Acevedomckee7550

Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1-mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion-dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1-induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface.T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins like actin and tubulin. In Leishmania donovani, γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms high molecular weight, homo-oligomeric complex that performs ATP dependent protein folding. In the present study, we evaluated the essentiality of LdTCP1γ gene. Gene replacement studies indicate that LdTCP1γ is essential for parasite survival. The LdTCP1γ single-allele replacement mutants exhibited slowed growth and decreased infectivity in mouse macrophages compared to the wild-type parasites. Modulation of LdTCP1γ expression in promastigotes, also modulate cell cycle progression. Suramin, an anti-trypanosomal drug, not only inhibited the luciferase refolding activity of recombinant LdTCP1γ homo-oligomeric complex but also exhibited potential antileishmanial efficacy both in vitro and in vivo. The interaction of suramin and LdTCP1γ was further validated by isothermal titration calorimetry. The study suggests LdTCP1γ as potential drug target and also provides a framework for the development of a new class of drugs.In response to the recent discussion on xdr typhoid in Pakistan1, we would like to bring attention towards critical genotypic evolution in Salmonella Typhi strains from Pakistan which would be of interest to healthcare community.….Resistance-nodulation-division (RND) efflux pumps are important contributors to bacterial antibiotic resistance. Here, we combine evolutionary sequence analyses, computational structural modeling and ligand docking to develop a framework that can explain the known antibiotic substrate selectivity differences between two Pseudomonas aeruginosa RND transporters, MexY and MexB. For efficient efflux, antibiotic substrates must possess a "Goldilocks affinity" binding strong enough to allow interaction with transporter, but not too tight as to impede movement through the pump.Chromosomal resistance to metronidazole has emerged in clinical Clostridioides difficile, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to interpret genetic variations in clinical isolates. We therefore constructed a mismatch repair mutator, in non-toxigenic ATCC 700057, to survey the mutational landscape for de novo resistance mechanisms. In separate experimental evolutions, the mutator adopted a deterministic path to resistance, with truncation of ferrous iron transporter FeoB1 as a first-step mechanism of low-level resistance. Deletion of feoB1 in ATCC 700057 reduced intracellular iron content, appearing to shift cells toward flavodoxin-mediated oxidoreductase reactions, which are less favorable for metronidazole's cellular action. Higher level resistance evolved from sequential acquisition of mutations to catalytic domains of pyruvate-ferredoxin/flavodoxin oxidoreductase (PFOR encoded by nifJ); a synonymous codon change to putative xdh (xanthine dehydrogenase encoded by CD630_31770), likely affecting mRNA stability; and lastly, frameshift and point mutations that inactivated the iron-sulfur cluster regulator (IscR). Gene silencing of nifJ, xdh or iscR with catalytically dead Cas9 revealed that resistance involving these genes only occurred when feoB1 was inactivated i.e. resistance was only seen in the feoB1-deletion mutant and not the isogenic WT parent. Interestingly, metronidazole resistance in CDI-associated strains, carrying mutations in nifJ, was reduced upon gene complementation. This supports that mutations to PFOR is one mechanism of metronidazole resistance in clinical strains. Our findings indicate that metronidazole resistance in C. selleck compound difficile is complex, involving multi-genetic mechanisms that could intersect with iron-dependent and oxidoreductive metabolic pathways.Novel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite Cryptosporidium parvum in vitro with limited cytotoxicity (EC50 = 120 nM vs. TC50 = 988 nM), and its treatment disrupted the parasite morphology. Besides expanded activity spectrum, occidiofungin as a glycolipopeptide is characterized by poor absorbability and its ability to retain in gastrointestinal tract, making it worth to also investigate its potential activities on other enteric parasites.KPC-50 is a KPC-3 variant identified from a Klebsiella pneumoniae clinical isolate recovered in Switzerland in 2019. As compared to KPC-3, KPC-50 shows i) a three amino-acid insertion (Glu-Ala-Val) between amino acids 276 and 277 amino acid sequence, (ii) an increased affinity to ceftazidime, (iii) a decreased sensitivity to avibactam, explaining the ceftazidime-avibactam resistance, and (iv) associated to a sharp reduction of its carbapenemase activity.