In our recent paper published in Current Biology, we unravel the direct and early role for Hox genes in the regulation and natural variation of the forelimb position in birds. Here I will share with you the story behind this paper.

I have always been fascinated by the question of how, from a single cell, a multicellular organism with a complex, highly organized three-dimensional structure can arise. Therefore, when I started my PhD in Dr. J. Gros’ lab and got the opportunity to work on the question of limb position in chicken embryos, I was thrilled. How limbs reproducibly form along the vertebrate body is a fascinating, long standing question for developmental but also for evolutionary biologists. Indeed, this question has two main aspects:

1. one purely developmental aspect – in trying to understand the cellular and molecular mechanisms establishing limb position during the embryo development
2. one evolutionary aspect – in tackling the question of diversity in limb position amongst tetrapod species.

The context

In tetrapods, while limbs always position at the level of the cervico-thoracic (for the forelimb) or lumbo-sacral (for the hindlimb) vertebral transitions, the position of these vertebral frontiers – and hence the limb position – is highly variable between species. Avian species especially, display a wide variation in the position of their forelimb – from the sparrow that form forelimbs at the level of the 10^th vertebra up to the swan in which forelimbs form at the level of the 25^th vertebra – a difference of no less than 15 vertebrae!

Despite major advances in our understanding of limb patterning in three dimensions, how limbs reproducibly form along the anteroposterior axis and how variations in these positions arise remained largely unresolved. Hox genes were long suspected to regulate limb position (Tanaka, 2013; Tickle, 2015). This assumption first arose because of their well-demonstrated role in patterning the vertebrae and was further supported by cross-species comparative studies which showed that Hox gene expression domains correlate with limb position in different species (Burke et al., 1995). But the different supportive evidences were mostly correlative (Burke et al., 1995; Cohn et al., 1997; Minguillon et al., 2012; Nishimoto et al., 2014). In addition, whereas Hox gene mutant mice display vertebral identity transformations (Mallo et al., 2010), functional studies in support for a role of Hox genes in regulating limb position were lacking. Therefore, whether Hox genes would control limb initiation and position was clearly unresolved at the time we started this work.

Our Results

Where do the limbs come from? They originate from the Lateral Plate Mesoderm (LPM), a mesodermal tissue that flanks axial embryonic structures (i.e. notochord, neural tube and somites), and will emerge from this tissue at their stereotypical position, at three days of development (Hamburger and Hamilton stage 15). First, we wanted to determine when the forelimb position is primarily established. We took advantage of the possibility to do grafting experiments in chicken and quail embryos, combined with the use of transgenic quail lines generated in the lab, to establish that the forelimb position is determined very early, 24h before limb initiation (i.e. at stage 11, 2 days of development).

The finding that the forelimb position is already established by stage 11 led us to think that this positional information could be established earlier – during the process of gastrulation. Gastrulation is this key morphological process during which the three germ layers – ectoderm, mesoderm and endoderm – are formed. The LPM is generated during this process and we wondered whether it was also patterned into limb- and non-limb domains while being generated. Whereas LPM precursor cells in the epiblast had been identified through lineage-tracing experiments (Psychoyos and Stern, 1996), how the forelimb, interlimb and hindlimb cells are generated was not characterized. The process of gastrulation is really dynamic and spans for about 24h. Therefore, in order to precisely catch the dynamic behaviors of LPM precursor cells, we used yet again another advantage of the chicken embryo, which is the possibility to do live-imaging, especially in the early stages of development as the embryo is flat and can be cultured ex ovo. We therefore performed a dynamic lineage analysis of the LPM formation, and could nicely characterize that the forelimb, interlimb and hindlimb domains are sequentially generated during gastrulation.

At this point, we had described how the LPM is formed and patterned into limb and non-limb domains at the cellular level. The next step was now to investigate the molecular mechanism underlying this process.

