This post was originally published as a Newsletter article from ShARM (Shared Ageing Research Models)

Scientists using animals in research have a responsibility to ensure that the studies are appropriately designed, conducted, analysed and reported so that they impartially and robustly answer the question they are intended to, and truly add to the knowledge base. Unfortunately there is a large body of evidence, including from the NC3Rs, to show that many animal studies are flawed and that this has significant implications in terms of reproducibility and the translation of findings into potential clinical benefits.

At the NC3Rs we have developed a new exciting online tool which is designed to tackle the problem – the Experimental Design Assistant (EDA).

The EDA is an online resource to help researchers improve the design and analysis of animal experiments. It complements the ARRIVE guidelines for reporting animal research and was developed in collaboration with an expert working group of in vivo scientists and statisticians from academia and industry, and Certus Technology, a team of software designers specialised in innovative software for the life sciences.

The resource is aimed at scientists who use animals in their research. Benefits include advice and feedback on the experimental plans, along with a range of functionalities providing support with the randomisation and blinding of the experiment, as well as sample size calculation. It equips researchers with practical information and knowledge, allowing them to determine the most efficient design for their experiment and understand the implications of choosing a particular design.

A central feature of the EDA is the use of a formal, diagrammatic notation to describe experimental plans and analyses. This is an approach that has been adopted by many technical disciplines to improve communications. It allows the design of an experiment to be recorded clearly and unambiguously and EDA diagrams help convey experimental plans efficiently.

The EDA is not designed to replace specialist statistical advice. For researchers who have limited access to statistical support, the feedback and advice provided by the system will be particularly pertinent, as it will provide users with information, which is specific to the experiment they are planning. For all scientists involved in the research process, the EDA is also extremely useful as a communication tool, for example, between students and their supervisors, or with colleagues and collaborators. These visual representations are far more explicit than the cursory text description traditionally included in grant applications, ethical review submissions or journal publications. Our goal is to integrate the EDA into the scientific process to facilitate better peer review of experimental plans.

We look forward to hearing what you think about the EDA. The feedback has been fantastic but this is a very new and novel system, which has to evolve according to the needs of the research community. Please contact us at eda@nc3rs.org.uk, your feedback will help us ensure that the system improves and evolves according to your needs.

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We know that cells are the building blocks of our bodies. But they are not like inert wooden blocks. They are complicated tiny machines that communicate with each other to make sure that the many simultaneously occurring processes in our bodies are in order.

Stem cells participate in many of these cellular conversations, and a particularly important dialogue is the one that turns certain stem cells into specific types of cells, while keeping others in stem cell state. Retaining stem cells ensures that our bodies can fix the wear and tear of our organs and tissues in future.

So how exactly do cells talk to each other? They send signals using molecules. Setting up a gradient of a certain molecule is one way cells send signals. With many molecules on the surface of cells in one area, and gradually less molecule across space, cells can receive a range of different messages depending on the density of the molecule.

Researchers from the Hubrecht Institute in Utrecht and UMC Utrecht visualized stem cell signaling in the gut for the first time. Their question was how one of the main growth signals in the gut sets up a gradient.

They used artificially made mini-guts (read more about organoids here: http://www.nature.com/news/the-boom-in-mini-stomachs-brains-breasts-kidneys-and-more-1.18064) to study this process.

The image above shows a part of this mini-gut called the crypt, which are the protrusions that give our guts high surface area to allow absorption of nutrients. In panel A, the protrusions are allowed to grow normally. In panels B, C and D, the signal that allows the cells to divide and form the gradient is blocked. Since the signal can’t spread the protrusion can’t grow.

Learning how stem cells signal is important for developing methods to help our bodies regenerate, and to stop this process when it goes awry in the formation of tumours.

Further reading:

http://www.hubrecht.eu/tissue-regeneration-in-the-gut-visible-for-first-time/

Credit

Farin, H. F., Jordens, I., Mosa, M. H., Basak, O., Korving, J., Tauriello, D. V., … & Clevers, H. (2016). Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature.

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One Postdoctoral position is available at the Institute of Biotechnology, University of Helsinki, Finland, in the laboratory of Dr. Nicolas Di-Poi. Our laboratory (http://www.biocenter.helsinki.fi/bi/di-poi/) is studying the development, evolution and regeneration of craniofacial and neural tissues in non-mammalian model organisms that reliably inform human diseases. This is a new and exciting research field, with the goal to provide an evolutionary context to the key signaling pathways of biological regeneration.

