β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

The increasing interest in click chemistry and its use to stabilize turn structures led us to compare the propensity for β‐turn stabilization of different analogs designed as mimics of the β‐turn structure found in tendamistat. The β‐turn conformation of linear β‐amino acid‐containing peptides and triazole‐cyclized analogs were compared to ‘conventional’ lactam‐ and disulfide‐bridged hexapeptide analogs. Their 3D structures and their propensity to fold in β‐turns in solution, and for those not structured in solution in the presence of α‐amylase, were analyzed by NMR spectroscopy and by restrained molecular dynamics with energy minimization. The linear tetrapeptide Ac‐Ser‐Trp‐Arg‐Tyr‐NH₂ and both the amide bond‐cyclized, c[Pro‐Ser‐Trp‐Arg‐Tyr‐D ‐Ala] and the disulfide‐bridged, Ac‐c[Cys‐Ser‐Trp‐Arg‐Tyr‐Cys]‐NH₂ hexapeptides adopt dominantly in solution a β‐turn conformation closely related to the one observed in tendamistat. On the contrary, the β‐amino acid‐containing peptides such as Ac‐(R)‐β³‐hSer‐(S)‐Trp‐(S)‐β³‐hArg‐(S)‐β³‐hTyr‐NH₂, and the triazole cyclic peptide, c[Lys‐Ser‐Trp‐Arg‐Tyr‐βtA]‐NH₂, both specifically designed to mimic this β‐turn, do not adopt stable structures in solution and do not show any characteristics of β‐turn conformation. However, these unstructured peptides specifically interact in the active site of α‐amylase, as shown by TrNOESY and saturation transfer difference NMR experiments performed in the presence of the enzyme, and are displaced by acarbose, a specific α‐amylase inhibitor. Thus, in contrast to amide‐cyclized or disulfide‐bridged hexapeptides, β‐amino acid‐containing peptides and click‐cyclized peptides may not be regarded as β‐turn stabilizers, but can be considered as potential β‐turn inducers. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Identification of a Novel 1033‐Nucleotide Deletion Polymorphism in the Prophage Region of ‘Candidatus Liberibacter asiaticus’: Potential Applications for Bacterial Epidemiology

The prophage/phage region in the genome of ‘Candidatus Liberibacter asiaticus’, an alpha‐proteobacterium associated with citrus Huanglongbing, included many valuable loci for genetic diversity studies. Previously, a mosaic genomic region (CLIBASIA_05640 to CLIBASIA_05650) was characterized, and this revealed inter‐ and intracontinental variations of ‘Ca. L. asiaticus’. In this study, 267 ‘Ca. L. asiaticus’ isolates collected from eight provinces in China were analysed with a primer set flanking the same mosaic region plus downstream sequence. While most amplicon sizes ranged from 1400 to 2000 bp, an amplicon of 550 bp (S550) was found in 14 samples collected from south‐western China. Sequence analyses showed that S550 was the result of a 1033 bp deletion which included the previously known mosaic region. The genetic nature of the deletion event remains unknown. The regional restriction of S550 suggests that the ‘Ca. L. asiaticus’ population from south‐western China is different from those in eastern China. The small and easy‐to‐detect S550 amplicon could serve as a molecular marker for ‘Ca. L. asiaticus’ epidemiology.     

Maternal effects and ecological divergence in aquatic plants: a case study in natural reciprocal hybrids between Potamogeton perfoliatus and P. wrightii

When parental taxa are adapted to different habitats, hybrid genotypes are often highly heterogeneous, such that habitat or ecological factors influence hybrid fate and ecological performance. Trait expression in hybrids is not always intermediate between the parents, but may instead be either parental‐like or extreme (transgressive) depending on genetic control of the phenotypes. Maternal effects arising from interspecific interaction between cytoplasmic and nuclear genomes are widely recognized as playing a role in character expression of natural hybrids. Such interaction often leads to hybrid sterility or inviability. When hybrids are viable, however, cytonuclear interaction may contribute to hybrid persistence through its influence on trait expression. To date, maternal influence on hybrid performance has been examined primarily in experimentally produced hybrids, or in natural hybrids without identification of the cross direction owing to difficulty in obtaining species‐specific molecular markers. In aquatic plants, many hybrids persist by extensive clonal growth and are important components of aquatic communities. Many such hybrids are known in Potamogeton (pondweeds), the largest aquatic genus. Because Potamogeton species are ecologically highly diverse and maternal lineages are readily distinguished using molecular markers, natural hybrids of Potamogeton are well‐suited for studies of maternal effects, especially those affecting vegetative performance. As a case study, we have focused on maternal effects on drought tolerance and depth distribution in the natural hybrid P. × anguillanus derived from the closely related species P. perfoliatus and P. wrightii.     

The anatomy of a ‘suture zone’ in Amazonian butterflies: a coalescent‐based test for vicariant geographic divergence and speciation

Attempts by biogeographers to understand biotic diversification in the Amazon have often employed contemporary species distribution patterns to support particular theories, such as Pleistocene rainforest refugia, rather than to test among alternative hypotheses. Suture zones, narrow regions where multiple contact zones and hybrid zones between taxa cluster, have been seen as evidence for past expansion of whole biotas that have undergone allopatric divergence in vicariant refuges. We used coalescent analysis of mutilocus sequence data to examine population split times in 22 pairs of geminate taxa in ithomiine and heliconiine butterflies. We test a hypothesis of simultaneous divergence across a suture zone in NE Peru. Our results reveal a scattered time course of diversification in this suture zone, rather than a tight cluster of split times. Additionally, we find rapid diversification within some lineages such as Melinaea contrasting with older divergence within lineages such as the Oleriina (Hyposcada and Oleria). These results strongly reject simple vicariance as a cause of the suture zone. At the same time, observed lineage effects are incompatible with a series of geographically coincident vicariant events which should affect all lineages similarly. Our results suggest that Pleistocene climatic forcing cannot readily explain this Peruvian suture zone. Lineage‐specific biological traits, such as characteristic distances of gene flow or varying rates of parapatric divergence, may be of greater importance.     

KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.Electronic supplementary materialThe online version of this article (10.1007/s13238-020-00766-y) contains supplementary material, which is available to authorized users.