The development of Wilms tumor: From WT1 and microRNA to animal models

Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF₂, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3′–5′ exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF₂ and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor.     

Structural Basis for the Presentation of Tumor-Associated MHC Class II-Restricted Phosphopeptides to CD4 T Cells

Dysregulated protein phosphorylation is a hallmark of malignant transformation. Transformation can generate major histocompatibility complex (MHC)-bound phosphopeptides that are differentially displayed on tumor cells for specific recognition by T cells. To understand how phosphorylation alters the antigenic identity of self-peptides and how MHC class II molecules present phosphopeptides for CD4⁺ T-cell recognition, we determined the crystal structure of a phosphopeptide derived from melanoma antigen recognized by T cells-1 (pMART-1), selectively expressed by human melanomas, in complex with HLA-DR1. The structure revealed that the phosphate moiety attached to the serine residue at position P5 of pMART-1 is available for direct interactions with T-cell receptor (TCR) and that the peptide N-terminus adopts an unusual conformation orienting it toward TCR. This structure, combined with measurements of peptide affinity for HLA-DR1 and of peptide-MHC recognition by pMART-1-specific T cells, suggests that TCR recognition is focused on the N-terminal portion of pMART-1. This recognition mode appears to be distinct from that of foreign antigen complexes but is remarkably reminiscent of the way autoreactive TCRs engage self- or altered self-peptides, consistent with the tolerogenic nature of tumor-host immune interactions.     

Pellicle formation in <Emphasis Type="Italic">Shewanella oneidensis</Emphasis>

Background  

Although solid surface-associated biofilm development of S. oneidensis has been extensively studied in recent years, pellicles formed at the air-liquid interface are largely overlooked. The goal of this work was to understand basic requirements and mechanism of pellicle formation in S. oneidensis.     

Influence of the Qinghai-Tibetan railway and highway on the activities of wild animals

The effect of traffic and railway construction on the activities of wild animals during the daytime along the Qinghai-Tibetan highway between Budongquan (35°17′ N; 93°16′ E) and Wudaliang (35°13′ N; 93°04′ E) was studied in August 2003 and August 2004. Furthermore, passageways cross the Qinghai-Tibetan railway were monitored to determine the relationship between the usage frequency of the passageways and the distance to the Qinghai-Tibetan highway and the dimension of the passageways. The results showed that the traffic during the daytime had some effects on the Tibetan antelope (Pantholops hodgsoni), Tibetan gazelle (Procapra picticaudata) and Kiang (Equus kiang) when they were crossing the road, and especially it is significant on the Tibetan antelope. At the same time, they could adapt themselves to the changes in the surroundings by learning and by adjusting their behavior. Most of their activities took place in the morning in order to avoid the effects of traffic, and they could also find and use the passageways cross the Qinghai-Tibetan railway. The dimensions of the passageways, the distance to the Qinghai-Tibetan highway, the surrounding habitat, and human activities could influence the efficiency of the passageways. Most passageways cross the Qinghai-Tibetan railway could not be effectively used by the wildlife because of the short length and low height or because of human activities in the contiguous areas of the passageways. However, the wildlife could adapt themselves to the changes in the surroundings caused by the construction of the Qinghai-Tibetan railway by learning and by adjusting their behavior.     

Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).     

Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase

From random screening of our compound libraries, we identified a hit compound with an IC50 of 27 microM against hepatitis C viral NS5B RNA-dependent RNA polymerase. By using a parallel synthetic strategy, a series of its derivatives were synthesized. From their anti-HCV activity screening, compounds with single digital 3.8 micromolar activity were obtained.     

Distinctive heat-shock response of bioleaching microorganism Acidithiobacillus ferrooxidans observed using genome-wide microarray

Temperature plays an important role in the heap bioleaching. The maldistribution of ventilation in the heap leads to local hyperthermia, which does exert a tremendous stress on bioleaching microbes. In this study, the genome-wide expression profiles of Acidithiobacillus ferrooxidans at 40?°C were detected using the microarray. The results showed that some classic proteases like Lon and small heat-shock proteins were not induced, and heat-inducible membrane proteins were suggested to be under the control of σ(E). Moreover, expression changes of energy metabolism are noteworthy, which is different from that in heterotrophic bacteria upon heat stress. The induced enzymes catalyzed the central carbon metabolism pathway that might mainly provide precursors of amino acids for protein synthesis. These results will deepen the understanding of the mechanisms of heat-shock response on autotrophic bacteria.     

One‐step separation and purification of rupestonic acid and chrysosptertin B from Artemisia rupestris L. by high‐speed counter‐current chromatography

Introduction – Artemisia rupestris L. is a well‐known traditional Chinese medicinal plant in Xinjiang. Rupestonic acid is the main active ingredient of A. rupestris L., and has been chosen as a ‘marker compound’ for the chemical evaluation or quality control of A. rupestris L. and its products. Although HSCCC separation method was developed before, the separation was performed with two steps using the same solvent system, which were time‐consuming and waste of the solvents. Objective – To develop a simple HSCCC method for the separation and purification of rupestonic acid in a single run. Methodology – The measurement of partition coefficient (K) was introduced to select the two‐phase solvent system. The simple HSCCC method was established according to the selected solvent system for separation and purification of rupestonic acid. The purity of target compound was test by HPLC and the structure was identified by MS, ¹H NMR and ¹³C NMR. Results – A total of 72.3 mg of rupestonic acid and 53.5 mg of chrysosptertin B with over 95% purity were yielded from 500 mg extracts of Artemisia rupestris L. in one‐step separation. Conclusion – The rupestonic acid was separated in a single run by HSCCC. Copyright © 2009 John Wiley & Sons, Ltd.