We report that the metazoan Wnt protease and signaling inhibitor TIKI shares sequence homology with bacterial TraB/PrgY proteins, inhibitors of pheromone signaling essential for propagation of ...antibiotic resistance. Our analysis suggests that these proteins represent an ancient metalloprotease clan regulating cellular communications across biological kingdoms.
Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), ...including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c(+) immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan PGN, lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides ODNs containing unmethylated CpG motifs), by producing IFN-alpha. CD11c(+) imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-alpha, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-alpha and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
Royal jelly is the queen-maker for the honey bee Apis mellifera, and has cross-species effects on longevity, fertility, and regeneration in mammals. Despite this knowledge, how royal jelly or its ...components exert their myriad effects has remained poorly understood. Using mouse embryonic stem cells as a platform, here we report that through its major protein component Royalactin, royal jelly can maintain pluripotency by activating a ground-state pluripotency-like gene network. We further identify Regina, a mammalian structural analog of Royalactin that also induces a naive-like state in mouse embryonic stem cells. This reveals an important innate program for stem cell self-renewal with broad implications in understanding the molecular regulation of stem cell fate across species.
The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll and human interleukin 1 receptors has sown the conviction that both molecules trigger related signaling pathways ...tied to the nuclear translocation of Rel-type transcription factors. This conserved signaling scheme governs an evolutionarily ancient immune response in both insects and vertebrates. We report the molecular cloning of a class of putative human receptors with a protein architecture that is similar to Drosophila Toll in both intra- and extracellular segments. Five human Toll-like receptors--named TLRs 1-5--are probably the direct homologs of the fly molecule and, as such, could constitute an important and unrecognized component of innate immunity in humans. Intriguingly, the evolutionary retention of TLRs in vertebrates may indicate another role--akin to Toll in the dorsoventralization of the Drosophila embryo--as regulators of early morphogenetic patterning. Multiple tissue mRNA blots indicate markedly different patterns of expression for the human TLRs. By using fluorescence in situ hybridization and sequence-tagged site database analyses, we also show that the cognate Tlr genes reside on chromosomes 4 (TLRs 1, 2, and 3), 9 (TLR4), and 1 (TLR5). Structure prediction of the aligned Toll-homology domains from varied insect and human TLRs, vertebrate interleukin 1 receptors and MyD88 factors, and plant disease-resistance proteins recognizes a parallel β /α fold with an acidic active site; a similar structure notably recurs in a class of response regulators broadly involved in transducing sensory information in bacteria.
Primal or dual strong-duality (or min-sup, inf-max duality) in nonconvex optimization is revisited in view of recent literature on the subject, establishing, in particular, new characterizations for ...the second case. This gives rise to a new class of quasiconvex problems having zero duality gap or closedness of images of vector mappings associated to those problems. Such conditions are described for the classes of linear fractional functions and that of quadratic ones. In addition, some applications to nonconvex quadratic optimization problems under a single inequality or equality constraint, are presented, providing new results for the fulfillment of zero duality gap or dual strong-duality.
Some production models in finance require infinite-dimensional commodity spaces, where efficiency is defined in terms of an ordering cone having possibly empty interior. Since weak efficiency is more ...tractable than efficiency from a mathematical point of view, this paper characterizes the equality between efficiency and weak efficiency in infinite-dimensional spaces without further assumptions, like closedness or free disposability. This is obtained as an application of our main result that characterizes the solutions to a unified vector optimization problem in terms of its scalarization. Standard models as efficiency, weak efficiency (defined in terms of quasi-relative interior), weak strict efficiency, strict efficiency, or strong solutions are carefully described. In addition, we exhibit two particular instances and compute the efficient and weak efficient solution set in Lebesgue spaces.
