Disgust Promotes Disposal: Souring the Status Quo

Humans naturally dispose of objects that disgust them. Is this phenomenon so deeply embedded that even incidental disgust – i.e., where the source of disgust is unrelated to a possessed object – triggers disposal? Two experiments were designed to answer this question. Two film clips served as disgust and neutral primes; the objects were routine commodities (boxes of office supplies). Results revealed that the incidental disgust condition powerfully increased the frequency with which decision makers traded away a commodity they owned for a new commodity (more than doubling the probability in each condition), thereby countering otherwise robust status quo bias (Samuelson & Zeckhauser, 1988). Decision makers were unaware of disgust’s impact. Even when warned to correct for it, they failed to do so. These studies presented real choices with tangible rewards. Their findings thus have implications not only for theories of affect and choice, but also for practical improvements in everyday decisions

Lift-and-Round to Improve Weighted Completion Time on Unrelated Machines

We consider the problem of scheduling jobs on unrelated machines so as to minimize the sum of weighted completion times. Our main result is a $(3/2-c)$-approximation algorithm for some fixed $c>0$, improving upon the long-standing bound of 3/2 (independently due to Skutella, Journal of the ACM, 2001, and Sethuraman & Squillante, SODA, 1999). To do this, we first introduce a new lift-and-project based SDP relaxation for the problem. This is necessary as the previous convex programming relaxations have an integrality gap of $3/2$. Second, we give a new general bipartite-rounding procedure that produces an assignment with certain strong negative correlation properties.Comment: 21 pages, 4 figure

Concurrent regulation of LKB1 and CaMKK2 in the activation of AMPK in castrate-resistant prostate cancer by a well-defined polyherbal mixture with anticancer properties

Abstract Background Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5′-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers. The objective was to interrogate how Zyflamend activates AMPK by determining the roles of LKB1 and CaMKK2. Methods AMPK activation was determined in CWR22Rv1 cells treated with a variety of inhibitors of LKB1 and CaMKK2 in the presence and absence of Zyflamend, and in LKB1-null HeLa cells that constitutively express CaMKK2, following transfection with wild type LKB1 or catalytically-dead mutants. Upstream regulation by Zyflamend of LKB1 and CaMKK2 was investigated targeting protein kinase C-zeta (PKCζ) and death-associated protein kinase (DAPK), respectively. Results Zyflamend’s activation of AMPK appears to be LKB1 dependent, while simultaneously inhibiting CaMKK2 activity. Zyflamend failed to rescue the activation of AMPK in the presence of pharmacological and molecular inhibitors of LKB1, an effect not observed in the presence of inhibitors of CaMKK2. Using LKB1-null and catalytically-dead LKB1-transfected HeLa cells that constitutively express CaMKK2, ionomycin (activator of CaMKK2) increased phosphorylation of AMPK, but Zyflamend only had an effect in cells transfected with wild type LKB1. Zyflamend appears to inhibit CaMKK2 by DAPK-mediated phosphorylation of CaMKK2 at Ser511, an effect prevented by a DAPK inhibitor. Alternatively, Zyflamend mediates LKB1 activation via increased phosphorylation of PKCζ, where it induced translocation of PKCζ and LKB1 to their respective active compartments in HeLa cells following treatment. Altering the catalytic activity of LKB1 did not alter this translocation. Discussion Zyflamend’s activation of AMPK is mediated by LKB1, possibly via PKCζ, but independent of CaMKK2 by a mechanism that appears to involve DAPK. Conclusions Therefore, this is the first evidence that natural products simultaneously and antithetically regulate upstream kinases, known to be involved in cancer, via the activation of AMPK.https://deepblue.lib.umich.edu/bitstream/2027.42/144515/1/12906_2018_Article_2255.pd

What Precision Electroweak Physics Says About the SU(6)/Sp(6) Little Higgs

We study precision electroweak constraints on the close cousin of the Littlest Higgs, the SU(6)/Sp(6) model. We identify a near-oblique limit in which the heavy W' and B' decouple from the light fermions, and then calculate oblique corrections, including one-loop contributions from the extended top sector and the two Higgs doublets. We find regions of parameter space that give acceptably small precision electroweak corrections and only mild fine tuning in the Higgs potential, and also find that the mass of the lightest Higgs boson is relatively unconstrained by precision electroweak data. The fermions from the extended top sector can be as light as 1 TeV, and the W' can be as light as 1.8 TeV. We include an independent breaking scale for the B', which can still have a mass as low as a few hundred GeV.Comment: 52 pages, 16 figure