As I mentioned earlier, our top candidates for the regulation of limb position were the Hox genes, well-known for their role in patterning vertebrae along the main body axis (Mallo et al., 2010). For our study, it is important to remember that these genes are arranged in four different clusters and display a specific chromosomal organization that reflects their sequence of activation (i.e. temporal collinearity) and their successive domains of expression along the antero-posterior axis (i.e. spatial collinearity) (Izpisúa-Belmonte et al., 1991). Interestingly, we noticed that the collinear sequence of Hoxb genes activation during gastrulation correlates with the temporal sequence of forelimb (e.g. Hoxb4) and interlimb (e.g. Hoxb7and Hoxb9) formation we had just identified, suggesting that they could play a role in the formation of these domains. To test it, we used the electroporation technique that allowed us to do functional perturbations precisely controlled in time and space. We performed overexpression and loss-of-function of different Hoxb genes in LPM precursor cells to perturb their activation during gastrulation. We could show that – as previously identified in the paraxial mesoderm (Iimura and Pourquié, 2006) – Hox genes, collinearly activated during gastrulation, establish their own stereotypical sequential expression domains in the LPM – domains that correlate with the forelimb (e.g. Hoxb4) and interlimb fields (e.g. Hoxb7 and Hoxb9).

But are these Hox expression domains important to position the forelimb?

One year before I started my PhD, a study showed that Hox4/5 genes could bind to a regulatory sequence of Tbx5 – a transcription factor essential for forelimb initiation – and activate the expression of a reporter gene under the control of this regulatory sequence (Minguillon et al., 2012). These results further supported a role for Hox genes in positioning the forelimb along the antero-posterior axis. We therefore decided to ectopically express Hoxb4 in the interlimb at stage 14 – when Hox domains are well-established – to see if we could perturb the forelimb position. We first screened embryos for an ectopic expression of Tbx5 in the interlimb, naively thinking that Hoxb4 overexpression should first induce Tbx5 expression. But that would have been too simple, Hoxb4 alone was not able to induce Tbx5 ectopic expression in the interlimb…

We were initially quite puzzled by this result. But the story could not stop there, we were missing something and we had to find out what. Then became a long journey during which we electroporated many different combinations of genes in the interlimb – e.g. Hoxb4 fused to VP16; combined Hox4/Hox5 genes; Hoxb4 plus activators of Retinoic Acid or Wnt/β catenin pathways, both involved in Tbx5 expression and forelimb initiation (Nishimoto et al., 2015); and several others – in an attempt to induce Tbx5 expression in the interlimb and a shift in limb position. Unfortunately, none of these combinations had an effect on Tbx5 expression nor limb position. At this point, we started to be somewhat desperate and were about to give up as the end of my PhD was getting closer. But reading again some of the literature, we came back to one paper in which it was shown that Hoxc9 – which is expressed in the interlimb – could repress Tbx5 expression (Nishimoto et al., 2014). Maybe the solution was there, this repressive activity was preventing all our attempts to posteriorly extend the Tbx5-positive forelimb field. This was it, the last-chance experiment! We decided to construct a dominant-negative form of Hoxc9 using a strategy others had established to generate Hox dominant-negative constructs (Denans et al., 2015). Then, we combined overexpression of Hoxb4 together with the repression of Hoxc9 in the interlimb and, not only we could nicely extend the Tbx5-positive forelimb domain in the interlimb, but we could displace the final forelimb position (Figure 1). There it was, many years after Hox genes where first suspected, we finally had the functional evidence of their direct role in regulating the forelimb position!

