The Strategic Implications of Scale in Choice-Based Conjoint Analysis

Choice-based conjoint (CBC) studies have begun to rely on simulators to forecast equilibrium prices for pricing, strategic product positioning, and patent/copyright valuations. Whereas CBC research has long focused on the accuracy of estimated relative partworths of attribute levels, predicted equilibrium prices and strategic positioning are surprisingly and dramatically dependent on scale: the magnitude of the partworths (including the price coefficient) relative to the magnitude of the error term. Although the impact of scale on the ability to estimate heterogeneous partworths is well known, neither the literature nor current practice address the sensitivity of pricing and positioning to scale. This sensitivity is important because (estimated) scale depends on seemingly innocuous market-research decisions such as whether attributes are described by text or by realistic images. We demonstrate the strategic implications of scale using a stylized model in which heterogeneity is modeled explicitly. If a firm shirks on the quality of a CBC study and acts on incorrectly observed scale, a follower, but not an innovator, can make costly strategic errors. Externally valid estimates of scale are extremely important. We demonstrate empirically that image realism and incentive alignment affect scale sufficiently to change strategic decisions and affect patent/copyright valuations by hundreds of millions of dollars

MAP3Kinase-dependent SnRK2-kinase activation is required for abscisic acid signal transduction and rapid osmotic stress response.

Abiotic stresses, including drought and salinity, trigger a complex osmotic-stress and abscisic acid (ABA) signal transduction network. The core ABA signalling components are snf1-related protein kinase2s (SnRK2s), which are activated by ABA-triggered inhibition of type-2C protein-phosphatases (PP2Cs). SnRK2 kinases are also activated by a rapid, largely unknown, ABA-independent osmotic-stress signalling pathway. Here, through a combination of a redundancy-circumventing genetic screen and biochemical analyses, we have identified functionally-redundant MAPKK-kinases (M3Ks) that are necessary for activation of SnRK2 kinases. These M3Ks phosphorylate a specific SnRK2/OST1 site, which is indispensable for ABA-induced reactivation of PP2C-dephosphorylated SnRK2 kinases. ABA-triggered SnRK2 activation, transcription factor phosphorylation and SLAC1 activation require these M3Ks in vitro and in plants. M3K triple knock-out plants show reduced ABA sensitivity and strongly impaired rapid osmotic-stress-induced SnRK2 activation. These findings demonstrate that this M3K clade is required for ABA- and osmotic-stress-activation of SnRK2 kinases, enabling robust ABA and osmotic stress signal transduction

Formation of hard VHE gamma-ray spectra of blazars due to internal photon-photon absorption

The energy spectra of TeV gamma-rays from blazars, after being corrected for intergalatic absorption in the Extragalactic Background Light (EBL), appear unusually hard, a fact that poses challenges to the conventional models of particle acceleration in TeV blazars and/or to the EBL models. In this paper we show that the internal absorption of gamma-rays caused by interactions with dense narrow-band radiation fields in the vicinity of compact gamma-ray production regions can lead to the formation of gamma-ray spectra of an almost arbitrary hardness. This allows significant relaxation of the current tight constraints on particle acceleration and radiation models, although at the expense of enhanced requirements to the available nonthermal energy budget. The latter, however, is not a critical issue, as long as it can be largely compensated by the Doppler boosting, assuming very large ($\geq 30$) Doppler factors of the relativistically moving gamma-ray production regions. The suggested scenario of formation of hard gamma-ray spectra predicts detectable synchrotron radiation of secondary electron-positron pairs which might require a revision of the current ``standard paradigm'' of spectral energy distributions of gamma-ray blazars. If the primary gamma-rays are of hadronic origin related to $pp$ or $p \gamma$ interactions, the ``internal gamma-ray absorption'' model predicts neutrino fluxes close to the detection threshold of the next generation high energy neutrino detectors.Comment: 10 pages, 8 figures, submitted to MNRA

Dissection of the Bradyrhizobium japonicum NifA+σ54 regulon, and identification of a ferredoxin gene ( fdxN ) for symbiotic nitrogen fixation

