Escalation of commitment in new product development has been studied extensively for the last four decades but the impact of culture on the escalation phenomenon remains largely unexplored. This ...study investigates how culture impacts the decision to escalate or deescalate commitment to new products. Americans are analytic thinkers whereas Chinese tend to be holistic thinkers. When it comes to decision making, analytic thinkers focus on field independent and abstract factors and believe that future is linear and static, whereas holistic thinkers focus more on contextual factors and believe that future is dynamic and nonlinear. Hence, Chinese are more likely to escalate their commitment relative to Americans on receiving a negative performance report in the new product development process. A lab experiment using weekend MBA students and managers was used to test this underlying hypothesis. The findings confirmed that analytical thinkers use fewer factors than holistic thinkers in making new product decisions, and that Chinese managers are more likely to escalate their commitment relative to American managers. The decision to escalate or de-escalate was moderated by perceived product innovativeness.
•Chinese managers (vs. U.S. managers) are more likely to escalate their commitment.•U.S. managers use fewer factors than Chinese managers in making NPD decisions.•Escalation decisions are moderated by the degree of product innovativeness.
Summary
Growth of bacteria and fungi on fatty acid substrates requires the catabolic β‐oxidation cycle and the anaplerotic glyoxylate cycle. Propionyl‐CoA generated by β‐oxidation of odd‐chain fatty ...acids is metabolized via the methylcitrate cycle. Mycobacterium tuberculosis possesses homologues of methylcitrate synthase (MCS) and methylcitrate dehydratase (MCD) but not 2‐methylisocitrate lyase (MCL). Although MCLs share limited homology with isocitrate lyases (ICLs) of the glyoxylate cycle, these enzymes are thought to be functionally non‐overlapping. Previously we reported that the M. tuberculosis ICL isoforms 1 and 2 are jointly required for growth on fatty acids, in macrophages, and in mice. ICL‐deficient bacteria could not grow on propionate, suggesting that in M. tuberculosis ICL1 and ICL2 might function as ICLs in the glyoxylate cycle and as MCLs in the methylcitrate cycle. Here we provide biochemical and genetic evidence supporting this interpretation. The role of the methylcitrate cycle in M. tuberculosis metabolism was further evaluated by constructing a mutant strain in which prpC (encoding MCS) and prpD (encoding MCD) were deleted. The ΔprpDC strain could not grow on propionate media in vitro or in murine bone marrow‐derived macrophages infected ex vivo; growth under these conditions was restored by complementation with a plasmid containing prpDC. Paradoxically, bacterial growth and persistence, and tissue pathology, were indistinguishable in mice infected with wild‐type or ΔprpDC bacteria.
Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting ...Wnt biosynthesis and secretion can be effective in Wnt-addicted cancers. An integral membrane protein known as Wntless (WLS/Evi) is essential for Wnt secretion. However, WLS remains undrugged thus far. The cryo-EM structure of WLS in complex with WNT8A shows that WLS has a druggable G-protein coupled receptor (GPCR) domain. Using Active Learning/Glide, we performed an ultra-large scale virtual screening from Enamine’s REAL 350/3 Lead-Like library containing nearly 500 million compounds. 68 hits were examined after on-demand synthesis in cell-based Wnt reporter and other functional assays. ETC-451 emerged as a potential first-in-class WLS inhibitor. ETC-451 blocked WLS-WNT3A interaction and decreased Wnt-addicted pancreatic cancer cell line proliferation. The current hit provides a starting chemical scaffold for further structure or ligand-based drug discovery targeting WLS.
Display omitted
•WLS is an essential WNT transporter with a GPCR pocket but it has not been drugged•Ultra-large scale virtual screening informed cell-based testing of WLS inhibitors•We identify ETC-451 as a first-in-class hit that blocks Wnt interaction with WLS•ETC-451 provides a structural template for small molecule drug design targeting WLS
Biochemistry; Biological sciences; Biomolecules
This paper explores how cultural metaphors in ethnic servicescapes enhance consumer pleasure. To date, marketing researchers have mainly explored how consumers respond to ambient conditions, ...functional layout and signs/symbols within servicescapes. However, few studies are available on consumer pleasure in ethnic servicescapes or the use of cultural metaphors in servicescapes to enhance consumer pleasure. The study here extends extant literature by contributing an additional dimension of pleasure named “ethno-pleasure.” This notion relates to consumer emotional responses to the cultural metaphors in the servicescapes associated with cultural self-construal. The three themes relating to ethno-pleasure include symbolic experience, imaginary experience, and reviving experience. Findings from this study have implications for assisting marketers in developing strategies for multi-cultural marketing.