A family of anti-apoptotic regulators known as IAP (inhibitor of apoptosis) proteins interact with multiple cellular partners and inhibit apoptosis induced by a variety of stimuli. c-IAP (cellular ...IAP) 1 and 2 are recruited to TNFR1 (tumour necrosis factor receptor 1)-associated signalling complexes, where they mediate receptor-induced NF-kappaB (nuclear factor kappaB) activation. Additionally, through their E3 ubiquitin ligase activities, c-IAP1 and c-IAP2 promote proteasomal degradation of NIK (NF-kappaB-inducing kinase) and regulate the non-canonical NF-kappaB pathway. In the present paper, we describe a novel ubiquitin-binding domain of IAPs. The UBA (ubiquitin-associated) domain of IAPs is located between the BIR (baculovirus IAP repeat) domains and the CARD (caspase activation and recruitment domain) or the RING (really interesting new gene) domain of c-IAP1 and c-IAP2 or XIAP (X-linked IAP) respectively. The c-IAP1 UBA domain binds mono-ubiquitin and Lys(48)- and Lys(63)-linked polyubiquitin chains with low-micromolar affinities as determined by surface plasmon resonance or isothermal titration calorimetry. NMR analysis of the c-IAP1 UBA domain-ubiquitin interaction reveals that this UBA domain binds the classical hydrophobic patch surrounding Ile(44) of ubiquitin. Mutations of critical amino acid residues in the highly conserved MGF (Met-Gly-Phe) binding loop of the UBA domain completely abrogate ubiquitin binding. These mutations in the UBA domain do not overtly affect the ubiquitin ligase activity of c-IAP1 or the participation of c-IAP1 and c-IAP2 in the TNFR1 signalling complex. Treatment of cells with IAP antagonists leads to proteasomal degradation of c-IAP1 and c-IAP2. Deletion or mutation of the UBA domain decreases this degradation, probably by diminishing the interaction of the c-IAPs with the proteasome. These results suggest that ubiquitin binding may be an important mechanism for rapid turnover of auto-ubiquitinated c-IAP1 and c-IAP2.
Missense variants are commonly identified in genomic sequence but only a small fraction directly contribute to oncogenesis. The ability to distinguish those missense changes that contribute to cancer ...progression from those that do not is a difficult problem usually only accomplished through functional in vivo analyses. Using two computational algorithms, Sorting Intolerant from Tolerant (SIFT) and the Pfam-based LogR.E-value method, we have identified features that distinguish cancer-associated missense mutations from other classes of missense change. Our data reveal that cancer mutants behave similarly to Mendelian disease mutations, but are clearly distinct from either complex disease mutations or common single-nucleotide polymorphisms. We show that both activating and inactivating oncogenic mutations are predicted to be deleterious, although activating changes are likely to increase protein activity. Using the Gene Ontology and data from the SIFT and LogR.E-value metrics, a classifier was built that predicts cancer-associated missense mutations with a very low false-positive rate. The classifier does remarkably well in a number of different experiments designed to distinguish polymorphisms from true cancer-associated mutations. We also show that recurrently observed mutations are much more likely to be predicted to be cancer-associated than rare mutations, suggesting that our classifier will be useful in distinguishing causal from passenger mutations. In addition, from an expressed sequence tag-based screen, we identified a previously unknown germ line change (P1104A) in tumor tissues that is predicted to disrupt the function of the TYK2 protein. The data presented here show that this novel bioinformatics approach to classifying cancer-associated variants is robust and can be used for large-scale analyses.
Breast cancers expressing high levels of Ki67 are associated with poor outcomes. Oncotype DX test was designed for ER+/HER2- early-stage breast cancers to help adjuvant chemotherapy decision by ...providing a Recurrent Score (RS). RS measures the expression of 21 specific genes from tumor tissue, including Ki67. The primary aim of this study was to assess the agreement between Ki67
obtained with Oncotype DX RS and Ki67
. Other objectives were to analyze the association between the event free survival (EFS) and the expression level of Ki67
; and association between RS and Ki67
. Herein, we report a low agreement of 0.288 by Pearson correlation coefficient test between Ki67
and Ki67
in a cohort of 98 patients with early ER+/HER2- breast cancers. Moreover, Ki67
tumors were significantly associated with the occurrence of events (p = 0.03). On the other hand, we did not find any association between Ki67
and EFS (p = 0.26). We observed a low agreement between expression level of Ki67
and Ki67 protein labelling by IHC. Unlike Ki67
and independently of the RS, Ki67
could have a prognostic value. It would be interesting to better assess the prognosis and predictive value of Ki67
measured by qRT-PCR. The Ki67
in medical routine could be a good support in countries where Oncotype DX is not accessible.
In the first half of the twentieth century, the South American Locust (SAL), Schistocerca cancellata (Serville, 1838), was a major pest of agriculture in Argentina, Bolivia, Paraguay, Uruguay, and ...Brazil. From 1954–2014, a preventive management program appeared to limit SAL populations, with only small- to moderate-scale treatments required, limited to outbreak areas in northwest Argentina. However, the lack of major locust outbreaks led to a gradual reduction in resources, and in 2015, the sudden appearance of swarms marked the beginning of a substantial upsurge, with many swarms reported initially in Argentina in 2015, followed by expansion into neighboring countries over the next few years. The upsurge required a rapid allocation of resources for management of SAL and a detailed examination of the improvements needed for the successful management of this species. This paper provides a review of SAL biology, management history, and perspectives on navigating a plague period after a 60-year recession.
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