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phorylation, cell-to-cell contact, cancer stem cell activation, and release of vascular endothelial growth factor.

The BRAF

mutation is an oncogenic driver associated with aggressive tumor behaviors and increased mortality among patients with papillary thyroid cancer (PTC). Although the BRAF inhibitor vemurafenib gave promising results in BRAF

-mutant PTC, resistance development remains a major clinical challenge. This study aimed to explore the mechanisms underlying drug resistance in PTC.

Two vemurafenib-resistant PTC cell lines (KTC1 and BCPAP) were established by continuous treatment with vemurafenib for 5months. The knockdown and upregulation of Tribbles homolog 2 (TRIB2) in PTC cells were achieved by the transfection with short hairpin RNA against TRIB2 or recombinant lentiviral vector carrying TRIB2, respectively. The β-catenin inhibitor, ICG-001, was used for the inhibition of the Wnt/β-catenin signaling in PTC cells.

Vemurafenib-resistant PTC cells showed higher TRIB2 expression, upregulated ERK and AKT activation, enhanced invasive capacity, and increased epithelial-mesenchymal transition compared to the drug-sensitive groups. TRIB2 knockdown repressed the activation of ERK and AKT, inhibited invasion and EMT, and induced apoptosis of PTC cells. TRIB2 deficiency also enhanced the sensitivity of both PTC cells to vemurafenib. Vemurafenib-resistant PTC cells showed elevated expression of β-catenin in both cytoplasm and nucleus. The pre-incubation of cells with β-catenin inhibitor significantly inhibited TRIB2 expression, suppressed EMT, and repressed the activation of ERK and AKT in vemurafenib-resistant cells.

Our study showed that the upregulation of TRIB2 by the Wnt/β-catenin activation confers resistance to vemurafenib in PTC with BRAF

mutation. These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.

Our study showed that the upregulation of TRIB2 by the Wnt/β-catenin activation confers resistance to vemurafenib in PTC with BRAFV600 mutation. check details These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.Bacterial cell has always been an attractive target for anti-infective drug discovery. MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) enzyme of Escherichia coli (E.coli) is crucial for peptidoglycan biosynthetic pathway, as it is involved in the early stages of bacterial cell wall biosynthesis. In the present study we aim to identify novel chemical structures targeting the MurA enzyme. For screening purpose, we used in silico approach (pharmacophore based strategy) for 52,026 library compounds (Chembridge, Chemdiv and in house synthetics) which resulted in identification of 50 compounds. These compounds were screened in vitro against MurA enzyme and release of inorganic phosphate (Pi) was estimated. Two compounds (IN00152 and IN00156) were found to inhibit MurA enzyme > 70% in primary screening and IC50 of 14.03 to 32.30 μM respectively. These two hits were further evaluated for their mode of inhibition studies and whole-cell activity where we observed 2-4 folds increase in activity in presence of Permeabilizer EDTA (Ethylenediaminetetraacetic acid). Combination studies were also performed with known antibiotics in presence of EDTA. Hits are reported for the first time against this target and our report also support the use of OM permeabilizer in combination with antibacterial compounds to address the permeability and efficacy issue. These lead hits can be further optimized for drug discovery. KEY POINTS • Emerging Gram negative resistant strains is a matter of concern. • Need for new screening strategies to cope with drying up antibiotics pipeline. • Outer membrane permeabilizers could be useful to improve potency of molecules to reach its target.Agroindustrial by-products and residues can be transformed into valuable compounds in biorefineries. Here, we present a new concept production of fuel ethanol, whey protein, and probiotic yeast from cheese whey. An initial screening under industrially relevant conditions, involving thirty Kluyveromyces marxianus strains, was carried out using spot assays to evaluate their capacity to grow on cheese whey or on whey permeate (100 g lactose/L), under aerobic or anaerobic conditions, in the absence or presence of 5% ethanol, at pH 5.8 or pH 2.5. The four best growing K. marxianus strains were selected and further evaluated in a miniaturized industrial fermentation process using reconstituted whey permeate (100 g lactose/L) with cell recycling (involving sulfuric acid treatment). After five consecutive fermentation cycles, the ethanol yield on sugar reached 90% of the theoretical maximum in the best cases, with 90% cell viability. Cells harvested at this point displayed probiotic properties such as the capacity to survive the passage through the gastrointestinal tract and capacity to modulate the innate immune response of intestinal epithelium, both in vitro. Furthermore, the CIDCA 9121 strain was able to protect against histopathological damage in an animal model of acute colitis. Our findings demonstrate that K. marxianus CIDCA 9121 is capable of efficiently fermenting the lactose present in whey permeate to ethanol and that the remaining yeast biomass has probiotic properties, enabling an integrated process for the obtainment of whey protein (WP), fuel ethanol, and probiotics from cheese whey.Key points• K. marxianus-selected strains ferment whey permeate with 90% ethanol yield.• Industrial fermentation conditions do not affect selected yeast probiotic capacity.• Whey permeate, fuel ethanol, and probiotic biomass can be obtained in a biorefinery.

Pistil AGPs display dynamic localization patterns in response to fertilization in tomato. SlyFLA9 (Solyc07g065540.1) is a chimeric Fasciclin-like AGP with enriched expression in the ovary, suggesting a potential function during pollen-pistil interaction. During fertilization, the male gametes are delivered by pollen tubes to receptive ovules, deeply embedded in the sporophytic tissues of the pistil. Arabinogalactan glycoproteins (AGPs) are a diverse family of highly glycosylated, secreted proteins which have been widely implicated in plant reproduction, particularly within the pistil. Though tomato (Solanum lycopersicum) is an important crop requiring successful fertilization for production, the molecular basis of this event remains understudied. Here we explore the spatiotemporal localization of AGPs in the mature tomato pistil before and after fertilization. Using histological techniques to detect AGP sugar moieties, we found that accumulation of AGPs correlated with the maturation of the stigma and we identified an AGP subpopulation restricted to the micropyle that was no longer visible upon fertilization.