This Press Release from the University of Oregon was originally posted on Eurekalert.

EUGENE, Ore. March 28, 2017

University of Oregon biologists have figured out how zebrafish perfectly regenerate amputated fins with a precisely organized skeleton.

Adult zebrafish fins, including their complex skeleton, regenerate exactly to their original form within two weeks after an amputation. The process, they found, is driven by clusters of specialized skin cells that migrate over reforming bones, known as rays, and escort bone cells into the right positions to form individual bones of a branched skeleton.

These skin cells produce a protein called Sonic hedgehog, which interacts with bone-building cells called osteoblasts to promote bone patterning during fin regeneration.

“The orderly reconstruction of zebrafish fins is amazing to see,” said Kryn Stankunas, a professor in the Department of Biology and member of the Institute of Molecular Biology. “Zebrafish fins, which are akin to our limbs, regenerate perfectly. The zebrafish bony rays re-branch just like the original structure. This would be like losing your arm and watching it progressively regenerate complete with a hand and fingers — all the bones restored in their original configuration.”

The findings will not lead to humans re-growing lost limbs, Stankunas said, but such advances in understanding the fundamental processes of regeneration in related vertebrate organisms will inform innovative and targeted therapeutic strategies to improve the repair of broken bones.

“The mechanism — how the skin and bone cells dynamically move and interact using the signaling pathway — is elegant and unexpected, broadening the project’s impact on regenerative medicine,” Stankunas said.

Hedgehog signaling, he added, is also linked to several human cancers.

“The zebrafish fin provides a tractable and simple model to decipher mechanisms of regenerative skeletal patterning,” the researchers wrote in their paper in the March 28 issue of the journal Development, a publication of the non-profit Company of Biologists in the United Kingdom.

Benjamin E. Armstrong, who earned a doctorate in biochemistry in 2016, was the study’s lead author. Scott Stewart, a research professor in the Institute of Molecular Biology, co-directed the project.

The research team used genetically modified zebrafish that produces a fluorescent protein that helps identify the subset of skin and bone cells that respond to Hedgehog signals. The fluorescent marker appears green under the microscope until illuminated with ultraviolet light to photo-convert the green protein to red.

This photo-conversion method revealed that repairing skin cells collectively move towards the tip of the regenerating fin. At particular times, Sonic hedgehog is induced in skin cell clusters that then split into two pools. Simultaneously, the skin cells activate a Hedgehog response in adjacent osteoblasts. That drives them to associate with the skin cells and co-migrate into split groups. The now separated bone cells continue to regenerate replacement bone, but now forming two rays instead of one – a branched skeleton.

“We could see that the bone cells responding to the skin-produced Sonic hedgehog become physically attached to the migrating skin cells”

“We could see that the bone cells responding to the skin-produced Sonic hedgehog become physically attached to the migrating skin cells,” Stewart said. “The pathway is quickly turned off but the now split groups of bone cells will then form two separated mature bony rays connected at a branch point.”

To define the functions of the Hedgehog signaling pathway, the researchers used a new chemical inhibitor, BMS-833923, to turn off Hedgehog signaling in their experimental fish. With Hedgehog blocked, the skin and bone cells failed to interact, and the fin regenerated with stick-like rays rather than forming a branched skeleton.

The inhibitor used in the study is in clinical trials against some forms of human cancers, but it had not been used in zebrafish. The Hedgehog pathway is most associated with basal cell carcinoma and medulloblastoma, Stankunas said.

“The Hedgehog response is absolutely required for branching and not essential for any other aspect of regeneration,” Stankunas said. “Instructions that drive the branching come from the skin cells moving into two groups and likewise dividing the osteoblasts. This is new information. It is the traffic pattern generated by the signaling that regenerates the fin. It is skin and bone working together.”

###

Astra Henner, lab manager and research assistant, was the fourth co-author of the paper.

The National Institutes of Health funded the project through a training grant to Armstrong and research grants to Stankunas and Stewart.

