Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression

Smad ubiquitin regulatory factors (Smurfs) belong to the HECT- family of E3 ubiquitin ligases and comprise mainly of two members, Smurf1 and Smurf2. Initially, Smurfs have been implicated in determining the competence of cells to respond to TGF-β/BMP signaling pathway. Nevertheless, the intrinsic catalytic activity has extended the repertoire of Smurf substrates beyond the TGF-β/BMP super family expanding its realm further to epigenetic modifications of histones governing the chromatin landscape. Through regulation of a large number of proteins in multiple cellular compartments, Smurfs regulate diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and metastasis. As the genomic ablation of Smurfs leads to global changes in histone modifications and predisposition to a wide spectrum of tumors, Smurfs are also considered to have a novel tumor suppressor function. This review focuses on regulation network and biological functions of Smurfs in connection with its role in cancer progression. By providing a portrait of their protein targets, we intend to link the substrate specificity of Smurfs with their contribution to tumorigenesis. Since the regulation and biological functions of Smurfs are quite complex, understanding the oncogenic potential of these E3 ubiquitin ligases may facilitate the development of mechanism-based drugs in cancer treatment.     

Annual gametogenic cycle of the freshwater pearl mussel,Lamellidens marginalis (Lamarck, 1819) collected from a perennial lentic habitat of Bangladesh

ABSTRACT

We investigated the annual gametogenic phenology of the freshwater pearl mussel, Lamellidens marginalis (Lamarck, 1819), collected from a lentic habitat at Mymensingh, Bangladesh, using biometry and histology through monthly sampling from August 2015 to July 2016. After biometric measurements, thin slices of dorso-ventral sections were cut from the middle of the mussels for histology to determine sex and level of gonadal maturation. The condition index (CI) ranged from 0.64 (March) to 0.99 (January) over the study period. The CI peaked three times (January, April and July) indicating that the mussels were ripe during these months and subsequent decreases in CI indicated spawning, which was consistent with histology. Both males and females exhibited similar patterns in terms of gonadal development, maturation and spawning activity. It was confirmed that natural populations of L. marginalis spawn throughout the year with remarkable temporal variations, except during December when the surface water temperature reaches annual minima (16.5°C). Highest spawning activity of L. marginalis was noted during February–March, May and July–November. The data obtained in the present study could be useful for the conservation managers of this commercial species by allowing harvesting of better quality mussels to be timed without interrupting major spawning activity.     

Folic Acid Conjugated δ-Valerolactone-Poly(ethylene glycol) Based Triblock Copolymer as a Promising Carrier for Targeted Doxorubicin Delivery

The aim of this study is to test the hypothesis that the newly synthesized poly(δ-valerolactone)/poly(ethylene glycol)/poly(δ-valerolactone) (VEV) copolymer grafted with folic acid would impart targetability and further enhance the anti-tumor efficacy of doxorubicin (DOX). Here, folic acid conjugated VEV (VEV-FOL) was synthesized by a modified esterification method and characterized using IR and NMR. DOX loaded VEV-FOL micelles were synthesized using a novel solvent evaporation method and were obtained with a mean diameter of 97 nm with high encapsulation efficiency and sustained in vitro release profile. Comparative studies of polymer micelles with and without folate for cellular uptake and cytotoxicity were done on folate receptor-positive breast cancer cell line, MDAMB231. The intracellular uptake tests showed significant increase in folate micellar uptake when compared to non-folate-mediated micelles. MTT assay followed by apoptosis assays clearly indicated that folate decorated micelles showed significantly better cytotoxicity (IC₅₀ = 0.014 µM) and efficiency to induce apoptosis than other treated groups. Moreover, a significant G2/M arrest was induced by DOX loaded VEV-FOL micelles at a concentration where free drug failed to show any activity. Thus, our results show that the folic acid-labeled VEV copolymer is a promising biomaterial with controlled and sustainable tumor targeting ability for anticancer drugs which can open new frontiers in the area of targeted chemotherapy.     

Impact of Library Preparation on Downstream Analysis and Interpretation of RNA-Seq Data: Comparison between Illumina PolyA and NuGEN Ovation Protocol

Objectives

The sequencing by the PolyA selection is the most common approach for library preparation. With limited amount or degraded RNA, alternative protocols such as the NuGEN have been developed. However, it is not yet clear how the different library preparations affect the downstream analyses of the broad applications of RNA sequencing.