Importantly, removing Hoxc9 repression from the interlimb alone was not sufficient to induce Tbx5 expression and limb initiation. Therefore, showing that to change the forelimb position, both a shift of the forelimb field (e.g. Hoxb4 expression) and the interlimb field (e.g. Hox9 expression) is necessary. These results brought to us one potential explanation to why the vast majority of Hox genes mutant mice do not show major perturbations in limb position. Indeed, our data argue that, to induce a shift in the forelimb position in mouse, a combination of gain-of-function for forelimb activator (e.g. Hoxb4) and loss-of-function for forelimb-repressor (e.g. Hox9) should be performed. Another interesting point worth commenting is that, while Hoxb4 and Hox9 activate and repress Tbx5 expression, eventually leading to the establishment of the definitive forelimb position, Tbx5 itself was shown to be not sufficient to induce limb initiation (Nishimoto et al., 2015). Therefore, implying that, to regulate forelimb initiation at its specific position, Hox genes do not solely act upon activation/repression of Tbx5. This point remains to be explored but one can speculate that Hox genes could activate/repress other regulators of limb initiation or act cooperatively with Tbx5 to activate the limb initiation program, as recently shown for Hoxc10 and Tbx4 in the context of hindlimb development (Jain et al., 2018).

At this point, we had now unraveled the developmental mechanism behind limb position establishment. But what about limb position diversity, how can variations in limb position arise?

Our results suggested that natural variations in the forelimb position should be traced back to changes in Hox genes activation during gastrulation. To test this hypothesis, we took advantage of the bird natural variation in limb position. We selected three different bird species: zebra finch, chicken and ostrich as they form forelimbs at the level of the 13^th, 15^th and 18^th vertebra, respectively, to perform a cross-species comparative analysis of Hoxb genes temporal and spatial dynamics of expression during early development. We then could provide evidence that, as predicted, changes in the timing of Hox activation during gastrulation prefigure variation in the spatial organization of these genes – i.e. in the spatial position of Hoxb4/Hoxb9 border of expression – in the LPM and ultimately, natural variation in forelimb position in birds. Working with non-conventional model organisms such as the ostrich was not trivial and required some troubleshooting and optimization at every step of the process, but it brought us with some very exciting outcomes and I think, shows the importance of using non-traditional model organisms when it comes to challenge and validate the models and predictions we establish using our favorite model organisms.

Finally, now that we had established the role of Hox genes in regulating limb position and variation, the next logical step was to investigate how such variation in Hox activation timing could be controlled. We got interested in the Retinoic Acid (RA) signaling pathway, and especially the RA catabolizing enzyme Cyp26a1, as it was already shown to be involved in hindlimb position regulation (Lee et al., 2010). We observed that Cyp26a1 onset of expression differs between the three avian species – i.e. its expression is premature and delayed in zebra finch and ostrich embryos, respectively, compared to chicken – consistent with a role for RA signaling in regulating Hox genes activation. Finally, modulating RA signaling during gastrulation in chicken embryos, provoked changes in Hox genes spatial organization in the LPM and in the Tbx5-positive forelimb field position, further suggesting that RA signaling might regulate the forelimb position through the regulation of Hox genes activation during gastrulation. This is an interesting point that will definitely need to be further investigated. Indeed, the possibility that Cyp26a1, already shown to regulate hindlimb position (Lee et al., 2010) could also regulate the forelimb position is particularly interesting. Especially, as it was recently proposed that differences in the onset of Gdf11 expression – i.e. the signaling molecule that induces Cyp26a1 expression – account for variations in hindlimb position amongst tetrapods (Matsubara et al., 2017). Therefore, one single signaling pathway would then be responsible for the regulation and natural variation of both fore- and hindlimb position.

Conclusion

From all these different results, the major conclusion of our work is that the forelimb position is determined very early, during gastrulation: it is the temporally controlled activation of Hox genes that progressively patterns the LPM into limb- and non-limb forming domains, as the main axis is being formed. And relative changes in this timed collinear activation underlie natural variation in forelimb position in birds (Figure 2).

One of the important points brought by our study is that we show the LPM is patterned by Hox genes during gastrulation following a similar mechanism as the one identified to pattern the somites (Iimura and Pourquié, 2006). These two tissues – that respectively give rise to the limb and vertebrae – both being generated and patterned during gastrulation by Hox genes, offers a simple mechanism to pattern the cervico-thoracic frontier in the somites and the forelimb position in the LPM, concomitantly therefore maintaining their tight association observed in all tetrapod species.