Source: Kryn Stankunas, associate professor of biology, 541-346-7416, kryn@uoregon.edu

Note: The UO is equipped with an on-campus television studio with a point-of-origin Vyvx connection, which provides broadcast-quality video to networks worldwide via fiber optic network. There also is video access to satellite uplink and audio access to an ISDN codec for broadcast-quality radio interviews.

Links

Development Paper: http://dev.biologists.org/content/144/7/1165

About Stankunas: http://molbio.uoregon.edu/stankunas/

About Scott Stewart: http://molbio.uoregon.edu/stewart/

Department of Biology: http://biology.uoregon.edu/

Institute of Molecular Biology: http://molbio.uoregon.edu/

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This is a 3 year Fixed Term contract

We are seeking an enthusiastic, highly motivated and productive postdoctoral research associate to join a BBSRC-funded research project investigating the formation of primordial follicles in the developing mammalian ovary, led by Dr Andrew Childs, Lecturer in the Department of Comparative Biomedical Sciences (Royal Veterinary College, University of London, UK).

The successful candidate will use a combination of in vitro and in vivo techniques to investigate how growth factor signalling converges with the transcriptional machinery in fetal ovarian somatic cells to regulate the timing and extent of follicle assembly in the mammalian ovary. The post-holder will be an active member of the research team, contributing to experimental design, data collection, analysis and dissemination, and student supervision.

The successful candidate should have a PhD in reproductive or developmental biology (or a closely related discipline). They will be proficient in a range of research techniques, including molecular biology, immunohistochemistry, and cell or organ culture. Excellent organisational and communication skills are essential, as is the ability to work independently and as part of a team. Experience of Chromatin Immunoprecipitation (ChIP), large scale transcriptomic analyses, and/or working with animal models would be advantageous.

Applicants should be available to start no later than 1^st May 2017.

Prospective applicants are encouraged to contact Dr Andrew Childs (Lecturer, Comparative Biomedical Sciences) at achilds@rvc.ac.uk.

For more informaiton, and to apply, please visit: https://jobs.rvc.ac.uk/Vacancy.aspx?ref=CBS-0072-17

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Here are the highlights from the new issue of Development:

Making thalamic neurons in vitro

In recent years, methods to derive multiple differentiated neuronal types from embryonic stem cells (ESCs) in vitro have been reported. Three-dimensional (3D) culture methods not only support differentiation but also recapitulate spatial aspects of brain development.

Such studies were pioneered by the late Yoshiki Sasai, and on p. 1211, his colleagues Atsushi Shiraishi and Keiko Muguruma adapt the original 3D culture conditions – which supported rostral neural fate – to derive thalamic neurons from mouse ESCs for the first time. They find that addition of insulin and FGF pathway inhibitors can specify caudal forebrain identity, and that subsequent treatment with BMP7 can promote thalamic fate. Within the neuroepithelial-sphere structure that forms in these cultures, there is significant spatial organisation: early progenitors are found by the apical cavity, while more mature cell types are located towards the outside, and the spheres display rostral-caudal regionalisation. The derived neurons can extend axons that – both in culture and in transplantation experiments in vivo – show projection patterns consistent with thalamic identity. Not only does this work allow the generation of thalamic neurons in vitro, but it also provides insights into the signalling mechanisms regulating thalamus development in vivo.

Bone regeneration in the fish fin

Zebrafish can fully regenerate their fins, a process that involves the reconstitution and patterning of multiple tissue types. New bone is regenerated via the de-differentiation, proliferation and re-differentiation of osteoblasts, which occur in a spatially organised manner to recapitulate the original fin shape and skeleton. How skeletal patterning – including outgrowth and bifurcation of new rays – is controlled in this context is incompletely understood, though is thought to involve Hedgehog signalling.

