Library Impact Data Project: hit, miss or maybe

Purpose In February 2011 the University of Huddersfield along with 7 partners were awarded JISC funding through the Activity Data programme to investigate the hypothesis that: “There is a statistically significant correlation across a number of universities between library activity data and student attainment” The Library Impact Data Project aimed to analyse users’ actions with regards to library usage and then linking those to final degree award. By identifying a positive correlation in this data those subject areas or courses which exhibit high usage of library resources can be used as models of good practice. Design, methodology or approach The overall approach of the project is to extract anonymised activity data from partners’ systems and analyse the findings. For each student who graduated in the sample years, the following data was required: final grade achieved; number of books borrowed; number of times e-resources were accessed; number of times each student entered the library and school or faculty. This data was then collated, normalised, and then analysed. In addition all partners were asked to hold a number of focus groups in order to secure qualitative data from students on library usage to provide a holistic picture of how students engage with library resources. Findings This paper will report on the findings of the project which ran from February to July 2011. It will consider whether the hypothesis was proven for the three indicators of library usage. Research or practical limitations or implications The main aim of the project was to support the hypothesis. The project acknowledges however, that the relationship between the two variables is not a causal relationship and there will be other factors which influence student attainment. Conclusions The paper will discuss the implications of the results and suggest further work that could result from the projects findings

The role of microRNA in regulation of lineage-specific gene expression through the cell cycle

The establishment and maintenance of highly specialised cell lineages is fundamental to the development of multicellular organisms. Cell identity is determined by specific transcriptional profiles, which are mediated by sequence-specific, chromatin-based and post-transcriptional mechanisms of gene regulation. Changes in cell morphology and chromatin structure which occur during the cell cycle present a challenge to the maintenance of lineage-specific gene expression profiles. This study investigates the role of post-transcriptional regulation by microRNAs in stabilising cell-specific gene expression through the process of cell growth and division. Data presented here show that microRNAs are inherited through mitosis in mammalian cells, and are capable of regulating target gene expression in recipient daughter cells. Genome-wide expression analysis indicates that key developmentally regulated genes marked by a bivalent chromatin signature are globally upregulated in microRNA-deficient ES cells. Binding sites for ES cell-specific microRNAs are significantly enriched in the 3'UTR of these transcripts compared to the rest of the transcriptome, strongly suggesting that microRNAs contribute to maintenance of ES cell identity by co-ordinately regulating multiple lineage inappropriate genes. Finally, analysis of the expression of validated microRNA targets and bivalent genes throughout the cell cycle shows that transcripts from these genes accumulate in G2/M to a greater extent in microRNA-deficient ES cells than in wildtype cells. Taken together, data presented in this study support a role for microRNAs in regulation of lineage-specific gene expression through the cell cycle

Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs

Background: Mammalian transcriptomes contain thousands of long noncoding RNAs (lncRNAs). Some lncRNAs originate from intragenic enhancers which, when active, behave as alternative promoters producing transcripts that are processed using the canonical signals of their host gene. We have followed up this observation by analyzing intergenic lncRNAs to determine the extent to which they might also originate from intergenic enhancers. Results: We integrated high-resolution maps of transcriptional initiation and transcription to annotate a conservative set of intergenic lncRNAs expressed in mouse erythroblasts. We subclassified intergenic lncRNAs according to chromatin status at transcriptional initiation regions, defined by relative levels of histone H3K4 mono- and trimethylation. These transcripts are almost evenly divided between those arising from enhancer-associated (elncRNA) or promoter-associated (plncRNA) elements. These two classes of 5′ capped and polyadenylated RNA transcripts are indistinguishable with regard to their length, number of exons or transcriptional orientation relative to their closest neighboring gene. Nevertheless, elncRNAs are more tissue-restricted, less highly expressed and less well conserved during evolution. Of considerable interest, we found that expression of elncRNAs, but not plncRNAs, is associated with enhanced expression of neighboring protein-coding genes during erythropoiesis. Conclusions: We have determined globally the sites of initiation of intergenic lncRNAs in erythroid cells, allowing us to distinguish two similarly abundant classes of transcripts. Different correlations between the levels of elncRNAs, plncRNAs and expression of neighboring genes suggest that functional lncRNAs from the two classes may play contrasting roles in regulating the transcript abundance of local or distal loci

