The miR-35-41 Family of MicroRNAs Regulates RNAi Sensitivity in Caenorhabditis elegans

RNA interference (RNAi) utilizes small interfering RNAs (siRNAs) to direct silencing of specific genes through transcriptional and post-transcriptional mechanisms. The siRNA guides can originate from exogenous (exo–RNAi) or natural endogenous (endo–RNAi) sources of double-stranded RNA (dsRNA). In Caenorhabditis elegans, inactivation of genes that function in the endo–RNAi pathway can result in enhanced silencing of genes targeted by siRNAs from exogenous sources, indicating cross-regulation between the pathways. Here we show that members of another small RNA pathway, the mir-35-41 cluster of microRNAs (miRNAs) can regulate RNAi. In worms lacking miR-35-41, there is reduced expression of lin-35/Rb, the C. elegans homolog of the tumor suppressor Retinoblastoma gene, previously shown to regulate RNAi responsiveness. Genome-wide microarray analyses show that targets of endo–siRNAs are up-regulated in mir-35-41 mutants, a phenotype also displayed by lin-35/Rb mutants. Furthermore, overexpression of lin-35/Rb specifically rescues the RNAi hypersensitivity of mir-35-41 mutants. Although the mir-35-41 miRNAs appear to be exclusively expressed in germline and embryos, their effect on RNAi sensitivity is transmitted to multiple tissues and stages of development. Additionally, we demonstrate that maternal contribution of miR-35-41 or lin-35/Rb is sufficient to reduce RNAi effectiveness in progeny worms. Our results reveal that miRNAs can broadly regulate other small RNA pathways and, thus, have far reaching effects on gene expression beyond directly targeting specific mRNAs

Long-Range Autocorrelations of CpG Islands in the Human Genome

In this paper, we use a statistical estimator developed in astrophysics to study the distribution and organization of features of the human genome. Using the human reference sequence we quantify the global distribution of CpG islands (CGI) in each chromosome and demonstrate that the organization of the CGI across a chromosome is non-random, exhibits surprisingly long range correlations (10 Mb) and varies significantly among chromosomes. These correlations of CGI summarize functional properties of the genome that are not captured when considering variation in any particular separate (and local) feature. The demonstration of the proposed methods to quantify the organization of CGI in the human genome forms the basis of future studies. The most illuminating of these will assess the potential impact on phenotypic variation of inter-individual variation in the organization of the functional features of the genome within and among chromosomes, and among individuals for particular chromosomes

Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing

Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture(1–4). We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis(5,6), we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos

A review of source tracking techniques for fine sediment within a catchment

Excessive transport of fine sediment, and its associated pollutants, can cause detrimental impacts in aquatic environments. It is therefore important to perform accurate sediment source apportionment to identify hot spots of soil erosion. Various tracers have been adopted, often in combination, to identify sediment source type and its spatial origin; these include fallout radionuclides, geochemical tracers, mineral magnetic properties and bulk and compound-specific stable isotopes. In this review, the applicability of these techniques to particular settings and their advantages and limitations are reviewed. By synthesizing existing approaches, that make use of multiple tracers in combination with measured changes of channel geomorphological attributes, an integrated analysis of tracer profiles in deposited sediments in lakes and reservoirs can be made. Through a multi-scale approach for fine sediment tracking, temporal changes in soil erosion and sediment load can be reconstructed and the consequences of changing catchment practices evaluated. We recommend that long-term, as well as short-term, monitoring of riverine fine sediment and corresponding surface and subsurface sources at nested sites within a catchment are essential. Such monitoring will inform the development and validation of models for predicting dynamics of fine sediment transport as a function of hydro-climatic and geomorphological controls. We highlight that the need for monitoring is particularly important for hilly catchments with complex and changing land use. We recommend that research should be prioritized for sloping farmland-dominated catchments

A review of source tracking techniques for fine sediment within a catchment

Excessive transport of fine sediment, and its associated pollutants, can cause detrimental impacts in aquatic environments. It is therefore important to perform accurate sediment source apportionment to identify hot spots of soil erosion. Various tracers have been adopted, often in combination, to identify sediment source type and its spatial origin; these include fallout radionuclides, geochemical tracers, mineral magnetic properties and bulk and compound-specific stable isotopes. In this review, the applicability of these techniques to particular settings and their advantages and limitations are reviewed. By synthesizing existing approaches, that make use of multiple tracers in combination with measured changes of channel geomorphological attributes, an integrated analysis of tracer profiles in deposited sediments in lakes and reservoirs can be made. Through a multi-scale approach for fine sediment tracking, temporal changes in soil erosion and sediment load can be reconstructed and the consequences of changing catchment practices evaluated. We recommend that long-term, as well as short-term, monitoring of riverine fine sediment and corresponding surface and subsurface sources at nested sites within a catchment are essential. Such monitoring will inform the development and validation of models for predicting dynamics of fine sediment transport as a function of hydro-climatic and geomorphological controls. We highlight that the need for monitoring is particularly important for hilly catchments with complex and changing land use. We recommend that research should be prioritized for sloping farmland-dominated catchments

Brief Engagement and Acceptance Coaching for Community and Hospice Settings (the BEACHeS Study): Protocol for the development and pilot testing of an evidence-based psychological intervention to enhance wellbeing and aid transition into palliative care

Background: Cancer affects millions of individuals globally, with a mortality rate of over eight million people annually. Although palliative care is often provided outside of specialist services, many people require, at some point in their illness journey, support from specialist palliative care services, for example, those provided in hospice settings. This transition can be a time of uncertainty and fear and there is a need for effective interventions to meet the psychological and supportive care needs of people with cancer that cannot be cured. While Acceptance and Commitment Therapy (ACT) has been shown to be effective across diverse health problems, robust evidence for its effectiveness in palliative cancer populations is not extensive. Method: This mixed-methods study uses a single-case experimental design with embedded qualitative interviews to pilot test a novel intervention for this patient group. Between 14 and 20 patients will be recruited from two hospices in England and Scotland. Participants will receive five face-to-face manualised sessions with a psychological therapist. Sessions are structured around teaching core ACT skills (Openness, Awareness and Engagement) as a way to deal effectively with challenges of transition into specialist palliative care services. Outcome measures include: cancer-specific quality of life (primary outcome) and distress (secondary outcome), which are assessed alongside measures of psychological flexibility. Daily diary outcome assessments will be taken for key measures, alongside more detailed weekly self-report, through baseline, intervention and one-month follow-up phases. After follow-up, participants will be invited to take part in a qualitative interview to understand their experience of taking part, and acceptability and perceived effectiveness of the intervention and its components. Discussion: This study is the first investigation of using ACT with terminally ill patients at the beginning of their transition into palliative treatment. Using in-depth single-case approaches, we will refine and manualise intervention content by the close of the study for use in follow-up research trials. Our long-term goal is then to test the intervention as delivered by non-psychologist specialist palliative care practitioners thus broadening the potential relevance of the approach