Kryn Stankunas, Scott Stewart and colleagues (p. 1165) now define distinct roles for the two Hedgehog ligands expressed in the regenerating fin: shha and ihha. shha is expressed in epidermal cells immediately adjacent to osteoblasts at the site of ray branching, and is required for branching. Intriguingly, it appears to act at short range, through direct contact with osteoblast progenitors via cellular protrusions, to promote splitting of the ray through cell movements. ihha, on the other hand, is expressed in the osteoblasts, where it promotes differentiation via a non-canonical signalling route. These data clarify the role of Hedgehog signalling in ray regeneration and shed light onto the mechanisms underlying skeletal patterning in regenerative contexts.

Turning off translation in germ cells

Stem cell quiescence has been reported in many systems, and typically involves the slowing or stalling of the cell cycle and low transcriptional activity. Primordial germ cells (PGCs) of sea urchin are known to enter a quiescent state prior to gastrulation, before re-activating later in development.

Now (p. 1201), Gary Wessel and co-workers show that this quiescence also involves a significant reduction in translational activity. Two potential mechanisms are uncovered. Firstly, Nanos2, which is expressed specifically in PGCs, binds to and downregulates the critical translation factor eIF1A. Secondly, mitochondrial number and activity is low in PGCs, which might induce a switch to glycolytic metabolism and hence an acidification of the cytoplasm. Increasing cellular pH promotes translational activity specifically in PGCs. This work raises many intriguing questions. For example, how is translational activity re-activated at later stages? How are the metabolic changes in PGCs orchestrated? How general might this be in quiescent stem cell populations? Thus, the identification of this previously unrecognised phenomenon of transient translational quiescence in sea urchin PGCs opens up many new avenues for investigation.

Timing is key to turn root into shoot

Plant cells show remarkable plasticity. For example, lateral roots can be converted into shoots by supplementing the culture medium with cytokinin, which induces shoot fate. When properly controlled, this conversion does not involve callus formation, and so allows a detailed analysis of the processes directing the switch of organ identity.

Using this system, Philippe Rech and colleagues (p. 1187) find that competence for root-to-shoot conversion is restricted to a narrow time window of lateral root development, coinciding with the stage at which the stem cell niche is formed in the new root. Furthermore, conversion can be reversed during this period – auxin treatment can switch the tissue back to a root – confirming that organ identity is not immediately fixed. Importantly, the authors provide evidence that root-to-shoot conversion does not occur via dedifferentiation, but rather via a direct transdifferentiation process. Transcriptome and methylome profiling provide insights into the gene expression and epigenetic changes occurring during conversion. This atypical mode of organogenesis may lead to novel methods for the vegetative multiplication of valuable plant cultivars.

How cell-cell contact defines fate

In many systems, stem cell fate is regulated by Notch signalling. One such example is the Drosophila midgut, where intestinal stem cells (ISCs) can divide either asymmetrically, generating a Notch-positive enteroblast (EB) and a Notch-negative ISC, or symmetrically, either forming two EBs or two ISCs. But what determines the outcome of ISC division, and how does Notch signalling influence this?

Joaquín de Navascués, Jordi Garcia-Ojalvo and co-workers address this question on p. 1177 using a combination of experimental and modelling approaches. Their key insight is that contact area between the two daughter cells correlates with cell fate: where the contact area is small, both cells tend to remain ISCs, where it is larger, one or both cells differentiate. Since Delta-Notch signalling involves direct contact between the two cells, the area of contact can influence the effective signalling threshold. Both the computational and experimental analyses support the idea that the pattern of cell fates following ISC division can be at least partly explained by variability in cell contact area, and hence in the levels of Notch-Delta signalling between the two daughter cells. That such a model might also apply in other stem cell systems is an intriguing possibility.

Spindle orientation: a question of complex positioning

Dan Bergstralh and colleagues discuss key features of the spindle-orientating complex and reviews how this complex is regulated and localized to allow correct mitotic spindle orientation.

Using synthetic biology to explore principles of development

Jamie Davies explores how synthetic biology-based approaches have been used to explore the principles underlying patterning, differentiation and morphogenesis during development.