Corrigendum: Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

In the above-mentioned article, one result reported in the third paragraph of the Results subsection “ceRNAts of individual lnceRNAs tend to be functionally related” was in error. This paragraph should now read: “On average, mESC-expressed lnceRNAs have 20.2 predicted MREs per kb of transcript that are specific to 12 different mESC-expressed miRNAs. This MRE density is similar to the density within 3′ UTRs of ceRNAts (20.4 MREs predicted per kb; P = 0.34, two-tailed Mann-Whitney U test) (Supplemental Fig. S9; Supplemental Table S8). A single lnceRNA might, therefore, be as likely as an mRNA to regulate post-transcriptionally the transcript abundance of many mRNAs via crosstalk with many miRNAs.” Corrected versions of Supplemental Figure S9 and Supplemental Table S8 are also now provided online. This correction does not affect any of the conclusions of the paper. The authors apologize for any confusion caused by this error

A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α

<p>Abstract</p> <p>Background</p> <p>Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acethycholine receptors (mAChRs). Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC), it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-α.</p> <p>Results</p> <p>Whilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-α. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms.</p> <p>Conclusion</p> <p>Our results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.</p

Progress towards antibiotic use targets in eight high-income countries

OBJECTIVE: To compare antibiotic sales in eight high-income countries using the 2019 World Health Organization (WHO) Access, Watch and Reserve (AWaRe) classification and the target of 60% consumption of Access category antibiotics. METHODS: We analysed data from a commercial database of sales of systemic antibiotics in France, Germany, Italy, Japan, Spain, Switzerland, United Kingdom of Great Britain and Northern Ireland, and United States of America over the years 2013-2018. We classified antibiotics according to the 2019 AWaRe categories: Access, Watch, Reserve and Not Recommended. We measured antibiotic sales per capita in standard units (SU) per capita and calculated Access group sales as a percentage of total antibiotic sales. FINDINGS: In 2018, per capita antibiotic sales ranged from 7.4 SU (Switzerland) to 20.0 SU (France); median sales of Access group antibiotics were 10.9 SU per capita (range: 3.5-15.0). Per capita sales declined moderately over 2013-2018. The median percentage of Access group antibiotics was 68% (range: 22-77 %); the Access group proportion increased in most countries between 2013 and 2018. Five countries exceeded the 60% target; two countries narrowly missed it (\u3e 55% in Germany and Italy). Sales of Access antibiotics in Japan were low (22%), driven by relatively high sales of oral cephalosporins and macrolides. CONCLUSION: We have identified changes to prescribing that could allow countries to achieve the WHO target. The 60% Access group target provides a framework to inform national antibiotic policies and could be complemented by absolute measures and more ambitious values in specific settings

Minimum Target Prices for Production of Direct-Acting Antivirals and Associated Diagnostics to Combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-na€ ıve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir1daclatasvir

Cdc14 phosphatase promotes segregation of telomeres through repression of RNA polymerase II transcription

[EN]Kinases and phosphatases regulate messenger RNA synthesis through post-translational modi cation of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II. In yeast, the phosphatase Cdc14 is required for mitotic exit and for segregation of repetitive regions4. Cdc14 is also a subunit of the silencing complex RENT, but no roles in transcriptional repression have been described. Here we report that inactivation of Cdc14 causes silencing defects at the intergenic spacer sequences of ribosomal genes during interphase and at Y0 repeats in subtelomeric regions during mitosis. We show that the role of Cdc14 in silencing is independent of the RENT deacetylase subunit Sir2. Instead, Cdc14 acts directly on RNA polymerase II by targeting CTD phosphorylation at Ser 2 and Ser 5. We also find that the role of Cdc14 as a CTD phosphatase is conserved in humans. Finally, telomere segregation defects in cdc14 mutants4 correlate with the presence of subtelomeric Y0 elements and can be rescued by transcriptional inhibition of RNA polymerase II

Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

The acute neurotoxicity of oligomeric forms of amyloid-beta 1-42 (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Abeta, an event that could be important during the early stages of the disease. We show that oligomerised Abeta induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Abeta oligomers is the rapid synaptic insertion of CP-AMPARs