As a conclusion, our work that combines experimental embryology, state-of-the-art live imaging and cross-species comparative studies, addresses the major question of how the forelimb position is determined and solves a 20-year long controversy on the role of Hox genes in regulating limb position. It also provides a general mechanism for generating variation in body plan organization in vertebrates and reinforces the importance of Hox genes in shaping animal body plans.

Chloé Moreau

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References

Burke, A.C., Nelson, C.E., Morgan, B.A., and Tabin, C. (1995). Hox genes and the evolution of vertebrate axial morphology. Dev. Camb. Engl. 121, 333–346.

Cohn, M.J., Patel, K., Krumlauf, R., Wilkinson, D.G., Clarke, J.D., and Tickle, C. (1997). Hox9 genes and vertebrate limb specification. Nature 387, 97–101.

Denans, N., Iimura, T., and Pourquié, O. (2015). Hox genes control vertebrate body elongation by collinear Wnt repression. ELife 4. e04379.

Iimura, T., and Pourquié, O. (2006). Collinear activation of Hoxb genes during gastrulation is linked to mesoderm cell ingression. Nature 442, 568–571.

Izpisúa-Belmonte, J.C., Falkenstein, H., Dollé, P., Renucci, A., and Duboule, D. (1991). Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body. EMBO J. 10, 2279–2289.

Jain, D., Nemec, S., Luxey, M., Gauthier, Y., Bemmo, A., Balsalobre, A., and Drouin, J. (2018). Regulatory integration of Hox factor activity with T-box factors in limb development. Development 145, dev159830.

Lee, Y.J., McPherron, A., Choe, S., Sakai, Y., Chandraratna, R.A., Lee, S.-J., and Oh, S.P. (2010). Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development. Dev. Biol. 347, 195–203.

Mallo, M., Wellik, D.M., and Deschamps, J. (2010). Hox genes and regional patterning of the vertebrate body plan. Dev. Biol. 344, 7–15.

Matsubara, Y., Hirasawa, T., Egawa, S., Hattori, A., Suganuma, T., Kohara, Y., Nagai, T., Tamura, K., Kuratani, S., Kuroiwa, A., et al. (2017). Anatomical integration of the sacral–hindlimb unit coordinated by GDF11 underlies variation in hindlimb positioning in tetrapods. Nat. Ecol. Evol. 1, 1392.

Minguillon, C., Nishimoto, S., Wood, S., Vendrell, E., Gibson-Brown, J.J., and Logan, M.P.O. (2012). Hox genes regulate the onset of Tbx5 expression in the forelimb. Dev. Camb. Engl. 139, 3180–3188.

Nishimoto, S., Minguillon, C., Wood, S., and Logan, M.P.O. (2014). A combination of activation and repression by a colinear Hox code controls forelimb-restricted expression of Tbx5 and reveals Hox protein specificity. PLoS Genet. 10, e1004245.

Nishimoto, S., Wilde, S.M., Wood, S., and Logan, M.P.O. (2015). RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation. Cell Rep. 12, 879–891.

Psychoyos, D., and Stern, C.D. (1996). Fates and migratory routes of primitive streak cells in the chick embryo. Development 122, 1523–1534.

Tanaka, M. (2013). Molecular and evolutionary basis of limb field specification and limb initiation. Dev. Growth Differ. 55, 149–163.

Tickle, C. (2015). How the embryo makes a limb: determination, polarity and identity. J. Anat. 227, 418-430.

(2 votes)

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This Spotlight article by Len Zon originally appeared in Development as part of our ‘Advocating developmental biology‘ campaign. We’d love to hear what you think about Len’s ideas.

Developmental biology is a prominent field that has captured the imagination of many scientists. Over the years, research in the area has seen a steady number of amazing accomplishments, with peaks in activity following the development and application of new technologies. Although the field continues to flourish and produce excellent work, I have recently noticed difficulty with its perception and visibility. Having joined the developmental biology community during the early 1990s, and contributing since as a stem cell researcher, cancer biologist and an MD, I have a unique perspective on these challenges. Here, I discuss these issues and challenges and offer potential solutions for a field that is very important to me.