Featured movie

In our featured movie, Naoto Ueno, Makoto Suzuki and colleagues show how two patterns of calcium fluctuation in the Xenopus neural plate control epithelial folding, with extracellular ATP and N-cadherin also participating in calcium-induced apical constriction.

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Two years postdoctoral position at INSERM U1065 (C3M)-team 3, Nice, France

on the study of cell death of motor neurons. Starting ASAP.

A two-year postdoctoral position starting ASAP, funded by the French National Research Agency is available in the ‘Metabolic control of cell death’ team (INSERM U1065), located at the Archet Hospital in Nice, south of France.

(http://www.unice.fr/c3m/index.php/research-teams/jean-ehrland-ricci/).

Title: How mitochondrial dysfunction leads to motor neuron disease?

Recently, in close collaboration with Pr. Paquis-Flucklinger, we showed that mitochondrial dysfunction can have a causative effect in motor neuron degeneration. We reported a large family with a mitochondrial myopathy associated with motor neuron disease and cognitive decline looking like frontotemporal dementia (FTD). We identified a missense mutation (p.Ser59Leu) in the HCHD10 gene coding for a mitochondrial protein whose function was unknown (Genin EC et al. EMBO Mol Med 2015 Dec 14:58-72).

We and others reported CHCHD10 mutations in patients with dementia-amyotrophic lateral sclerosis (FTDALS) and familial or sporadic pure ALS.

Project: Amyotrophic lateral sclerosis is a devastating disease affecting upper and lower motor neurons leading to progressive failure of the neuromuscular system and death from respiratory failure. Among all factors involved in ALS pathogenesis, mitochondrial dysfunction has always been recognized as a candidate major player. However, whether mitochondria have a causative role in ALS has been always debated. Our results open a new field to explore the pathogenesis of motor neuron disease by showing that mitochondrial dysfunction may be at the origin of some of these phenotypes.

Our goals are:

(i) to better characterize the role of the CHCHD10 protein on cell death and to compare the effects of

different CHCHD10 mutations leading to different clinical phenotypes,

(ii) to understand how CHCHD10 mutations lead to motor neuron cell death by generating specific human cellular (IPS) and characterizing in vivo models,

Candidate profile:

The candidate should hold a PhD in physiology, pharmacology or related disciplines and have previous expertise in cell culture / characterization of primary neuronal cells.

Practice or knowledge of in vivo animal experimentation techniques as well as in cellular and molecular biology techniques would be appreciated.

How to apply? 

Candidates should send a curriculum vitae with publication list, a short summary of research achievements, and the names and email addresses of at least two references to ricci@unice.fr

Dr. J-E Ricci
INSERM U1065, C3M
Directeur de l'équipe- 3
Batiment Universitaire Archimed
151 Route de Ginestière
BP 2 3194
06204 NICE Cedex 3
Tel 33+ (0)4 89 06 43 04
Fax 33+(0)4 89 06 42 21
Email: ricci@unice.fr

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A postdoctoral fellow position is available in the laboratory of Dr. Paul Burridge in the Department of Pharmacology and the Center for Pharmacogenomics at Northwestern University Feinberg School of Medicine, Chicago, IL.

Successful candidates will participate in NIH- and AHA-funded projects to study the application of human induced pluripotent stem cells (hiPSCs) in predictive medicine. Our goal is to develop the next generation of tools for predicting drug responses and validating SNPs to allow the use of genomic information in precision medicine and drug discovery. With these data, we will probe the mechanisms of action of a range of drugs to provide individualized treatment selections and regimens to improve drug efficacy and eliminate off-target toxicity.

