Cirquent calculus deepened

Cirquent calculus is a new proof-theoretic and semantic framework, whose main distinguishing feature is being based on circuits, as opposed to the more traditional approaches that deal with tree-like objects such as formulas or sequents. Among its advantages are greater efficiency, flexibility and expressiveness. This paper presents a detailed elaboration of a deep-inference cirquent logic, which is naturally and inherently resource conscious. It shows that classical logic, both syntactically and semantically, is just a special, conservative fragment of this more general and, in a sense, more basic logic -- the logic of resources in the form of cirquent calculus. The reader will find various arguments in favor of switching to the new framework, such as arguments showing the insufficiency of the expressive power of linear logic or other formula-based approaches to developing resource logics, exponential improvements over the traditional approaches in both representational and proof complexities offered by cirquent calculus, and more. Among the main purposes of this paper is to provide an introductory-style starting point for what, as the author wishes to hope, might have a chance to become a new line of research in proof theory -- a proof theory based on circuits instead of formulas.Comment: Significant improvements over the previous version

InterAKTions with FKBPs - mutational and pharmacological exploration

The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

AIP1 is a novel Agenet/Tudor domain protein from Arabidopsis that interacts with regulators of DNA replication, transcription and chromatin remodeling

Background: DNA replication and transcription are dynamic processes regulating plant development that are dependent on the chromatin accessibility. Proteins belonging to the Agenet/Tudor domain family are known as histone modification "readers" and classified as chromatin remodeling proteins. Histone modifications and chromatin remodeling have profound effects on gene expression as well as on DNA replication, but how these processes are integrated has not been completely elucidated. It is clear that members of the Agenet/Tudor family are important regulators of development playing roles not well known in plants. Methods: Bioinformatics and phylogenetic analyses of the Agenet/Tudor Family domain in the plant kingdom were carried out with sequences from available complete genomes databases. 3D structure predictions of Agenet/Tudor domains were calculated by I-TASSER server. Protein interactions were tested in two-hybrid, GST pulldown, semi-in vivo pulldown and Tandem Affinity Purification assays. Gene function was studied in a T-DNA insertion GABI-line. Results: In the present work we analyzed the family of Agenet/Tudor domain proteins in the plant kingdom and we mapped the organization of this family throughout plant evolution. Furthermore, we characterized a member from Arabidopsis thaliana named AIP1 that harbors Agenet/Tudor and DUF724 domains. AIP1 interacts with ABAP1, a plant regulator of DNA replication licensing and gene transcription, with a plant histone modification "reader" (LHP1) and with non modified histones. AIP1 is expressed in reproductive tissues and its down-regulation delays flower development timing. Also, expression of ABAP1 and LHP1 target genes were repressed in flower buds of plants with reduced levels of AIP1. Conclusions: AIP1 is a novel Agenet/Tudor domain protein in plants that could act as a link between DNA replication, transcription and chromatin remodeling during flower development

Calibration and data quality of warm IRAC

We present an overview of the calibration and properties of data from the IRAC instrument aboard the Spitzer Space Telescope taken after the depletion of cryogen. The cryogen depleted on 15 May 2009, and shortly afterward a two-month- long calibration and characterization campaign was conducted. The array temperature and bias setpoints were revised on 19 September 2009 to take advantage of lower than expected power dissipation by the instrument and to improve sensitivity. The final operating temperature of the arrays is 28.7 K, the applied bias across each detector is 500 mV and the equilibrium temperature of the instrument chamber is 27.55 K. The final sensitivities are essentially the same as the cryogenic mission with the 3.6 μm array being slightly less sensitive (10%) and the 4.5 μm array within 5% of the cryogenic sensitivity. The current absolute photometric uncertainties are 4% at 3.6 and 4.5 μm, and better than milli-mag photometry is achievable for long-stare photometric observations. With continued analysis, we expect the absolute calibration to improve to the cryogenic value of 3%. Warm IRAC operations fully support all science that was conducted in the cryogenic mission and all currently planned warm science projects (including Exploration Science programs). We expect that IRAC will continue to make ground-breaking discoveries in star formation, the nature of the early universe, and in our understanding of the properties of exoplanets

Loss of flotillin expression results in weakened desmosomal adhesion and Pemphigus vulgaris-like localisation of desmoglein-3 in human keratinocytes

