UK Criteria for Uterus Transplantation: A Review

Absolute Uterine Factor Infertility (AUFI) is the final hurdle for assisted reproductive treatments. Uterus transplant trials are happening worldwide; in order to advance the debate around uterine transplantation (UTx) this article considers selection criteria for clinical trials from a UK perspective and makes recommendations for future selection criteria for UTx treatment. Recommendations advanced include the use of donor eggs, access for single women and women in same-sex relationships, prohibiting participation of women who are already mothers, and a preference for deceased donors and bioengineered uteri. With UTx treatment on the horizon it is important to proactively consider future selection criteria

Notorious places: image, reputation, stigma: the role of newspapers in area reputations for social housing estates

This paper reviews work in several disciplines to distinguish between image, reputation and stigma. It also shows that there has been little research on the process by which area reputations are established and sustained through transmission processes. This paper reports on research into the portrayal of two social housing estates in the printed media over an extended period of time (14 years). It was found that negative and mixed coverage of the estates dominated, with the amount of positive coverage being very small. By examining the way in which dominant themes were used by newspapers in respect of each estate, questions are raised about the mode of operation of the press and the communities' collective right to challenge this. By identifying the way regeneration stories are covered and the nature of the content of positive stories, lessons are drawn for programmes of area transformation. The need for social regeneration activities is identified as an important ingredient for changing deprived-area reputations

Utilizing gene pair orientations for HMM-based analysis of promoter array ChIP-chip data

Motivation: Array-based analysis of chromatin immunoprecipitation (ChIP-chip) data is a powerful technique for identifying DNA target regions of individual transcription factors. The identification of these target regions from comprehensive promoter array ChIP-chip data is challenging. Here, three approaches for the identification of transcription factor target genes from promoter array ChIP-chip data are presented. We compare (i) a standard log-fold-change analysis (LFC); (ii) a basic method based on a Hidden Markov Model (HMM); and (iii) a new extension of the HMM approach to an HMM with scaled transition matrices (SHMM) that incorporates information about the relative orientation of adjacent gene pairs on DNA

Delivering a multi-functional and resilient urban forest

Tree planting is widely advocated and applied in urban areas, with large-scale projects underway in cities globally. Numerous potential benefits are used to justify these planting campaigns. However, reports of poor tree survival raise questions about the ability of such projects to deliver on their promises over the long-term. Each potential benefit requires different supporting conditions—relating not only to the type and placement of the tree, but also to the broader urban system within which it is embedded. This set of supporting conditions may not always be mutually compatible and may not persist for the lifetime of the tree. Here, we demonstrate a systems-based approach that makes these dependencies, synergies, and tensions more explicit, allowing them to be used to test the decadal-scale resilience of urban street trees. Our analysis highlights social, environmental, and economic assumptions that are implicit within planting projects; notably that high levels of maintenance and public support for urban street trees will persist throughout their natural lifespan, and that the surrounding built form will remain largely unchanged. Whilst the vulnerability of each benefit may be highly context specific, we identify approaches that address some typical weaknesses, making a functional, resilient, urban forest more attainable

Delivering a multi-functional and resilient urban forest

Tree planting is widely advocated and applied in urban areas, with large-scaleprojects underway in cities globally. Numerous potential benefits are used to justify these planting campaigns. However, reports of poor tree survival raise questions about the ability of such projects to deliver on their promises over the long-term. Each potential benefit requires different supporting conditions—relating not only to the type and placement of the tree, but also to the broader urban system within which it is embedded. This set of supportingconditions may not always be mutually compatible and may not persist for the lifetime of the tree. Here, we demonstrate a systems-based approach that makes these dependencies, synergies, and tensions more explicit, allowing them to be used to test the decadal-scale resilience of urban street trees. Our analysis highlights social, environmental, and economic assumptions that are implicit within planting projects; notably that high levels of maintenance and public support for urban street trees will persist throughout their natural lifespan, andthat the surrounding built form will remain largely unchanged. Whilst the vulnerability of each benefit may be highly context specific, we identify approaches that address some typical weaknesses, making a functional, resilient, urban forest more attainable.

An Improved, Bias-Reduced Probabilistic Functional Gene Network of Baker's Yeast, Saccharomyces cerevisiae

Background: Probabilistic functional gene networks are powerful theoretical frameworks for integrating heterogeneous functional genomics and proteomics data into objective models of cellular systems. Such networks provide syntheses of millions of discrete experimental observations, spanning DNA microarray experiments, physical protein interactions, genetic interactions, and comparative genomics; the resulting networks can then be easily applied to generate testable hypotheses regarding specific gene functions and associations. Methodology/Principal Findings: We report a significantly improved version (v. 2) of a probabilistic functional gene network [1] of the baker's yeast, Saccharomyces cerevisiae. We describe our optimization methods and illustrate their effects in three major areas: the reduction of functional bias in network training reference sets, the application of a probabilistic model for calculating confidences in pair-wise protein physical or genetic interactions, and the introduction of simple thresholds that eliminate many false positive mRNA co-expression relationships. Using the network, we predict and experimentally verify the function of the yeast RNA binding protein Puf6 in 60S ribosomal subunit biogenesis. Conclusions/Significance: YeastNet v. 2, constructed using these optimizations together with additional data, shows significant reduction in bias and improvements in precision and recall, in total covering 102,803 linkages among 5,483 yeast proteins (95% of the validated proteome). YeastNet is available from http://www.yeastnet.org.This work was supported by grants from the N.S.F. (IIS-0325116, EIA-0219061), N.I.H. (GM06779-01,GM076536-01), Welch (F-1515), and a Packard Fellowship (EMM). These agencies were not involved in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.Cellular and Molecular Biolog