I recently had a discussion with some colleagues at a stem cell meeting about impact factors and the conversation morphed to the topic of developmental biology journals. It appears that the impact factors of all classical developmental biology journals (Development, Developmental Biology, Genes and Development, Developmental Cell, etc.) have been declining over the years. Thus, although the field continues to publish excellent studies in top tier journals, the general area of developmental biology may need help. Of course, impact factor is not a great measure of real importance, and authors may be artificially infatuated with these numbers, as they are thought to impact promotion and other academic criteria (discussed by Pourquié, 2018). However, to me, the numbers are consistent with my perception that much of developmental biology research has not been as appreciated by other fields or the public as it used to be. I left the table feeling pretty depressed and wanted to figure out what could be done to improve the general visibility of developmental biology to scientists.

So how did this happen? Historically, developmental biology has been very successful, spawning a remarkable number of new fields such as stem cell biology, single cell genomics and chemical genetics (reviewed by Gilbert, 2017). Strangely, it appears that these new areas were not fully embraced and I believe it is this lack of inclusiveness that is the key to the problem. For example, stem cell research came from developmental biology but then, as the stem cell community grew, it was only welcomed by a few of the classical developmental biologists and journals. Stem cell journals were established and became successful and, although developmental biology journals tried to recover the stem cell field, the damage was already done. Organoids are also becoming very popular models, but are often not considered as a major area of developmental biology, or even stem cell biology. Will there be separate journals or societies for organoids? Given that all of these fields are close to each other, it would make sense – with regard to outside perception – to be as inclusive as possible by pooling them together and trumpeting all of their successes.

Notably, the stem cell field was able to grow very quickly. This was because of excellent science and, of course, the medical potential of stem cells, but it was also because of inclusiveness and clever marketing. Stem cell biologists figured out how to market developmental biology. When I started the International Society of Stem Cell Research (ISSCR) as the first President, I invited many well-known developmental biologists to join the board. At our first meeting, several of them felt that we should not talk to the press about our work. This group was worried that the press might misrepresent their views and this could affect public perception. I made the point that if we didn’t provide the public with accurate information, then there would be misinformation in the public eye and this could instead create long-term problems. The decision was made to have all of the board talk about stem cell science to as many groups as possible, including the public, government officials and other scientific groups. When creating our first meetings, we were as inclusive as possible, including many talks on animal model systems and plants. I was very happy to include one talk on stem cells in trees at the first meeting. We formed an alliance with Cell Press so that we could establish a venue for publishing our top papers (in the journal Cell Stem Cell) and the field was very supportive of progress. We engaged funding bodies and governments, and included members of various foundations on panels and committees. Ethical guidelines were put in place. Lastly, we involved physicians who might be able to translate our basic research into the clinic. Overall, we tried to be as inclusive as possible and developed an educational strategy for the public, funders, governments and scientists.

Based on my experience, I think there are a number of steps that could be taken to improve visibility of the developmental biology field:

1. As a field, we should consider marketing the attributes of developmental biology. There are several different audiences – potential students, post-docs and other researchers, grant funders, editors, general scientists, and the public – and we need to develop a different message for each audience. We also need to point out the successes and technologies of the field and say why it is so important for everyone to know about developmental biology and why it is a great area to be part of. Perhaps a video series could be used to illustrate great examples of success or future directions. These should also clearly state what the field is trying to accomplish now. Is there medical relevance? If so, we need to say it loudly. Overall, better marketing will make developmental biology more attractive, which will hopefully lead to more papers being published, and this will expand the community’s impact.