Methods and Materials

Eight human mammary epithelial cell (HMEC) lines with high quality RNA were sequenced by Illumina’s mRNA-Seq PolyA selection and NuGEN ENCORE library preparation. The following analyses and comparisons were conducted: 1) the numbers of genes captured by each protocol; 2) the impact of protocols on differentially expressed gene detection between biological replicates; 3) expressed single nucleotide variant (SNV) detection; 4) non-coding RNAs, particularly lincRNA detection; and 5) intragenic gene expression.

Results

Sequences from the NuGEN protocol had lower (75%) alignment rate than the PolyA (over 90%). The NuGEN protocol detected fewer genes (12–20% less) with a significant portion of reads mapped to non-coding regions. A large number of genes were differentially detected between the two protocols. About 17–20% of the differentially expressed genes between biological replicates were commonly detected between the two protocols. Significantly higher numbers of SNVs (5–6 times) were detected in the NuGEN samples, which were largely from intragenic and intergenic regions. The NuGEN captured fewer exons (25% less) and had higher base level coverage variance. While 6.3% of reads were mapped to intragenic regions in the PolyA samples, the percentages were much higher (20–25%) for the NuGEN samples. The NuGEN protocol did not detect more known non-coding RNAs such as lincRNAs, but targeted small and “novel” lincRNAs.

Conclusion

Different library preparations can have significant impacts on downstream analysis and interpretation of RNA-seq data. The NuGEN provides an alternative for limited or degraded RNA but it has limitations for some RNA-seq applications.     

Lead optimization of isocytosine-derived xanthine oxidase inhibitors

We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.     

A value chain approach to improve biomass policy formation

Biomass value chains for energy, fuels and bio‐based products involve complex, cross sector interactions between their upstream and downstream stages. Overarching policymaking to date has included the use of biomass to deliver sector specific aims (e.g. climate change, energy, etc.) however, this is mostly planned without adjusting support across the most challenging stages of biomass value chains and exploiting specific advantages related to their geographic settings (e.g. domestic feedstocks, local markets, etc.). Policies to date have, therefore, resulted in fragmented, suboptimal biomass use and debates for sustainability and resource efficiency. This opinion paper arose from the project Strategic Initiative for Resource Efficient Biomass Policies Funded by the EU Commission. It discusses the development of a dedicated Biomass Policy Framework which applies the principles of value chain analysis in policy design to enable the market uptake of sustainable, domestic, resource efficient biomass solutions. Firstly, it explains how to provide context by identifying value chains which can offer competitive advantages for biomass mobilization, market infrastructures, rural and economic development within their geographic setting. Then the work builds on the context and prioritized value chains and further rationalizes policy needs and aims within individual value chain stages. This is done by identifying policy‐related challenges and gaps that constrain sustainable and resource efficient deployment of the selected value chains. Also, it suggests policy interventions that will overcome challenges, resolve gaps and as a result mobilize local biomass and improve market uptake. Finally, it discusses the contrasting paradigms for biomass policy formation within single sector target setting and the value chain approach of the Biomass Policy Framework and uses the case of low carbon biomass heat to illustrate the strengths of the suggested approach. The paper concludes with remarks for the concept of biomass value chain analysis in policy.     

Nanoscale engineering of extracellular matrix-mimetic bioadhesive surfaces and implants for tissue engineering

Background

The goal of tissue engineering is to restore tissue function using biomimetic scaffolds which direct desired cell fates such as attachment, proliferation and differentiation. Cell behavior in vivo is determined by a complex interaction of cells with extracellular biosignals, many of which exist on a nanoscale. Therefore, recent efforts in tissue engineering biomaterial development have focused on incorporating extracellular matrix- (ECM) derived peptides or proteins into biomaterials in order to mimic natural ECM. Concurrent advances in nanotechnology have also made it possible to manipulate protein and peptide presentation on surfaces on a nanoscale level.

Scope of Review

This review discusses protein and peptide nanopatterning techniques and examples of how nanoscale engineering of bioadhesive materials may enhance outcomes for regenerative medicine.

Major Conclusions

Synergy between ECM-mimetic tissue engineering and nanotechnology fields can be found in three major strategies: (1) Mimicking nanoscale orientation of ECM peptide domains to maintain native bioactivity, (2) Presenting adhesive peptides at unnaturally high densities, and (3) Engineering multivalent ECM-derived peptide constructs.

General Significance

Combining bioadhesion and nanopatterning technologies to allow nanoscale control of adhesive motifs on the cell–material interface may result in exciting advances in tissue engineering.This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.