p21-activated kinases and gastrointestinal cancer

Abstractp21-activated kinases (PAKs) were initially identified as effector proteins downstream from GTPases of the Rho family. To date, six members of the PAK family have been discovered in mammalian cells. PAKs play important roles in growth factor signalling, cytoskeletal remodelling, gene transcription, cell proliferation and oncogenic transformation. A large body of research has demonstrated that PAKs are up-regulated in several human cancers, and that their overexpression is linked to tumour progression and resistance to therapy. Structural and biochemical studies have revealed the mechanisms involved in PAK signalling, and opened the way to the development of PAK-targeted therapies for cancer treatment. Here we summarise recent findings from biological and clinical research on the role of PAKs in gastrointestinal cancer, and discuss the current status of PAK-targeted anticancer therapies

Light dominates the diurnal emissions of herbivore-induced volatiles in wild tobacco

BACKGROUND: Timing is everything when it comes to the fitness outcome of a plant’s ecological interactions, and accurate timing is particularly relevant for interactions with herbivores or mutualists that are based on ephemeral emissions of volatile organic compounds. Previous studies of the wild tobacco N. attenuata have found associations between the diurnal timing of volatile emissions, and daytime predation of herbivores by their natural enemies. RESULTS: Here, we investigated the role of light in regulating two biosynthetic groups of volatiles, terpenoids and green leaf volatiles (GLVs), which dominate the herbivore-induced bouquet of N. attenuata. Light deprivation strongly suppressed terpenoid emissions while enhancing GLV emissions, albeit with a time lag. Silencing the expression of photoreceptor genes did not alter terpenoid emission rhythms, but silencing expression of the phytochrome gene, NaPhyB1, disordered the emission of the GLV (Z)-3-hexenyl acetate. External abscisic acid (ABA) treatments increased stomatal resistance, but did not truncate the emission of terpenoid volatiles (recovered in the headspace). However, ABA treatment enhanced GLV emissions and leaf internal pools (recovered from tissue), and reduced internal linalool pools. In contrast to the pattern of diurnal terpenoid emissions and nocturnal GLV emissions, transcripts of herbivore-induced plant volatile (HIPV) biosynthetic genes peaked during the day. The promotor regions of these genes were populated with various cis-acting regulatory elements involved in light-, stress-, phytohormone- and circadian regulation. CONCLUSIONS: This research provides insights into the complexity of the mechanisms involved in the regulation of HIPV bouquets, a mechanistic complexity which rivals the functional complexity of HIPVs, which includes repelling herbivores, calling for body guards, and attracting pollinators. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-021-03179-z

An unbiased approach elucidates variation in (S)-(+)-linalool, a context-specific mediator of a tri-trophic interaction in wild tobacco

Plant volatile organic compounds (VOCs) mediate many interactions, and the function of common VOCs is especially likely to depend on ecological context. We used a genetic mapping population of wild tobacco, Nicotiana attenuata, originating from a cross of 2 natural accessions from Arizona and Utah, separated by the Grand Canyon, to dissect genetic variation controlling VOCs. Herbivory-induced leaf terpenoid emissions varied substantially, while green leaf volatile emissions were similar. In a field experiment, only emissions of linalool, a common VOC, correlated significantly with predation of the herbivore Manduca sexta by native predators. Using quantitative trait locus mapping and genome mining,we identified an (S)-(+)-linalool synthase (NaLIS). Genome resequencing, gene cloning, and activity assays revealed that the presence/absence of a 766-bp sequence in NaLIS underlies the variation of linalool emissions in 26 natural accessions. We manipulated linalool emissions and composition by ectopically expressing linalool synthases for both enantiomers, (S)-(+)- and (R)-(−)-linalool, reported to oppositely affect M. sexta oviposition, in the Arizona and Utah accessions.We used these lines to test ovipositingmoths in increasingly complex environments. The enantiomers had opposite effects on oviposition preference, but themagnitude of the effect depended strongly both on plant genetic background, and complexity of the bioassay environment. Our study reveals that the emission of linalool, a common VOC, differs by orders-of-magnitude among geographically interspersed conspecific plants due to allelic variation in a linalool synthase, and that the response of a specialist herbivore to linalool depends on enantiomer, plant genotype, and environmental complexity

Natural variation in linalool metabolites: One genetic locus, many functions?