The Human Nucleolar Protein FTSJ3 Associates with NIP7 and Functions in Pre-rRNA Processing

NIP7 is one of the many trans-acting factors required for eukaryotic ribosome biogenesis, which interacts with nascent pre-ribosomal particles and dissociates as they complete maturation and are exported to the cytoplasm. By using conditional knockdown, we have shown previously that yeast Nip7p is required primarily for 60S subunit synthesis while human NIP7 is involved in the biogenesis of 40S subunit. This raised the possibility that human NIP7 interacts with a different set of proteins as compared to the yeast protein. By using the yeast two-hybrid system we identified FTSJ3, a putative ortholog of yeast Spb1p, as a human NIP7-interacting protein. A functional association between NIP7 and FTSJ3 is further supported by colocalization and coimmunoprecipitation analyses. Conditional knockdown revealed that depletion of FTSJ3 affects cell proliferation and causes pre-rRNA processing defects. The major pre-rRNA processing defect involves accumulation of the 34S pre-rRNA encompassing from site A′ to site 2b. Accumulation of this pre-rRNA indicates that processing of sites A0, 1 and 2 are slower in cells depleted of FTSJ3 and implicates FTSJ3 in the pathway leading to 18S rRNA maturation as observed previously for NIP7. The results presented in this work indicate a close functional interaction between NIP7 and FTSJ3 during pre-rRNA processing and show that FTSJ3 participates in ribosome synthesis in human cells

Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins. © 2018 The Author(s)

The Essential Nucleolar Yeast Protein Nop8p Controls the Exosome Function during 60S Ribosomal Subunit Maturation

The yeast nucleolar protein Nop8p has previously been shown to interact with Nip7p and to be required for 60S ribosomal subunit formation. Although depletion of Nop8p in yeast cells leads to premature degradation of rRNAs, the biochemical mechanism responsible for this phenotype is still not known. In this work, we show that the Nop8p amino-terminal region mediates interaction with the 5.8S rRNA, while its carboxyl-terminal portion interacts with Nip7p and can partially complement the growth defect of the conditional mutant strain Δnop8/GAL::NOP8. Interestingly, Nop8p mediates association of Nip7p to pre-ribosomal particles. Nop8p also interacts with the exosome subunit Rrp6p and inhibits the complex activity in vitro, suggesting that the decrease in 60S ribosomal subunit levels detected upon depletion of Nop8p may result from degradation of pre-rRNAs by the exosome. These results strongly indicate that Nop8p may control the exosome function during pre-rRNA processing

Neoadjuvant Endocrine Therapy in Breast Cancer Upregulates the Cytotoxic Drug Pump ABCG2/BCRP, and May Lead to Resistance to Subsequent Chemotherapy

Introduction: Neoadjuvant treatments for primary breast cancer are becoming more common; however, little is known about how these impact on response to subsequent adjuvant therapies. Conveniently, neoadjuvant therapy provides opportunities to consider this question, by studying therapy-induced expression changes using comparisons between pre- and posttreatment samples. These data are relatively lacking in the context of neoadjuvant endocrine therapy, as opposed to the more common neoadjuvant chemotherapy. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of neoadjuvant endocrine therapy and particularly with reference to subsequent chemotherapy treatment. Materials and Methods: ABCG2/BCRP expression was assessed by immunohistochemistry or by expression arrays in matched patient samples pre- and post-neoadjuvant endocrine therapy. Cell culture was used to model the impact of endocrine therapy-induced changes in ABCG2/BCRP on subsequent chemotherapy response, using Western blots, quantitative polymerase chain reaction, survival assays, and cell cycle analyses. Results: ABCG2/BCRP was commonly and significantly upregulated in breast cancers after treatment with neoadjuvant endocrine therapy in 3 separate cohorts encompassing a total of 200 patients. Treatment with the endocrine therapeutic tamoxifen similarly induced ABCG2/BCRP upregulation in a relevant model cell line, the estrogen receptor-positive line T47D. Critically, this upregulation was associated with significantly increased chemoresistance to subsequent treatment with epirubicin, an anthracycline commonly used in breast cancer adjuvant chemotherapy. Conclusion: Our data suggest that neoadjuvant endocrine therapy may induce poor responses to adjuvant chemotherapy, and therefore, that clinical outcomes following this treatment sequence warrant further study