2. We also need to think more carefully about the scope and aims of developmental biology meetings. Although the meetings are highly attended by developmental biologists, it would be beneficial to aim higher and reach out to those who are at the periphery of the field, or those in the newer disciplines that run the risk of splitting off from the core community. Consider that many researchers who study human disease might rather attend a meeting about their tissue, technology or cell biology than go to a broad meeting about developmental biology. Maybe we could create a new meeting or retrofit an old meeting to be more inclusive. Perhaps this could be centered on developmental biology techniques. We have seen huge advances in bar coding and single cell techniques, for example, and many of the questions that are being tackled using these techniques are now about organ development and function. This is an opportunity to bring interesting papers into the field. The term ‘applied developmental biology’ has been used in the past (see Maartens, 2017), but perhaps we should re-visit this idea and do a better job of marketing ‘applied developmental biology’ and including it in meetings. In general, meetings should be used to show off: invite every editor possible, invite every program officer for funding, get the heavyweights of the field to attend as well as the newcomers…and do not be scared to have 2000 people there.

3. The field of developmental biology could also benefit from reaching out and inviting the medical community into the group. Twenty-five years ago, I was invited into the developmental biology community by some really excellent scientists. It made me want to become part of a group that included rigorous scientists with bold ideas who wanted to extend their concepts to a young doctor. I am now very proud to be part of the community. So, moving forward, we should make sure we invite more medics and translational researchers to developmental biology meetings. Companies should also be invited to participate: there is a lot of developmental biology in companies right now and they are increasingly recognizing its importance. For example, one company that I founded (Scholar Rock) works on making antibodies to members of the TGF-β family for therapeutics, and it often discusses the developmental biology that is regulated by these ligands. Developmental biology is clearly relevant to companies, so it will be important to interact with them and foster good relationships.

4. The ‘journal experience’ is becoming very important when deciding where to submit a paper, so this is also something that, as a community, we need to improve. Much of developmental biology work is inherently harder to do in vivo, and experiments take a long time. The field, as a whole, needs to be more wary of this. Reviewers should recognize that, sometimes, descriptive in vivo work is just as important, revealing and fascinating as complicated molecular manipulations. As such, the same level of experiments that would be requested for a more accessible and/or manipulatable system may not be appropriate. As an author, you may need to remind your editors of this and liaise with them to streamline the crucial experiments that are requested before a paper is published.

5. Finally, we also need to educate funding bodies and the general public about the value of basic research in developmental biology. Pointing out the impact of basic biology on the development of clinical therapies has great effect. Checkpoint blockade for cancer therapy, for example, could not have been initiated without a significant literature on T-cell developmental biology. Anti-cancer therapies that target the Hedgehog pathway would not have been possible without basic research into how this pathway functions in normal development (discussed by Ingham, 2018). Collecting a number of these anecdotes works, but researchers should also consider how their own studies add to this impact, establish novelty and push the field forward. Indeed, in a recent commentary it was pointed out by Claude Desplan that the reuse of the same signaling pathways in most developmental processes created reader and reviewer fatigue (discussed by Desplan, 2017). The fact that NOTCH mutations cause lymphoma as well as congenital heart defects may be less exciting than finding a new pathway that causes cancer, but if you are the patient with a NOTCH mutation, you will no doubt be thanking the developmental biologists for bringing some understanding of its action. Driving research forward in this way, and highlighting the importance of this progression, may help with how the field is perceived. The newly developed single cell profiling approaches open up huge research, diagnostic and therapeutic avenues to study stem cells, organ development, regeneration and cancer. We should be telling the public about this work now and claim victory when new mechanisms are found or when new applications occur. This is something that everyone can do; we all need to be advocates for the field.

In summary, it is clear to many of us that developmental biology continues to establish new principles and techniques that are helpful to many other fields. It spawns areas of research that become fields themselves. My perception is that the community could do better to enhance its visibility to other researchers and to the public. Inclusivity is very important and enhanced marketing strategies could be helpful in sending out the right signal. Much like Spemann’s organizer, we need this signal to ‘induce’ change, to ‘specify’ more developmental biologists, and to invoke a ‘community effect’ to bring as many groups as possible together to show how exciting the field is.

References

Desplan, C. (2017). What is the future of developmental biology? Cell 170, 6-7.

Gilbert, S. F. (2017). Developmental biology, the stem cell of biological disciplines. PLoS Biol. 15, e2003691.