The ubiquitous volatile linalool is metabolized in plants to nonvolatile derivatives. We studied Nicotiana attenuata plants which naturally vary in (S)‐(+)‐linalool contents, and lines engineered to produce either (R)‐(‐)‐ or (S)‐(+)‐linalool. Only (S)‐(+)‐linalool production was associated with slower growth of a generalist herbivore, and a large fraction was present as nonvolatile derivatives. We found that variation in volatile linalool and its nonvolatile glycosides mapped to the same genetic locus which harbored the biosynthetic gene, NaLIS, but that free linalool varied more in environmental responses. This study reveals how (S)‐(+)‐linalool and conjugates differ in their regulation and possible functions in resistance

A near Fourier-transform limited optical parametric oscillator/amplifier system as a pulsed source for high resolution spectroscopy

© Copyright 2005 IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE. This material is presented to ensure timely dissemination of scholarly and technical work. Copyright and all rights therein are retained by authors or by other copyright holders. All persons copying this information are expected to adhere to the terms and constraints invoked by each author's copyright. In most cases, these works may not be reposted without the explicit permission of the copyright holder.We use optical heterodyne and nonlinear-optical spectroscopic techniques to measure the near Fourier-transform limited output from a narrowband tunable injection-seeded, pulsed optical parametric oscillator/amplifier system that has a controllable frequency chirp of <10 MHzK.G.H. Baldwin, M. Kono, Y. He, R. T. White, B. J. Or

Use of an alternative method to evaluate erythema severity in a clinical trial: difference in vehicle response with evaluation of baseline and postdose photographs for effect of oxymetazoline cream 1·0% for persistent erythema of rosacea in a phase IV study.

BackgroundOnce-daily topical oxymetazoline cream 1·0% significantly reduced persistent facial erythema of rosacea in trials requiring live, static patient assessments.ObjectivesTo evaluate critically the methodology of clinical trials that require live, static patient assessments by determining whether assessment of erythema is different when reference to the baseline photograph is allowed.MethodsIn two identically designed, randomized, phase III trials, adults with persistent facial erythema of rosacea applied oxymetazoline or vehicle once daily. This phase IV study evaluated standardized digital facial photographs from the phase III trials to record ≥ 1-grade Clinician Erythema Assessment (CEA) improvement at 1, 3, 6, 9 and 12 h postdose.ResultsAmong 835 patients (oxymetazoline n = 415, vehicle n = 420), significantly greater proportions of patients treated with oxymetazoline vs. vehicle achieved ≥ 1-grade CEA improvement. For the comparison between phase IV study results and the original phase III analysis, when reference to baseline photographs was allowed while evaluating post-treatment photographs, the results for oxymetazoline were similar to results of the phase III trials (up to 85.7%), but a significantly lower proportion of vehicle recipients achieved ≥ 1-grade CEA improvement (up to 29.7% [phase 4] vs. 52.3% [phase 3]; P&lt;0.001). In the phase IV study, up to 80·2% of patients treated with oxymetazoline achieved at least moderate erythema improvement vs. up to 22·9% of patients treated with vehicle. The association between patients' satisfaction with facial skin redness and percentage of erythema improvement was statistically significant.ConclusionsAssessment of study photographs, with comparison to baseline, confirmed significant erythema reduction with oxymetazoline on the first day of application. Compared with the phase III trial results, significantly fewer vehicle recipients attained ≥ 1-grade CEA improvement, suggesting a mitigated vehicle effect. This methodology may improve the accuracy of clinical trials evaluating erythema severity

Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1α and β-catenin via a p-21 activated kinase 1-dependent pathway

Abstractp-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/β-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1α (HIF-1α), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [3H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1α and β-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1α and β-catenin via a PAK1-dependent pathway

日本の科学技術の現状と今後の予測―科学技術振興による経済・社会・国民生活への寄与の定性的評価・分析 国公立大学及び公的研究機関の代表的成果調査―

A study towards the natural product tetrodecamycin is reported. A modified Schlosser–Wittig reaction was utilized to prepare the precursor for the subsequent intramolecular Diels–Alder reaction, which delivered the trans-decalin ring of the natural product. The tetronic acid moiety of the molecule was prepared by a Dieckmann cyclization­. The cyclization of the tetronic acid to the trans-decalin double bond to form a seven-membered ring was examined

Control of frequency chirp in nanosecond-pulsed laser spectroscopy. 1. Optical-heterodyne chirp analysis techniques

Richard T. White, Yabai He, Brian J. Orr, Mitsuhiko Kono, and K. G. H. Baldwi