The bicyclic 4‐nitroimidazoles PA‐824 and OPC‐67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clinical development. Both compounds are pro‐drugs ...that are reductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Herein we describe the biochemical properties of Ddn including the optimal enzymatic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA‐824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo‐oxazoles bearing only short alkyl substituents at the C‐7 position of the oxazole were reduced by Ddn without any stereochemical preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metabolism of PA‐824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO production by Ddn. Binding affinity of PA‐824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover‐independent assessment of affinity. Our results indicate that (R)‐PA‐824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C‐3 of the imidazole ring orienting in a non‐productive position with respect to the incoming hydride from F420. The results presented provide insight into the biochemical mechanism of reduction and elucidate structural features important for understanding substrate binding.
PA‐824, a bicyclic‐nitroimidazole in clinical development against tuberculosis, is bioreductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Substrate and stereospecificity of Ddn is directed by the presence of a long hydrophobic tail. (R)‐PA‐824 binds Ddn with the same affinity as the active (S)‐PA‐824, despite not being turned over. Docking studies suggest that (R)‐PA‐824 likely binds non‐productively to the enzyme.
A quantitative and objective assessment of background electroencephalograph (EEG) in sick neonates remains an everyday clinical challenge. We studied whether long range temporal correlations ...quantified by detrended fluctuation analysis (DFA) could be used in the neonatal EEG to distinguish different grades of abnormality in the background EEG activity. Long-term EEG records of 34 neonates were collected after perinatal asphyxia, and their background was scored in 1 h epochs (8 h in each neonate) as mild, moderate or severe. We applied DFA on 15 min long, non-overlapping EEG epochs (n = 1088) filtered from 3 to 8 Hz. Our formal feasibility study suggested that DFA exponent can be reliably assessed in only part of the EEG epochs, and in only relatively short time scales (10-60 s), while it becomes ambiguous if longer time scales are considered. This prompted further exploration whether paradigm used for quantifying multifractal DFA (MF-DFA) could be applied in a more efficient way, and whether metrics from MF-DFA paradigm could yield useful benchmark with existing clinical EEG gradings. Comparison of MF-DFA metrics showed a significant difference between three visually assessed background EEG grades. MF-DFA parameters were also significantly correlated to interburst intervals quantified with our previously developed automated detector. Finally, we piloted a monitoring application of MF-DFA metrics and showed their evolution during patient recovery from asphyxia. Our exploratory study showed that neonatal EEG can be quantified using multifractal metrics, which might offer a suitable parameter to quantify the grade of EEG background, or to monitor changes in brain state that take place during long-term brain monitoring.
Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis ...treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria.
Cell-permeable small molecules that inhibit their targets on fast timescales are powerful probes of cell-division mechanisms. Such inhibitors have been identified using phenotype-based screens with ...chemical libraries. However, the characteristics of compound libraries needed to effectively span cell-division phenotype space, to find probes that target different mechanisms, are not known. Here we show that a small collection of 100 diaminopyrimidines (DAPs) yields a range of cell-division phenotypes, including changes in spindle geometry, chromosome positioning and mitotic index. Monopolar mitotic spindles are induced by four inhibitors, including one that targets Polo-like kinases (Plks), evolutionarily conserved serine/threonine kinases. Using chemical inhibitors and high-resolution live-cell microscopy, we found that Plk activity is needed for the assembly and maintenance of bipolar mitotic spindles. Plk inhibition destabilizes kinetochore microtubules while stabilizing other spindle microtubules, leading to monopolar spindles. Further testing of compounds based on 'privileged scaffolds', such as the DAP scaffold, could lead to new cell-division probes and antimitotic agents.
This article analyzes the downside risk and loss profiles of hedge funds in North America and Asia to identify any significant differences between the geographic markets and to determine how these ...differences have converged or diverged over time. An attempt is made to understand the performance drivers that differentiate Asian from North American hedge funds. In the downside-risk analysis of 2,631 North American and 994 Asian hedge funds from January 1995 to February 2013, event-driven investment strategies for both geographic regions perform better than the other hedge fund investment strategies in relation to both risk and return and downside risk. More diversified funds, such as multistrategy hedge funds, do not necessarily perform better than single-manager strategies in relation to downside risk, while relative value strategies exhibit the most similar characteristics across the two geographies. Following their lackluster performance during the Asian financial crisis, Asian hedge funds improved their risk-adjusted performance, particularly during the recent global financial crisis when their loss profile reached a level similar to that of their North American peers. Lastly,nearby funds (i.e., funds whose managers are located in the same investment geography) have slightly worse loss profiles thandistant funds in both geographic markets, a result that is slightly contrary to extant empirical evidence.
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the ...driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