The research projects include complementary state-of-the-art methods, including cellular biology, molecular embryology, developmental genetics and phylogenomics, and they offer an interdisciplinary environment for research training (see e.g., Science 339:78-81 (2013), EvoDevo 4:19 (2013), Nature 464:99-103 (2010)). The exact topic of research projects will be discussed in detail during interview.

The successful candidate will have an excellent PhD Degree in Biology and a proven record of excellence in Neuroscience and/or Evo-Devo research. In addition, the Postdoctoral candidate will have a genuine interest in multidisciplinary research and a previous experience of work with central nervous system, brain disease models and/or non-mammalian vertebrate models.

The Institute of Biotechnology (BI) at the University of Helsinki (ranked in the world’s top 100 Universities) is an independent research institute with a mission to increase knowledge in biotechnology and multidisciplinary bioscience and use this for the benefit of society. BI has research programs in Molecular Cell Biology, Developmental Biology, Genome Biology, and Structural Biology & Biophysics. BI offers state-of-the-art facilities in imaging, model organisms, proteomics, genomics, bioinformatics and crystallography. For more information, visit the website: http://www.biocenter.helsinki.fi/bi/.

To apply, please send (in a single pdf document) a cover letter describing your previous research and motivation, your detailed CV including a list of publications, as well as contact information for at least 2 references (including PhD supervisor) to Dr Nicolas Di-Poi (nicolas.di-poi@helsinki.fi). The salary is defined in accordance with the University salary system for teaching and research personnel. The position could start as early as September 2016 or as agreed with the selected candidate. The deadline for the applications is July 31, 2016, but candidates will be considered until the position is filled.

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Post Doctoral Fellowship(s)

‘Deciphering the link between adhesion and pluripotency,”

University of Copenhagen, Denmark

The Danish Stem Cell Center (http://danstem.ku.dk/) is seeking one or two postdoctoral fellow(s) to join the Brickman Lab/DanStem & Michael Lund Nielsen Lab/Centre for Protein Research (CPR)

The post-doctoral positions will initially be supported by a grant from the Lundbeck Foundation and seek to probe the link between pluripotency and cell-cell adhesion. They will follow up recent observations on that focus the gene regulatory network (GRN) sustaining pluripotency on adhesion. The first project, based in the Brickman lab, will follow up the means by which the GRN regulates adhesion and the second, in the Nielsen lab, will focus on deciphering the nature of the adherns junction complex in pluripotent vs differentiating cells

Project description

Embryonic Stem Cells (ESCs) are genetically normal, immortal cell lines with the capacity to become any cell type in the future organism. This project will explore the role of cell-cell adhesion supporting a pluripotent state, both in vivo and in vitro. We recently found that the evolutionarily conserved gene rergulatory network (GRN) downstream of one of the central pluripotency regulators, Oct4, was primarily concerned with regulating cell-cell adhesion (Livigni et al Curr Biol. 2013). Moreover, we found that force expression of E-cadherin could partially block differentiation in response to reduced Oct4 levels in both ESCs and embryos.  These projecst will follow up these observations on at a transcriptional and post-transcriptional level, using a combination of genetic models and mass spectrophotometry.

Qualifications

• Candidates should have experience in embryonic stem cells, developmental biology (mouse and Xenopus) or mass spectrophotometry
• Must be eligible for and prepared to write fellowship applications with in 12 months of being in the laboratory
• Experience with bio-informatics would be considered an advantage

Terms of salary, work, and employment

The employment is for 3 years and is scheduled to start October 1^st or upon agreement. Place of work: DanStem and CPR, University of Copenhagen, Blegdamsvej 3B, Copenhagen. Terms of employment are in accordance with the collective agreement between the Danish Government and the Danish Confederation of Professional Associations

Questions Contact professor Joshua Brickman; Joshua.brickman@sund.ku.dk

Application must include:

• Motivation letter

• Curriculum vitae incl. education, experience, previous employments, language skills and other relevant skills

• Copy of diplomas/degree certificate(s)

• Other information for consideration, e.g. list of publications (if any), letters of recommendationThe University of Copenhagen welcomes applications from all qualified candidates regardless of personal backgroundHow to apply:

• The application, in English, must be submitted electronically. Go to: http://danstem.ku.dk/join/jobs/

The application will be assessed according to the Ministerial Order no. 284 of 25 April 2008 on the Appointment of Academic Staff at Universities

Application deadline: July 10^th 2016

Only applications received in time and consisting of the above listed documents will be considered