We are looking for highly motivated and creative candidates with an interest in studying SNPs and molecular mechanisms involved in chemotherapy-induced toxicity (primarily cardiovascular) of tyrosine kinase inhibitors and monoclonal antibodies using patient-specific hiPSC-derived cells. Projects will utilize a wide range of state-of-the-art techniques such as genome editing, high-content imaging, high-throughput drug screening, electrophysiology, whole genome sequencing, RNA-seq, and eQTL. The Burridge Laboratory is stably supported by NIH, AHA, and institutional funding. More about the lab can be found here: http://burridgelab.com/

Qualifications: PhD or MD/PhD degree (either about to graduate or graduated within the last year) and a strong record of peer-reviewed publications including first author publications are essential. Expertise in several of the following areas is required: mechanisms of chemotherapy agents and toxicity, disease modeling, pharmacogenomics, WGS, RNA-seq, eQTL, GWAS, bioinformatics, CRISPR-based genome editing, high-throughput biology and drug screening, electrophysiology, hiPSC derivation, culture, and differentiation (cardiac/vascular smooth muscle/endothelial/blood/hepatic/renal/neural), direct reprogramming, engraftment, and developmental/cardiovascular biology. Good verbal and written communication skills in English are essential. The successful candidate will join a dynamic research environment in the Department of Pharmacology, which offers both basic science and clinical translational opportunities to explore fundamental questions in pharmacogenomics.

Salary will be per the NIH (NRSA) Scale and commensurate with experience.

This position is highly suitable for those interested in pursuing a career as an independent academic scientist. Those without experience in the above fields, those more than one year after graduating their PhD, and those who wish to pursue a career in the pharma/biotechnology industry are asked not to apply.

Please send a CV, a cover letter containing a brief description of research experience and interests, and a list of 2-3 references to: paul.burridge@northwestern.edu

Northwestern University is an Equal Opportunity, Affirmative Action Employer of all protected classes, including veterans and individuals with disabilities. Women and minorities are encouraged to apply. Hiring is contingent upon eligibility to work in the United States.

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I am delighted to announce that we are offering an opportunity for a 3-month internship on the Node. This is being offered as a PIPS placement to students on the BBSRC DTP program, or on similar programs where an internship forms part of the PhD training.

If you have a passion for science communication and writing, as well as a love of developmental biology, this could be the perfect internship for you! We will provide a great insight into what it’s like to work in the online scicomm environment, giving you the opportunity to come up with ideas for Node posts, talk to potential authors about writing for us, help Node users with their posts, and run the Node’s social media accounts. Working in a publishing company, you’ll also learn about how science publishing works from the inside.

You can find out more here, or please get in touch with me, Katherine Brown (Development’s Executive Editor) if you want to know more.

We look forward to your application!

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The Company of Biologists and its journal Development are looking for an intern, through the BBSRC DTP/PIPS or equivalent schemes, to help run the successful community website ‘the Node’ . This is a great opportunity to gain experience in the rapidly growing online science communication environment, to develop writing skills, and to learn about academic publishing.

Launched in 2010, the Node is the place for the developmental biology community to share news, discuss issues relevant to the field and read about the latest research and events. The intern will be involved in the day-to-day running of the Node, mentored by the Node’s Community Manager. The internship will be based in our office in Cambridge.

Core responsibilities of the position include:

• Creating and commissioning content for the Node, including writing posts and soliciting content from the academic community, societies and other organisations
• Providing user support
• Running Development’s and the Node’s social media accounts (Twitter and Facebook)

The successful intern will have:

• Relevant scientific expertise (ideally in developmental biology or a related field)
• Strong writing and communication skills
• Keen interest in science communication
• Experience of and interest in blogging and/or social media (ideally including experience with WordPress)

The Company of Biologists (http://www.biologists.com) exists to support biologists and inspire advances in biology. At the heart of what we do are our five specialist journals – Development, Journal of Cell Science, Journal of Experimental Biology, Disease Models & Mechanisms and Biology Open – two of them fully open access. All are edited by expert researchers in the field, and all articles are subjected to rigorous peer review. We take great pride in the experience of our editorial team and the quality of the work we publish. We believe that the profits from publishing the hard work of biologists should support scientific discovery and help develop future scientists. Our grants help support societies, meetings and individuals. Our workshops and meetings give the opportunity to network and collaborate.

