Developmental regulation of an organelle tether coordinates mitochondrial remodeling in meiosis.

Cellular differentiation involves remodeling cellular architecture to transform one cell type to another. By investigating mitochondrial dynamics during meiotic differentiation in budding yeast, we sought to understand how organelle morphogenesis is developmentally controlled in a system where regulators of differentiation and organelle architecture are known, but the interface between them remains unexplored. We analyzed the regulation of mitochondrial detachment from the cell cortex, a known meiotic alteration to mitochondrial morphology. We found that mitochondrial detachment is enabled by the programmed destruction of the mitochondria-endoplasmic reticulum-cortex anchor (MECA), an organelle tether that bridges mitochondria and the plasma membrane. MECA regulation is governed by a meiotic transcription factor, Ndt80, which promotes the activation of a conserved kinase, Ime2. We further present evidence for Ime2-dependent phosphorylation and degradation of MECA in a temporally controlled manner. Our study defines a key mechanism that coordinates mitochondrial morphogenesis with the landmark events of meiosis and demonstrates that cells can developmentally regulate tethering to induce organelle remodeling

Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter.

Cell differentiation programs require dynamic regulation of gene expression. During meiotic prophase in Saccharomyces cerevisiae, expression of the kinetochore complex subunit Ndc80 is downregulated by a 5' extended long undecoded NDC80 transcript isoform. Here we demonstrate a transcriptional interference mechanism that is responsible for inhibiting expression of the coding NDC80 mRNA isoform. Transcription from a distal NDC80 promoter directs Set1-dependent histone H3K4 dimethylation and Set2-dependent H3K36 trimethylation to establish a repressive chromatin state in the downstream canonical NDC80 promoter. As a consequence, NDC80 expression is repressed during meiotic prophase. The transcriptional mechanism described here is rapidly reversible, adaptable to fine-tune gene expression, and relies on Set2 and the Set3 histone deacetylase complex. Thus, expression of a 5' extended mRNA isoform causes transcriptional interference at the downstream promoter. We demonstrate that this is an effective mechanism to promote dynamic changes in gene expression during cell differentiation

Kinetochore inactivation by expression of a repressive mRNA.

Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis. Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes. How the meiotic gene expression program temporally restricts kinetochore function is unknown. We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80. Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression. Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5' leader. Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis. This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression

Reconstructing aspects of human embryogenesis with pluripotent stem cells.

Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown. Here, we attempt to model human early embryo development with expanded pluripotent stem cells (EPSCs) in 3-dimensions. We define a protocol that allows us to generate self-organizing cystic structures from human EPSCs that display some hallmarks of human early embryogenesis. These structures mimic polarization and cavitation characteristic of pre-implantation development leading to blastocyst morphology formation and the transition to post-implantation-like organization upon extended culture. Single-cell RNA sequencing of these structures reveals subsets of cells bearing some resemblance to epiblast, hypoblast and trophectoderm lineages. Nevertheless, significant divergences from natural blastocysts persist in some key markers, and signalling pathways point towards ways in which morphology and transcriptional-level cell identities may diverge in stem cell models of the embryo. Thus, this stem cell platform provides insights into the design of stem cell models of embryogenesis

Cluster vs. Field Elliptical Galaxies and Clues on their Formation

Using new observations for a sample of 931 early-type galaxies we investigate whether the \mg2--\so relation shows any dependence on the local environment. The galaxies have been assigned to three different environments depending on the local overdensity: clusters, groups, and field, having used our completeredshift database to guide the assignment of galaxies. It is found that cluster, group and field early-type galaxies follow almost identical \mg2--\so\ relations, with the largest \mg2 zero-point difference (clusters minus field) being only $0.007\pm 0.002$ mag. No correlation of the residuals is found with the morphological type or the bulge to disk ratio. Using stellar population models in a differential fashion, this small zero-point difference implies a luminosity-weighted age difference of only $\sim 1$ Gyr between the corresponding stellar populations, with field galaxies being younger. The mass-weighted age difference could be significantly smaller, if minor events of late star formation took place preferentially in field galaxies. We combine these results with the existing evidence for the bulk of stars in cluster early-type galaxies having formed at very high redshift, and conclude that the bulk of stars in galactic spheroids had to form at high redshifts (z\gsim 3), no matter whether such spheroids now reside in low or high density regions. The cosmological implications of these findings are briefly discussed.Comment: 16 pages, 2 figures, accepted for publication in the ApJ.