Hierarchically organized regulatory proteins form a complex network for expression control of symbiotic and accessory genes in the nitrogen-fixing soybean symbiont Bradyrhizobium japonicum. A genome-wide survey of regulatory interactions was made possible with the design of a custom-made gene chip. Here, we report the first use of the microarray in a comprehensive and complete characterization of the B. japonicum NifA+σ54 regulon which forms an important node in the entire network. Comparative transcript profiles of anaerobically grown wild-type, nifA, and rpoN 1/2 mutant cells were complemented with a position-specific frequency matrix-based search for NifA- and σ54-binding sites plus a simple operon definition. One of the newly identified NifA+σ54-dependent genes, fdxN, encodes a ferredoxin required for efficient symbiotic nitrogen fixation, which makes it a candidate for being a direct electron donor to nitrogenase. The fdxN gene has an unconventional, albeit functional σ54 promoter with the dinucleotide GA instead of the consensus GC motif at position −12. A GC-containing mutant promoter and the atypical GA-containing promoter of the wild type were disparately activated. Expression analyses were also carried out with two other NifA+σ54 targets (ectC; ahpC). Incidentally, the tiling-like design of the microarray has helped to arrive at completely revised annotations of the ectC- and ahpC-upstream DNA regions, which are now compatible with promoter locations. Taken together, the approaches used here led to a substantial expansion of the NifA+σ54 regulon size, culminating in a total of 65 genes for nitrogen fixation and diverse other processe

Role of a ZF-HD Transcription Factor in miR157-Mediated Feed-Forward Regulatory Module That Determines Plant Architecture in Arabidopsis

In plants, vegetative and reproductive development are associated with agronomically important traits that contribute to grain yield and biomass. Zinc finger homeodomain (ZF-HD) transcription factors (TFs) constitute a relatively small gene family that has been studied in several model plants, including Arabidopsis thaliana L. and Oryza sativa L. The ZF-HD family members play important roles in plant growth and development, but their contribution to the regulation of plant architecture remains largely unknown due to their functional redundancy. To understand the gene regulatory network controlled by ZF-HD TFs, we analyzed multiple loss-of-function mutants of ZF-HD TFs in Arabidopsis that exhibited morphological abnormalities in branching and flowering architecture. We found that ZF-HD TFs, especially HB34, negatively regulate the expression of miR157 and positively regulate SQUAMOSA PROMOTER BINDING-LIKE 10 (SPL10), a target of miR157. Genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) analysis revealed that miR157D and SPL10 are direct targets of HB34, creating a feed-forward loop that constitutes a robust miRNA regulatory module. Network motif analysis contains overrepresented coherent type IV feedforward motifs in the amiR zf-HD and hbq mutant background. This finding indicates that miRNA-mediated ZF-HD feedforward modules modify branching and inflorescence architecture in Arabidopsis. Taken together, these findings reveal a guiding role of ZF-HD TFs in the regulatory network module and demonstrate its role in plant architecture in Arabidopsis

Hsa-miR-375 is a predictor of local control in early stage breast cancer

Background: A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer. Results: Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value = 0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p = 0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value = 0.000195 HR = 0.76, 95 % CI 0.66-0.88;corrected p value = 0.005). Conclusions: Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor alpha (ER-alpha)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted

PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation

P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1–p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells

Spontaneous Altruism by Chimpanzees and Young Children

People often act on behalf of others. They do so without immediate personal gain, at cost to themselves, and even toward unfamiliar individuals. Many researchers have claimed that such altruism emanates from a species-unique psychology not found in humans' closest living evolutionary relatives, such as the chimpanzee. In favor of this view, the few experimental studies on altruism in chimpanzees have produced mostly negative results. In contrast, we report experimental evidence that chimpanzees perform basic forms of helping in the absence of rewards spontaneously and repeatedly toward humans and conspecifics. In two comparative studies, semi–free ranging chimpanzees helped an unfamiliar human to the same degree as did human infants, irrespective of being rewarded (experiment 1) or whether the helping was costly (experiment 2). In a third study, chimpanzees helped an unrelated conspecific gain access to food in a novel situation that required subjects to use a newly acquired skill on behalf of another individual. These results indicate that chimpanzees share crucial aspects of altruism with humans, suggesting that the roots of human altruism may go deeper than previous experimental evidence suggested