Ingham, P. W. (2018). From Drosophila segmentation to human cancer therapy.
Development 145, dev168898.

Maartens, A. (2017). An interview with Jim Smith. Development 144, 2704-2707.

Pourquié, O. (2018). Ce n’est qu’un au revoir. Development 145, dev172437

(1 votes)

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Tills O, Spicer JI, Grimmer A, Marini S, Jie VW, Tully E, Rundle SD. 2018. A high-throughput and open-source platform for embryo phenomics. PLOS Biology, 16:1-19.

https://doi.org/10.1371/journal.pbio.3000074

Background

A seasoned graduate student gave me some valuable advice at the outset of my PhD. She told me to FIND A BETTER WAY!  We were both working on heterochrony – changes in the timing of developmental events. She had worked on between-species comparisons – I was about to start investigating within-species differences. The challenge in both research areas lies in its temporal nature – a poorly-timed lunch, or rest-room break and the developmental events of interest are literally a thing of the past. Development shows little regard for the diurnal rhythms of scientists either. Her advice drove me to develop a technology that would enable me to (occasionally) leave the lab. As a by-product, it produced a step change in the quality of the developmental data we were generating and, in turn, our understanding of development at the level of the whole-organism.

OpenVIM

OpenVIM is the result – a modular open-source video light microscope (Fig.1). Specifically tailored for automated time-lapse imaging of large numbers of aquatic embryos, for the duration of their development, or the experiment. The key with OpenVIM is that we can capture the dynamic process of embryonic development by generating realtime image sequences of each embryo. These acquisitions are repeated over the duration of the experiment (or their development). I started my career as a marine biologist, and despite my growing interest in development, my research continues to be set in the context of understanding how animals respond to changes in their environment. Therefore, environmental control was central and so this is also integrated and we can heat, cool and provide mixtures of gases during the course of an experiment.

 

Fig.1. OpenVIM – Open-source video microscope, www.openvim.org.

 

OpenVIM produces many Terabytes (and hours) of video potentially leading to a serious bottleneck in its use. Fortunately a NERC Technology grant provided us the support to develop some complimentary analytical software that would relieve this bottleneck. We called this software EmbryoCV and it sits alongside OpenVIM and extracts as much biological information from these rich video time series as possible. The powerful combination of hardware and software we call EmbryoPhenomics – an open-source platform for phenomics in embryos.

 

EmbryoCV

EmbryoCV is a Python-based, high-throughput image analysis software. It sits alongside OpenVIM and automates the process of  identifying embryos, measuring size, shape and movements all the way through to measuring physiological traits such as cardiac activity. This is performed on millions of frames, and hours of video, capturing both the real-time and developmental responses of embryos.

Fig.2. Video generated by OpenVIM of three Radix balthica embryos cultured at different temperatures. EmbryoCV generated measures of embryo size, movement and heart rate produced from 40 embryos at each temperature are shown in an XYZ plot.

 

A core component of EmbryoCV is the use of temporal fluctuations in pixel intensities in image sequences at different spatial resolutions. These signals can be used to make measurements of physiological traits such as heart rate. They can also be used to produce holistic measures such as lethal end points. to be identified.

 

EmbryoPhenomics

The combination of OpenVIM hardware and EmbryoCV software is called EmbryoPhenomics – an open-source platform for phenomics in embryos (Fig.2). Our recent paper describes the application of EmbryoPhenomics to perform four distinct climate-change themed experiments, using a freshwater gastropod and a marine amphipod – two species with very different types of development. In combination these experiments generated > 30 M images (approx 50 TB of image data). The EmbryoCV software was able to analyse > 93 % of these images.

 

Why phenomics?

David Houle comments ‘Organisms are fantastically complicated. Traditional biological intuition comes down to choosing an interesting character as the the object of study, from the essentially infinite number of characters that could be identified. Scientists who pick characters that are both biologically important and readily measured can obtain interesting results that resonate with others; those that do not pick so fortunately struggle‘.