Maya y Marco

Victoria Rodrigo, PhD- Serie Leamos’ EditorProfessor of Spanish World Languages and Cultures DepartmentGeorgia State Universityhttps://scholarworks.gsu.edu/wcl_leamos/1033/thumbnail.jp

Staff perceptions following a training programme about reducing psychotropic medication use in adults with intellectual disability : the need for a realistic professional practice framework

Background: Adults with intellectual disability are at higher risk of being administered psychotropic medications. The UK-developed SPECTROM (Short-term PsychoEducation for Carers To Reduce Over Medication of people with intellectual disabilities) training programme educates disability support workers on psychotropic medications and alternatives to these medications. Method: Interviews were conducted with 10 participants who took part in the pilot SPECTROM training programme to elicit their views on the programme and its appropriateness in an Australian context. Results: The key theme was ‘Need for a psychotropic medication practice framework’. Four sub-themes were Broad satisfaction with the SPECTROM training programme; Disability support workers acknowledging the limitations of their scope of practice; Empowering training through prescriptive and reflective methods and; Need for future mentoring from Multi-Disciplinary Team members in the application of new knowledge. Conclusions: Participants felt that whilst they could improve their knowledge and attitudes surrounding psychotropic medication administration for behaviours of concern through SPECTROM training, a national practice framework is needed to execute its goals at scale

Short-Term Psycho-Education for Caregivers to Reduce Overmedication of People with Intellectual Disabilities (SPECTROM): An Australian Feasibility Study

Many people with intellectual disability display behaviours of concern. Oftentimes, these are managed using a range of approaches that includes the use of psychotropic medications even though the person does not have a psychiatric diagnosis. Finding ways to reduce the use of psychotropic medication is important, and disability support workers play an important role in achieving this goal. This study trained disability support workers about psychotropic medications and alternatives to them using the SPECTROM training program and resources. Data collected included measuring disability support workers' knowledge and attitude, in addition to exploring the appropriateness of the training program. Although disability support workers' knowledge increased after the training program, their attitudes did not change. The SPECTROM training program is feasible in the Australian context despite the need for an Australian practice framework in this area

Translating statistical species-habitat models to interactive decision support tools

Understanding species-habitat relationships is vital to successful conservation, but the tools used to communicate species-habitat relationships are often poorly suited to the information needs of conservation practitioners. Here we present a novel method for translating a statistical species-habitat model, a regression analysis relating ring-necked pheasant abundance to landcover, into an interactive online tool. The Pheasant Habitat Simulator combines the analytical power of the R programming environment with the user-friendly Shiny web interface to create an online platform in which wildlife professionals can explore the effects of variation in local landcover on relative pheasant habitat suitability within spatial scales relevant to individual wildlife managers. Our tool allows users to virtually manipulate the landcover composition of a simulated space to explore how changes in landcover may affect pheasant relative habitat suitability, and guides users through the economic tradeoffs of landscape changes. We offer suggestions for development of similar interactive applications and demonstrate their potential as innovative science delivery tools for diverse professional and public audience

Investigation of the international comparability of population-based routine hospital data set derived comorbidity scores for patients with lung cancer

Introduction: The International Cancer Benchmarking Partnership (ICBP) identified significant international differences in lung cancer survival. Differing levels of comorbid disease across ICBP countries has been suggested as a potential explanation of this variation but, to date, no studies have quantified its impact. This study investigated whether comparable, robust comorbidity scores can be derived from the different routine population-based cancer data sets available in the ICBP jurisdictions and, if so, use them to quantify international variation in comorbidity and determine its influence on outcome. Methods: Linked population-based lung cancer registry and hospital discharge data sets were acquired from nine ICBP jurisdictions in Australia, Canada, Norway and the UK providing a study population of 233 981 individuals. For each person in this cohort Charlson, Elixhauser and inpatient bed day Comorbidity Scores were derived relating to the 4–36 months prior to their lung cancer diagnosis. The scores were then compared to assess their validity and feasibility of use in international survival comparisons. Results: It was feasible to generate the three comorbidity scores for each jurisdiction, which were found to have good content, face and concurrent validity. Predictive validity was limited and there was evidence that the reliability was questionable. Conclusion: The results presented here indicate that interjurisdictional comparability of recorded comorbidity was limited due to probable differences in coding and hospital admission practices in each area. Before the contribution of comorbidity on international differences in cancer survival can be investigated an internationally harmonised comorbidity index is required