We are looking for an intern to start in Autumn 2017, though can be somewhat flexible with start dates and encourage interested candidates to submit their application as soon as possible. To apply, please send a CV and cover letter, stating why you are interested in this opportunity, to recruitment@biologists.com and Katherine Brown (Development’s Executive Editor) at katherine.brown@biologists.com. Please also direct informal enquiries to the same addresses.

Deadline for applications: June 18th, 2017

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Introduction
Graphs (or charts or plots) are often used for the display and summary of data. They are essential tools for the communication of results in presentations or manuscripts. One particular type of graph, the bar graph, is often used to quantitatively compare (multiple) conditions. The earliest known example of a bar graph, dates from the 18th century and its invention is attributed to William Playfair (Beniger and Robyn, 1978).
Proper use of bar graphs includes the display of counts or frequencies of observations, where the length of the bar represents the corresponding value. However, bar graphs are often used to summarise multiple data-points per condition. In this situation, the top of the bar equals the mean value calculated from the data points. The bars are often accompanied by error bars that show the standard error of the mean (SEM) or standard deviation (SD). This type of plot has been coined a ‘dynamite plunger plot’ (footnote 1) for its cartoonesque similarity to a detonator for explosives. The dynamite plunger plot has gained wide popularity and is often the graph of choice to summarise and present data in presentations or manuscripts. One of the reasons for the popularity of bar graphs is that these are easily made by (commercial) software.

Bar graphs are bad graphs

A bar graph with errors bars has one major problem: it conceals the underlying data. Bar graphs do not allow independent interpretation of the data by the reader of a manuscript or the audience of a presentation. Moreover, it is often unclear what the error bars depict (SEM, SD or 95% confidence intervals). Many related issues that add to the notion that bar graphs are bad graphs and should no longer be used have been repeatedly addressed by others, for example here, here, here and here. Clearly, the bar graph is in need of a complete make-over.

Steps toward transparent data presentation

To improve transparency in data presentation, several features of the bar graph can be modified. Below, I describe 5 steps, departing from a standard bar graph, that aim at improving transparency and interpretation. Each step changes one aspect, as shown in figure 1 (or in this animated version). A motivation of each step is presented below.

1. Remove the bar

The top horizontal line of the bar equals the average value. This single value is the only information carried by the bar, and therefore the bar (except for the horizontal line) can be removed without loosing information. This action increases the data-ink ratio, which is defined by E.R.Tufte, pioneer in the field of data visualization, as the ratio of non-erasable data-ink to the total amount of ink used in the graph. To further increase the data-ink ratio, a single dot and two lines could be used to depict the average and error margins, respectively.

2. Show the data

Error bars may not give a realistic impression of the variability of the data. The error bars conceal outliers, multi-component distributions and asymmetric distributions. Therefore, it is more informative to show the actual data-points as dots. When many data-points need to be plotted (>100) the dots may start to overlap. This can be remedied by using semi-transparent dots. Alternative ways to show dense distributions is by using a bean plot or a sinaplot, which is an improved version of the violin plot.

3. Replace the mean by the median

The mean value, indicated by the horizontal line, informs us about the central value of the data. Mean values, however, are sensitive to outliers and may not be a proper representative of the central value in case of asymmetric data distributions. An alternative, robust measures of the central value is the median (or geometric mean). The median is not sensitive to outliers and equals the mean when the data adheres to a normal distribution. In case of asymmetric distributions, the median is a better indicator of a typical value of the data. Since the median is a more robust indicator of the central value of the data, the mean should be replaced by the median. When the number of data points, n, is low (typically n<10), it is recommended to show only the data and median, omitting any error bars. So, in case of low n, the make-over of the bar graph is completed at this stage.

