells for the production of 68 recombinant mAbs. Ten of these mAbs were HIV-1 Env specific with neutralizing activity against V3 and the CD4 binding site, as well as non-neutralizing mAbs to gp41. The remaining 58 mAbs were non-HIV-1 Env mAbs with undefined specificities. Analysis revealed that biased usage of Ig genes was restricted only to anti-HIV-1 but not to non-HIV-1 mAbs. The VH1 family genes were dominantly used, followed by VH3, VH4, and VH5 among anti-HIV-1 mAbs, while non-HIV-1 specific mAbs preferentially used VH3 family genes, followed by VH4, VH1 and VH5 families in a pattern identical to Abs derived from healthy individuals. This observation suggests that the biased usage of Ig genes by anti-HIV-1 mAbs is driven by structural requirements of the virus antigens rather than by compensation to any depletion of VH3 B cells due to autoreactive mechanisms, according to the gp120 superantigen hypothesis

HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV

It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a “genetic bottleneck”, and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4+ T cells express high levels of CCR5, and a subset of these CD4+/CCR5high cells express the integrin α4β7, the gut homing receptor. CD4+/CCR5high/ α4β7high T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α4β7 on CD4+ T cells. On CD4+/CCR5high/ α4β7high T cells, α4β7 is closely associated with CD4 and CCR5. Furthermore, α4β7 is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α4β7 interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α4β7 is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α4β7 interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α4β7 interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infectio