Variations of Little Higgs Models and their Electroweak Constraints

We calculate the tree-level electroweak precision constraints on a wide class of little Higgs models including: variations of the Littlest Higgs SU(5)/SO(5), SU(6)/Sp(6), and SU(4)^4/SU(3)^4. By performing a global fit to the precision data we find that for generic regions of the parameter space the bound on the symmetry breaking scale f is several TeV, where we have kept the normalization of f constant in the different models. For example, the ``minimal'' implementation of SU(6)/Sp(6) is bounded by f>3.0 TeV throughout most of the parameter space, and SU(4)^4/SU(3)^4 is bounded by f^2 = f_1^2+f_2^2 > (4.2 TeV)^2. In certain models, such as SU(4)^4/SU(3)^4, a large f does not directly imply a large amount of fine tuning since the heavy fermion masses that contribute to the Higgs mass can be lowered below f for a carefully chosen set of parameters. We also find that for certain models (or variations) there exist regions of parameter space in which the bound on f can be lowered into the range 1-2 TeV. These regions are typically characterized by a small mixing between heavy and standard model gauge bosons, and a small (or vanishing) coupling between heavy U(1) gauge bosons and the light fermions. Whether such a region of parameter space is natural or not is ultimately contingent on the UV completion.Comment: 32 pages, 13 figures; revised discussion of SU(4)^4/SU(3)^4 model, bound on f is slightly highe

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses.

Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, we identified small-molecule hit 1 that inhibited Nedd4-PPxY interaction and PPxY-dependent budding. This lead candidate was subsequently improved with additional structure-activity relationship (SAR) analog testing which enhanced antibudding activity into the nanomolar range. Current lead compounds 4 and 5 exhibit on-target effects by specifically blocking the MARV VP40 PPxY-host Nedd4 interaction and subsequent PPxY-dependent egress of MARV VP40 VLPs. In addition, lead compounds 4 and 5 exhibited antibudding activity against Ebola and Lassa fever VLPs, as well as vesicular stomatitis and rabies viruses (VSV and RABV, respectively). These data provide target validation and suggest that inhibition of the PPxY-Nedd4 interaction can serve as the basis for the development of a novel class of broad-spectrum, host-oriented antivirals targeting viruses that depend on a functional PPxY L domain for efficient egress. IMPORTANCE: There is an urgent and unmet need for the development of safe and effective therapeutics against biodefense and high-priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (e.g., Lassa and Junin) which cause severe hemorrhagic fever syndromes with high mortality rates. We along with others have established that efficient budding of filoviruses, arenaviruses, and other viruses is critically dependent on the subversion of host proteins. As disruption of virus budding would prevent virus dissemination, identification of small-molecule compounds that block these critical viral-host interactions should effectively block disease progression and transmission. Our findings provide validation for targeting these virus-host interactions as we have identified lead inhibitors with broad-spectrum antiviral activity. In addition, such inhibitors might prove useful for newly emerging RNA viruses for which no therapeutics would be available

Collective Quartics from Simple Groups

This article classifies Little Higgs models that have collective quartic couplings. There are two classes of collective quartics: Special Cosets and Special Quartics. After taking into account dangerous singlets, the smallest Special Coset models are SU(5)/SO(5) and SU(6)/Sp(6). The smallest Special Quartic model is SU(5)/SU(3) x SU(2) x U(1) and has not previously been considered as a candidate Little Higgs model.Comment: 22 pages, 2 figure

Scalar Dark Matter From Theory Space

The scalar dark matter candidate in a prototypical theory space little Higgs model is investigated. We review all details of the model pertinent to dark matter. We perform a thermal relic density calculation including couplings to the gauge and Higgs sectors of the model. We find two regions of parameter space that give acceptable dark matter abundances. The first region has a dark matter candidate with a mass of order 100 GeV, the second region has a heavy candidate with a mass greater than about 500 GeV$. The dark matter candidate in either region is an admixture of an SU(2) triplet and an SU(2) singlet, thereby constituting a WIMP (weakly interacting massive particle).Comment: 18 pages, 2 figures, version to appear in PR