4. Add 95% Confidence intervals

In the original bar graph, the error bars depicted the standard error of the mean (SEM). There are convincing arguments that 95% confidence intervals (95%CI) are better suited to summarise variation. First, the 95%CI give a more realistic impression of the variation in the data than SEM. Second, the 95%CI can be used for statistical inference by eye, i.e. judging whether two conditions are statistically different. If the 95%CI do not overlap, this implies a statistical difference. In this example, the 95%CI around the median is calculated by using the equation from McGill et al. (1978). An alternative strategy that can be used to calculate the 95%CI of the median is by bootstrapping, allowing for asymmetric 95%CI.

5. Add a box

Instead of the median (or mean) with 95%CI, a notched boxplot can be shown to summarise the data and allow for inferences. By convention, the center of the boxplot indicates the median, and the limits of the box define the interquartile range (IQR = middle 50% of the data). The notches indicate the 95%CI around the median, which is an estimation of the interval that includes the population median in 95 out of 100 cases, if the experiment was performed multiple times. The whiskers (shown here as vertical lines) can be defined in multiple ways. Here, we used the Tukey definition, i.e. the whiskers extend to data points that are no further from the box than 1.5*IQR.

Conclusion

The bar plot has infested the scientific literature. The disadvantages of bar plots have been documented by many. Several good alternatives for bar plots exist, which allow for a more transparent presentation of results and enable inferences by eye. The end result of the complete make-over of the bar graph that is presented here is the box&dotplot. The box&dotplot differs in at least five essential aspects from a bar graph with error bars and is a major improvement since the box&dotplot reports data in a transparent way, enabling independent interpretation of the results by others. In an era of increased focus on open science and data availability it is time to step away from the bar graph and expose the data.

Methods

The graphs were made using R/Rstudio with the library ggplot2. The data and code is available at http://doi.org/10.5281/zenodo.375944. A user-friendly alternative to create dotplots and boxplots online is provided by boxplotR.

Shout-out

I am grateful to anyone sharing code, the twitter community and to my colleagues for comments and the exchange of thoughts.

Footnote 1: I attempted to trace the origin of the term ‘dynamite plunger plot’ (with help from Gordon Drummond and Sarah Vowler). One of its first documented uses was in the books ”How to display data” and “Statistics at Square One“, co-authored by M.J.Campbell. In an e-mail, replying to my inquiry, Michael J Campbell states “I am pretty sure I thought of the phrase, since that is what they look like, but others may also have thought of it.”

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The idea sounded intriguing at first: 30 scientists in an isolated and stunning old house discussing intercellular interactions in the context of tissues and organs. It became even more intriguing when we were asked to prepare slides about ourselves, not only about our research but also about our non-scientific life!

The day before the workshop began, a puzzled friend told me “why would you want to go to such secluded place and spend 4 days surrounded by scientists?” At the beginning the question made me laugh, but then it made me think about the unique context of the meeting. Definitely I could not anticipate what I was going to encounter.

The meeting took place at Wiston House, a historic and really charming country house filled with British history. We even got a chance to hear all the tales and chronicles of the place from the historian of Wiston House. Currently, it is used as a conference centre to promote discussion and exchange of ideas, an ideal scenario for a scientific meeting!

The first surprise came when I saw the meeting room. Instead of sitting in rows, we were around a horseshoe-shaped table. This may sound a trivial detail, but I think it definitely helped the discussion and the interactions. The first session was opened by one of the organisers, Andy Ewald, who described specific molecular requirements for mammary epithelial cell invasion. Among other examples, he showed that collective invasion requires leader cells to adopt an epithelial program (Cheung et al., 2013). Parallels were drawn between the cellular features of branching morphogenesis during development and of collective epithelial migration during cancer invasion (Ewald et al., 2008). This idea was especially relevant, given that the workshop brought together cellular and developmental biologists and cancer researchers. During gastrulation, cells undergo changes in shape, position and fate at the primitive streak. Kees Weijer presented a very detailed light-sheet microscopy study of primitive streak formation in the chick embryo, which is characterized by large-scale tissue movements (Rozbicki et al., 2015). On the other hand, Peter Friedl presented beautiful two-photon microscopy studies of collective cancer cell invasion in vivo. A cross-fertilization of ideas could help us understand the complexity of embryonic and cancer cell behaviors. To achieve this goal, the development of new and improved imaging techniques will be fundamental, as was nicely shown by Scott Fraser.