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Research assistant position for subsequent appointment as PhD fellow

to the project Deciphering the link between adhesion and pluripotency

The Danish Stem Cell Center (http://danstem.ku.dk) at Faculty of Health & Medical Sciences, University of Copenhagen seeks a Research assistant subsequent appointed as PhD fellow

Job description

Embryonic Stem Cells (ESCs) are genetically normal, immortal cell lines with the capacity to become any cell type in the future organism. This project will explore the role of cell-cell adhesion supporting a pluripotent state, both in vivo and in vitro. We recently found that the evolutionarily conserved gene regulatory network (GRN) downstream of one of the central pluripotency regulators, Oct4, was primarily concerned with regulating cell-cell adhesion (Livigni et al Curr Biol. 2013). Moreover, we found that forced expression of E-cadherin could partially block differentiation in response to reduced Oct4 levels in both ESCs and embryos. This project will follow up these observations. We seek to understand how Oct4 regulates cell-cell adhesion, both at a transcriptional and post-transcriptional level. The project will explore how Oct4 regulates E-cadherin dynamics and how Oct4 targets regulate signaling.

Qualifications

• Master’s degree in biology, biochemistry, medicine or human biology, or similar, and a general understanding of developmental and/or stem cell biology
• Strong motivation and very good scientific skills are essential
• Publications and practical experience are an advantage
• Good communication skills oral and written

Terms of salary, work, and employment

The position as research assistant is for 1 year and as PhD fellow for 3 years. Start October 1^st 2016 or upon agreement.

The employment as a PhD student is conditioned upon a positive assessment of the candidate´s research performance and enrolment in the Graduate School at the Faculty of Health and Medical Sciences. The PhD study must be completed in accordance with the ministerial orders from the Ministry of Education on the PhD degree and the University´s rules on achieving the degree.

Work place: DanStem, University of Copenhagen, Blegdamsvej 3B, Copenhagen. Terms of employment accord to the agreement between the Ministry of Finance and The Danish Confederation of Professional Associations on Academics in the State

Questions Contact Professor Joshua Brickman joshua.brickman@sund.ku.dk.

The application must include

• Cover Letter, detailing your motivation and background for applying for the specific PhD project
• CV
• Diploma and transcripts of records (BSc and MSc)
• Other information for consideration, e.g. list of publications (if any),
• Full contact details of 1-3 professional referees

The application, in English, must be submitted electronically. Go to: http://danstem.ku.dk/join/jobs/

The application will be assessed according to the Ministerial Order no. 284 of 25 April 2008 on the Appointment of Academic Staff at Universities

The University of Copenhagen welcomes applications from all qualified candidates regardless of personal background

Application deadline: July 10^th 2016

Only applications received in time and consisting of the above listed documents will be considered

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Emergence of functional polarity in a tubular epithelium

Applications are invited for a PhD project in the laboratory of Dr. Barry Denholm in the School of Biomedical Sciences at Edinburgh University, UK.

This exciting scholarship scheme provides a unique framework for postgraduate research students to undertake research training and development, together with experience of teaching and mentoring in an international context. Each scholarship covers the UK/EU rate of tuition fee as well as a stipend of £14,296 per annum. Subject to satisfactory progress, the scholarships are awarded for 4 years.

For more information: http://www.ed.ac.uk/biomedical-sciences/postgraduate-studying/phd-research/university-of-edinburgh-career-development-phd/emergence-of-functional-polarity-in-a-tubular-epit

To apply for the position:

http://www.ed.ac.uk/biomedical-sciences/postgraduate-studying/phd-research/university-of-edinburgh-career-development-phd

For informal enquires please contact: Barry.Denholm@ed.ac.uk

Applications due by Friday 17^th June

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May was most notable for the departure of the Node’s brilliant Community Manager, Cat Vicente. Cat said her goodbyes here, but we’d like to take this opportunity to thank her again for her great work over the last 3 years.

And Cat still found time to keep posting right up to the end – both with the latest in our Forgotten Classics series, and her reflections on the inspiration behind Eric Satie’s piano composition ‘Desiccated Embryos‘.

In Cat’s absence, the community has been fantastic at keeping the Node full of content – we’ve had a particularly busy month on the jobs page, and lots of other really interesting content. Thanks to all of you for posting!

Research

Lei wrote about her recent work on the lineage and connectivity of mouse germ cell cysts – and the similarities and differences with Drosophila  oogenesis.

Elizabeth posted on sex determination in flies, and how this translates into sexual dimorphism in body size and in gut physiology.

Hernan and colleagues recently published a software platform for quantitative analysis of tissue organisation. He told us more about the pipeline and its potential applications.