Desmosomes are adhesion plaques that mediate cell-cell adhesion in many tissues, including the epidermis, and generate mechanical resistance to tissues. The extracellular domains of desmosomal cadherin proteins, desmogleins and desmocollins, are required for the interaction with cadherins of the neighbouring cells, whereas their cytoplasmic tails associate with cytoplasmic proteins which mediate connection to intermediate filaments. Disruption of desmosomal adhesion by mutations, autoantibodies or bacterial toxins results in severe human disorders of e.g. the skin and the heart. Despite the vital role of desmosomes in various tissues, the details of their molecular assembly are not clear. We here show that the two members of the flotillin protein family directly interact with the cytoplasmic tails of desmogleins. Depletion of flotillins in human keratinocytes results in weakened desmosomal adhesion and reduced expression of desmoglein-3, most likely due to a reduction in the desmosomal pool due to increased turnover. In the absence of flotillins, desmoglein-3 shows an altered localisation pattern in the cell-cell junctions of keratinocytes, which is highly similar to the localisation observed upon treatment with pemphigus vulgaris autoantibodies. Thus, our data show that flotillins, which have previously been connected to the classical cadherins, are also of importance for the desmosomal cell adhesion

KIC 8462852 - The Infrared Flux

We analyzed the warm Spitzer/IRAC data of KIC 8462852. We found no evidence of infrared excess at 3.6 micron and a small excess of 0.43 +/- 0.18 mJy at 4.5 micron, below the 3 sigma threshold necessary to claim a detection. The lack of strong infrared excess 2 years after the events responsible for the unusual light curve observed by Kepler, further disfavors the scenarios involving a catastrophic collision in a KIC 8462852 asteroid belt, a giant impact disrupting a planet in the system or a population of a dust-enshrouded planetesimals. The scenario invoking the fragmentation of a family of comets on a highly elliptical orbit is instead consistent with the lack of strong infrared excess found by our analysis.Comment: Published on The Astrophysical Journal Letter

Fyn-Mediated Regulation of Protein Kinase A

Protein kinases are enzymes important for signal transduction in the regulation of cellular processes. The cAMP-dependent protein kinase A (PKA) has been previously reported to regulate the activity of the Src family kinase Fyn, an event important for cellular migration. This study aimed to characterize the reciprocal interaction, in which Fyn regulates PKA. In addition to our preliminary, unpublished findings that Fyn phosphorylates the PKA catalytic subunit at Y69 to increase its catalytic activity, we have shown through co-immunoprecipitation that Fyn physically associates with PKA in HEK293 cells. Quantitative mass spectrometry and subsequent biochemical validation shows that PKACα undergoes enhanced binding to a complex of centrosomal and Golgi-localized A-kinase anchoring proteins when Fyn is overexpressed, independent of Fyn kinase activity. Fyn was found in this complex, as well, implicating its involvement as an adaptor protein. Co-immunoprecipitation experiments with various Fyn alleles demonstrated the dispensability of the Fyn SH3 domain and the functioning SH2 domain in binding to PKACα. GST-fusion proteins containing either of these domains were also unable to enrich PKACα from HEK293 lysates. Fyn was found to bind PKACα independent of its association with the regulatory subunit, and preliminary data suggests that this interaction is direct through purified protein pulldown experiments. We hypothesize that this regulatory interaction activates PKA at the centrosome and Golgi apparatus, facilitating the potential phosphorylation of proximal substrates involved in cytoskeletal organization and mitotic processes

Advanced Message Routing for Scalable Distributed Simulations

The Joint Forces Command (JFCOM) Experimentation Directorate (J9)'s recent Joint Urban Operations (JUO) experiments have demonstrated the viability of Forces Modeling and Simulation in a distributed environment. The JSAF application suite, combined with the RTI-s communications system, provides the ability to run distributed simulations with sites located across the United States, from Norfolk, Virginia to Maui, Hawaii. Interest-aware routers are essential for communications in the large, distributed environments, and the current RTI-s framework provides such routers connected in a straightforward tree topology. This approach is successful for small to medium sized simulations, but faces a number of significant limitations for very large simulations over high-latency, wide area networks. In particular, traffic is forced through a single site, drastically increasing distances messages must travel to sites not near the top of the tree. Aggregate bandwidth is limited to the bandwidth of the site hosting the top router, and failures in the upper levels of the router tree can result in widespread communications losses throughout the system. To resolve these issues, this work extends the RTI-s software router infrastructure to accommodate more sophisticated, general router topologies, including both the existing tree framework and a new generalization of the fully connected mesh topologies used in the SF Express ModSAF simulations of 100K fully interacting vehicles. The new software router objects incorporate the scalable features of the SF Express design, while optionally using low-level RTI-s objects to perform actual site-to-site communications. The (substantial) limitations of the original mesh router formalism have been eliminated, allowing fully dynamic operations. The mesh topology capabilities allow aggregate bandwidth and site-to-site latencies to match actual network performance. The heavy resource load at the root node can now be distributed across routers at the participating sites