The second surprise came at dinnertime: seats were assigned! We have all been at big meetings in which students and postdocs end up sitting together, and PIs, who in many cases have known each other for a really long time, interact among themselves. The idea of assigning seats turned out to be simple and very effective. We all had the opportunity to the engage in stimulating conversations with PIs, postdocs, students and editors. Scientific interactions are critical, and so are cellular interactions, both in physiology and disease. Elke Ober showed how interactions between epithelial and mesenchymal cells regulate organ positioning during development. In particular, Ephrin-mediated crosstalk between lateral plate mesoderm cells and hepatoblasts coordinates the migration of these two cell types to position the embryonic liver (Cayuso et al., 2016). Another example is the effect of stromal cells on branching of the mammary gland. Johanna Ivaska showed that expression of SHARPIN in mesenchymal cells is required to organize the extracellular matrix allowing ductal outgrowth (Peuhu et al., 2017). By using simplified model systems, we can also gain relevant information on the mechanisms of organogenesis. With this in mind, Anne Grapin-Botton talked about the cellular interactions that regulate 3D pancreatic organoid formation (Greggio et al., 2013). On the other side of the coin, interactions between Cancer-Associated Fibroblasts (CAFs) and tumor cells are known to promote cancer growth and invasion, but whether this requires a direct physical interaction has not been addressed. Erik Sahai showed a mechanical coupling between CAFs and tumor cells that drives collective invasion (Labernadie et al., 2017). Paul Timpson took a translational approach and discussed the results of targeting the stroma for cancer treatment (Pajic et al., 2015).

The third unconventional event was the out of the box sessions, dedicated to reflect on specific concepts and topics. A recurring theme was junctional tension. We discussed how to define it, how to measure it, and what are the implications for tissue morphogenesis, aspects that were also covered by different speakers. Alpha Yap and Carien Nissen analysed the role of adherens junctions as mechanotransducers using different epithelial models; and Valerie Weaver discussed how the mechanical properties of the substrate impact on human embryonic stem cell differentiation (Przybyla et al., 2016). When discussing junctional tension, there is a key element to take into consideration: the actomyosin cytoskeleton. Benedicte Sanson discussed how a planar polarized localization of actomyosin regulates collective cellular movements during Drosophila germ-band extension (Tetley et al., 2016). This was complemented by the studies of John Wallingford and Danelle Devenport on the role of planar cell polarity proteins in the control of epithelial morphogenesis. Michael Way and Laura Machesky presented their latest research on the regulation of actin dynamics and reorganization using different model systems (vaccinia infection and melanocyte migration respectively).

By the end of the workshop I remembered the words of my friend and wondered why I wanted to be part of it. The workshop was superb in so many different ways. Indeed, there were only reasons to be part of it! But probably the best reason was inspiration. Many talks and ideas were inspirational, and I would like to highlight the concept of “building instead of destroying” that was presented by Dan Fletcher and Darren Gilmour. By interfering with the function of genes through genetic studies we have learned a lot about the function of specific molecules and pathways. The time has come to move ahead, and the current challenge is to interfere with protein function in a spatiotemporal-controlled manner, and to devise ways to study how the different components of a cell self-assemble to generate cells, tissues and organs. Meetings like this provide the context to make it happen.

I am grateful to Katherine Brown for comments on the text.

References

Cayuso, J., A. Dzementsei, J.C. Fischer, G. Karemore, S. Caviglia, J. Bartholdson, G.J. Wright, and E.A. Ober. 2016. EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality. Dev Cell. 39:316-328.

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