Meetings

Erin and Matthias were at the Inaugural Sainsbury Lab Symposium on Induced Plant Development. They tell us all about the latest advances in this fascinating field.

The latest Company of Biologists’ Workshop “Metabolism in Development and Disease” brought together a diverse group of researchers, including Carlos and Patricia – who give us their reflections on the meeting.

Development is hosting a meeting this September, focussing on the use of stem cell technologies to understand human development. Find out more here, and register soon to secure your place!

Also on the Node

The recent Kumamoto earthquakes devastated the Institute of Molecular Embryology and Genetics. Find out about their recovery efforts.

Nestor got involved with the recent ‘Science Saturday‘ event with The Rockefeller University’s outreach team.

And the SDB is offering the John Doctor Education Prize for the best video explaining ‘Induction’ to a lay audience. Get your thinking caps on and enter for the chance to win $1000!

We hope you enjoy these and all the other posts featured on the Node in the past month. June sees the arrival of our new Community Manager – find out more in a couple of weeks!

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Disease Models & Mechanisms invites you to submit original research for consideration for an upcoming Special Collection ‘Neurodegeneration: From Models to Mechanisms to Therapies‘. This ongoing collection will focus on mechanistic insights into neurodegenerative diseases using model systems, with an emphasis on key translational advances made in recent years. This collection will be launched with a dedicated issue that will benefit from high visibility to basic researchers through to clinicians interested in understanding and treating neurodegenerative diseases.

Guest editors of the launch issue are:

Aaron Gitler (Stanford University)

James Shorter (University of Pennsylvania)

Submissions should describe original research in the form of a Research or Resource article. Find out more at dmm.biologists.org or send us a presubmission enquiry by email.

SUBMISSION DEADLINE 13th September 2016

SUBMIT HERE

Key benefits of publishing in DMM include:

High visibility and impact (2014 Impact Factor 5)
Open Access (CC-BY licence) and PMC deposition
Rapid peer review and publication
Indexed in Medline, ISI and Scopus
Not-for-profit publisher

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Here are the highlights from the current issue of Development:

A new paradigm for Wnt/β-catenin signalling

The Wnt/β-catenin signalling pathway is a key pathway involved in a myriad of developmental processes, from body axis patterning to cell migration and fate specification. The role of the Wnt pathway is to regulate transcription of specific target genes, and it has long been thought that the driving event for this is the recruitment of β-catenin to specific gene loci on the chromatin. Now, however, on p. 1914, Stefan Hoppler and colleagues provide in vivo evidence that, rather than β-catenin recruitment, it is instead the context-specific events that occur subsequent to β-catenin binding that enable gene-specific regulation. The authors use ChIP-seq to show that β-catenin is recruited to many genomic loci in Xenopus early embryonic development, while RNA-seq reveals that many of these β-catenin-bound loci are not transcriptionally regulated by Wnt signalling in this context. Instead, the transcriptional response depends on the presence or absence of additional mechanisms, for example FGF and BMP signalling. This important study advances the current understanding and interpretation of how Wnt/β-catenin signalling operates to regulate gene-specific transcription in different developmental contexts.

Oocyte maturation: cAMP and PKA called into question

The production of a mature vertebrate egg is a lengthy process in which the developing oocyte undergoes meiotic arrest followed by a long incubation period, before finally resuming meiosis in preparation for ovulation. The prevailing dogma in the field has been that, in Xenopus, meiotic arrest is released through a drop in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity, which occurs following exposure to progesterone. In this issue (p. 1926), Khaled Machaca and colleagues provide evidence that challenges this dogma, as they demonstrate that no change is detectable in cAMP levels and PKA activity as meiotic arrest is released in the Xenopus oocyte. The authors use in vivo reporters to detect cAMP and PKA levels in real time in single cells, and show that there is no correlation between the rate of meiotic resumption and levels of cAMP or PKA inhibition. Furthermore, the authors develop conditions in which meiotic release is indeed possible in the presence of high levels of cAMP. These surprising results provide a new model for the release of meiotic arrest in the Xenopus oocyte and suggest that this phenomenon occurs through a positive signal downstream of the progesterone receptor that overcomes cAMP/PKA inhibition of meiosis resumption.

Uncovering the mechanisms of Müller glia activation

Radial glia cells in the central nervous system serve as an important source of progenitor cells for generating a range of neural cell types. Retinal regeneration in vertebrates relies on a specialised type of radial glia, called Müller glia, which are normally quiescent but can be stimulated to undergo proliferation and differentiation in order to generate new neurons. In this issue (p. 1859 and p. 1874), two studies shed light on the molecular mechanisms that regulate Müller glia activation and proliferation in response to injury and in different vertebrate species.

