Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.

In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS

Power efficiency analysis of a multi-oscillated current resonant type DC-DC converter

This paper deals with an analysis of the power efficiency of a multi-oscillated current resonant type DC-DC converter. The current resonant type converter employs generally the pulse frequency modulation. For this reason, the magnetizing current through the converter causes not only a power loss under a light load, but also a loss during stand-by. In order to solve these problems, a multi-oscillated current resonant type DC-DC converter has been proposed, and revealed the advantage of its control method which can reduce power loss under light load and keep low switching noise. An analytical relationship of among states, operating mode and efficiency characteristics of this converter are defined. As a result, it was confirmed that for this converter, the output power depends on the voltage of resonant capacitor, and consequently, it is important to determine constants of resonant capacitor and inductance of transformer. The maximum efficiency is 95.4% with the magnetizing inductance 1.8 mH.2008 IEEE Power Electronics Specialists Conference - PESC 2008 : Rhodes, Greece, 2008.06.15-2008.06.1

Mutual information challenges entropy bounds

We consider some formulations of the entropy bounds at the semiclassical level. The entropy S(V) localized in a region V is divergent in quantum field theory (QFT). Instead of it we focus on the mutual information I(V,W)=S(V)+S(W)-S(V\cup W) between two different non-intersecting sets V and W. This is a low energy quantity, independent of the regularization scheme. In addition, the mutual information is bounded above by twice the entropy corresponding to the sets involved. Calculations of I(V,W) in QFT show that the entropy in empty space cannot be renormalized to zero, and must be actually very large. We find that this entropy due to the vacuum fluctuations violates the FMW bound in Minkowski space. The mutual information also gives a precise, cutoff independent meaning to the statement that the number of degrees of freedom increases with the volume in QFT. If the holographic bound holds, this points to the essential non locality of the physical cutoff. Violations of the Bousso bound would require conformal theories and large distances. We speculate that the presence of a small cosmological constant might prevent such a violation.Comment: 10 pages, 2 figures, minor change

Fixing the conformation of calix[4]arenes: When are three carbons not enough?

Calix[4]arenes are unique macrocycles that through judicious functionalisation at the lower-rim can be either fixed in one of four conformations or remain conformationally flexible. Introduction of propynyl or propenyl groups unexpectedly provides a new possibility; a unidirectional conformational switch, with the 1,3-alternate and 1,2-alternate conformers switching to the partial cone conformation, whilst the cone conformation is unchanged, under standard experimental conditions. Using 1H NMR kinetic studies, rates of switching have been shown to be dependent on the starting conformation, upper-rim substituent, where reduction in bulk enables faster switching, solvent and temperature with 1,2-alternate conformations switching fastest. Ab initio calculations (DFT) confirmed the relative stabilities of the conformations and point towards the partial cone conformer being the most stable of the four. The potential impact on synthesis through the ‘click’ reaction has been investigated and found not to be significant

Relative entanglement entropies in 1 + 1-dimensional conformal field theories

We study the relative entanglement entropies of one interval between excited states of a 1+1 dimensional conformal field theory (CFT). To compute the relative entropy S(\u3c11\u2016\u3c10) between two given reduced density matrices \u3c11 and \u3c10 of a quantum field theory, we employ the replica trick which relies on the path integral representation of Tr(\u3c11\u3c1n 1210) and define a set of R\'enyi relative entropies Sn(\u3c11\u2016\u3c10). We compute these quantities for integer values of the parameter n and derive via the replica limit, the relative entropy between excited states generated by primary fields of a free massless bosonic field. In particular, we provide the relative entanglement entropy of the state described by the primary operator i 02\u3d5, both with respect to the ground state and to the state generated by chiral vertex operators. These predictions are tested against exact numerical calculations in the XX spin-chain finding perfect agreement. \ua9 2017, The Author(s)

Characterization of Transcription from TATA-Less Promoters: Identification of a New Core Promoter Element XCPE2 and Analysis of Factor Requirements

More than 80% of mammalian protein-coding genes are driven by TATA-less promoters which often show multiple transcriptional start sites (TSSs). However, little is known about the core promoter DNA sequences or mechanisms of transcriptional initiation for this class of promoters.Here we identify a new core promoter element XCPE2 (X core promoter element 2) (consensus sequence: A/C/G-C-C/T-C-G/A-T-T-G/A-C-C/A(+1)-C/T) that can direct specific transcription from the second TSS of hepatitis B virus X gene mRNA. XCPE2 sequences can also be found in human promoter regions and typically appear to drive one of the start sites within multiple TSS-containing TATA-less promoters. To gain insight into mechanisms of transcriptional initiation from this class of promoters, we examined requirements of several general transcription factors by in vitro transcription experiments using immunodepleted nuclear extracts and purified factors. Our results show that XCPE2-driven transcription uses at least TFIIB, either TFIID or free TBP, RNA polymerase II (RNA pol II) and the MED26-containing mediator complex but not Gcn5. Therefore, XCPE2-driven transcription can be carried out by a mechanism which differs from previously described TAF-dependent mechanisms for initiator (Inr)- or downstream promoter element (DPE)-containing promoters, the TBP- and SAGA (Spt-Ada-Gcn5-acetyltransferase)-dependent mechanism for yeast TATA-containing promoters, or the TFTC (TBP-free-TAF-containing complex)-dependent mechanism for certain Inr-containing TATA-less promoters. EMSA assays using XCPE2 promoter and purified factors further suggest that XCPE2 promoter recognition requires a set of factors different from those for TATA box, Inr, or DPE promoter recognition.We identified a new core promoter element XCPE2 that are found in multiple TSS-containing TATA-less promoters. Mechanisms of promoter recognition and transcriptional initiation for XCPE2-driven promoters appear different from previously shown mechanisms for classical promoters that show single "focused" TSSs. Our studies provide insight into novel mechanisms of RNA Pol II transcription from multiple TSS-containing TATA-less promoters

Probiotic Bifidobacterium breve Induces IL-10-Producing Tr1 Cells in the Colon

Specific intestinal microbiota has been shown to induce Foxp3+ regulatory T cell development. However, it remains unclear how development of another regulatory T cell subset, Tr1 cells, is regulated in the intestine. Here, we analyzed the role of two probiotic strains of intestinal bacteria, Lactobacillus casei and Bifidobacterium breve in T cell development in the intestine. B. breve, but not L. casei, induced development of IL-10-producing Tr1 cells that express cMaf, IL-21, and Ahr in the large intestine. Intestinal CD103+ dendritic cells (DCs) mediated B. breve-induced development of IL-10-producing T cells. CD103+ DCs from Il10−/−, Tlr2−/−, and Myd88−/− mice showed defective B. breve-induced Tr1 cell development. B. breve-treated CD103+ DCs failed to induce IL-10 production from co-cultured Il27ra−/− T cells. B. breve treatment of Tlr2−/− mice did not increase IL-10-producing T cells in the colonic lamina propria. Thus, B. breve activates intestinal CD103+ DCs to produce IL-10 and IL-27 via the TLR2/MyD88 pathway thereby inducing IL-10-producing Tr1 cells in the large intestine. Oral B. breve administration ameliorated colitis in immunocompromised mice given naïve CD4+ T cells from wild-type mice, but not Il10−/− mice. These findings demonstrate that B. breve prevents intestinal inflammation through the induction of intestinal IL-10-producing Tr1 cells

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding abilit