In the first study, Andy Fischer and colleagues investigate the role of mTor signalling in the formation of Müller glia-derived progenitor cells (MGPCs) in the chick retina. The authors use NMDA to induce a cytotoxic response, and observe that mTor signalling is transiently activated upon activation of Müller glia cells. Inhibition of mTor signalling in vivo prevents the proliferation of the Müller glia cells and blocks the regenerative response. Using a range of inhibitors and readouts, the authors show that mTor signalling is required for the proliferation of MGPCs. The authors further show that mTor signalling is activated in response to insulin, IGF1 and FGF2, and that this response is most likely independent of the MAPK pathway.

In the second study, Joachim Wittbrodt and colleagues look at the role of a single factor, Atoh7, in directing Müller glia cells to proliferate and differentiate in the absence of an injury. The authors use a fluorescent transcriptional reporter of atoh7 to demonstrate atoh7 expression in proliferating Müller glia cells after retinal injury in medaka. The authors then use an inducible system to activate expression of atoh7 in vivo in the Müller glia cells, and find that this is sufficient to drive the cells to re-enter the cell cycle and undergo proliferation. Forced expression of atoh7 in these cells activates Notch signalling, and indeed the authors show that overexpression of the Notch intracellular domain can recapitulate the effects seen by atoh7 overexpression. Importantly, not only did atoh7 overexpression in Müller glia lead to cell cycle re-entry and proliferation, but the authors also observed the formation of neurogenic clusters and subsequent de novo neurogenesis following atoh7 overexpression in these cells. Together, these two studies bring together novel and exciting findings regarding the regulation of Müller glia proliferation following injury and the subsequent regenerative response.

PLUS…

Cell fate control by pioneer transcription factors

Recent studies have shown that pioneer factors are crucial for cellular reprogramming and that they are implicated in the marked changes in gene regulatory networks that occur in various cancers. Here, Makiko Iwafuchi-Doi and Kenneth Zaret provide an overview of the contexts in which pioneer factors function, how they can target silent genes, and their limitations at regions of heterochromatin. See the Development at a Glance poster article on p. 1833

Circular RNAs: analysis, expression and potential functions

In early 2012, circular RNA (circRNA) was shown to be a transcriptional product in thousands of human and mouse genes and in hundreds of cases constituted the dominant RNA isoform. Subsequent studies revealed that the expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across the eukaryotic tree of life, suggesting important functions for these molecules. Here, Steven Barrett and Julia Salzman describe major advances in the field of circRNA biology, focusing on the regulation of and functional roles played by these molecules. See the Primer on p. 1838

The regulation and plasticity of root hair patterning and morphogenesis

Root hairs are highly specialized cells found in the epidermis of plant roots that play a key role in providing the plant with water and mineral nutrients. Many studies have shown that the fate of root epidermal cells, which differentiate into either root hair or non-hair cells, is determined by a complex interplay of intrinsic and extrinsic cues. Here, Wolfgang Schmidt and colleagues review these studies and discuss recent evidence suggesting that environmental information can be integrated at multiple points in the root hair morphogenetic pathway and affects multifaceted processes at the chromatin, transcriptional and post-transcriptional levels. See the Review on p. 1848

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Earlier this month, two papers were published (from the Brivanlou and Zernicka-Goetz labs) that reported in vitro systems to study development of the human embryo through implantation stages. These experiments have kept human embryos developing for longer than any previous work, and close in on the 14-day limit imposed by many governmental and regulatory bodies. 14 days were set as a limit (at a time when it was technically impossible to keep embryos alive this long) because this is the stage at which the primitive streak emerges – the time at which embryos can no longer split or fuse – and has been considered by some to be the stage at which a ‘morally significant individual’ comes into being (see this discussion in Nature). But now that we can culture human embryos up to this point, is this 14-day rule still appropriate? Would it be ethically ‘wrong’ to try and study human gastrulation in culture, or do the potential advances in our understanding of human development (along with their possible therapeutic implications) outweigh any ethical concerns involved? This month we are asking:

Should the 14 day limit on human embryo culture remain in place, or should it be extended or even dropped?

Share your thoughts by leaving a comment below! You can comment anonymously if you prefer. We are also collating answers on social media via this Storify. And if you have any ideas for future questions please drop us an email!

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