 

Phenomics can be defined as the acquisition of high-dimensional phenotypic data on an organism-wide scale Houle et al 2010. Technologies for high-throughput screening in phenomics address the challenge of data acquisition in much the same way that Next Generation Sequencing did in genomics – it reduces the limitations of traditional approaches, by applying high-throughput technologies to capture the complexity and interconnectedness of biological responses. Phenomics can provide a quality and quantity of data supportive of new approaches to understanding responses.

 

Biology is complex. Capturing the dynamic process of embryonic development using a handful of measures, perhaps chosen as much for their ease of measurement as their biological relevance is never going to be an optimal strategy. Nonetheless, this is the challenge faced by the majority of biologists, who do not possess the means to perform experiments to the scale that they would like.

 

Where next?

EmbryoPhenomics is open-source – both OpenVIM hardware and EmbryoCV software are freely accessible to people to adapt and modify to their own needs. The downstream data produced by EmbryoCV are vast and we are actively exploring different approaches to interrogate these, including deep learning. We are also streamlining the workflow of EmbryoPhenomics so that data are produced during, rather than after, an experiment.

 

Check out our Vimeo Channel for some examples of the types of video and diversity of organisms that we work with.

 

More information on EmbryoPhenomics can be found in the paper or on these websites:

EmbroPhenomics platform: www.embryophenomics.org

OpenVIM: www.openvim.org

EmbryoCV: www.embryocv.org

Dr Oliver Tills

Teaching and Research Associate, University of Plymouth

oliver.tills@plymouth.ac.uk

(3 votes)

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A PhD position is open in the QARMA team (LIS – Marseille, France).  The recruited student will join Paul Villoutreix’s group ( @paulvilloutreix ): Data Science and Developmental Biology. PhD students will also be part of the Turing Centre for Living Systems (CENTURI), an interdisciplinary research centre located in Marseille.

PhD project: The intrinsic geometry of a developing embryo – More info

Deadline: March 01, 2019

PhD duration: 3 years

Expected profile – selection criteria

The team is expecting students with a background in machine learning and a good knowledge of biology as well as a will to open new avenues at the intersection of biology and computer science. Candidates will be evaluated based on the following criteria:

• Academic achievements
• Past research experience (internships, master thesis)
• Interest to work in a multidisciplinary research environment
• Enthusiasm and communication skills

How to apply: Students are required to apply on CENTURI’s website. Applications must include the following documents (compiled into a single PDF file):

• CV
• cover letter
• transcript of your MSc’s grades (M1 and M2 if available)

2 letters of recommendation must also be sent by your references to info@centuri-livingsystems.org.

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Last year, I started to experiment with signing my reports for peer review of manuscripts, inspired by other people on twitter (@kaymtye, @AndrewPlested who in turn were inspired by Leslie Voshall). This year, the experiment is a bit different. I will only review for journals that allow non-anonymous peer-review.

Why?

That was the question raised by an editor. At first the editor did not want me to sign my review, since that was the default. However, after some back-and-forth over email, permission was granted. My main argument to sign was that I think it makes me a better reviewer (that’s right “I think”, these things are difficult to quantify, you know), since I will be less sloppy more precise, more constructive and more realistic in terms of requesting new experiments. Another advantage is that the authors have a better idea of who they are dealing with. They can better assess the expertise of the referee and respond accordingly. Recently, I received non-anonymous reviews for a submitted manuscript for the first time. This was a very positive experience and it strengthens my opinion that signed reviews make the peer review process more human.

I realize that I can sign my reviews and reveal my identity because I am privileged. I have a permanent position at a well-regarded university in a research group with a solid track record. However, being privileged should not stop me. And I think that the privileged have an important role in improving the peer review system. Signed peer reviews are not necessarily a magic bullet, but a good start would be to move away from the anonymous review as a standard. Journals that allow signed reviews should make that clear to reviewers during the peer review process.

What’s next?

The debate around signed reviews is not new. Similar issues with disclosing one’s identity apply to commenting on preprints. Signing reviews or other type of comments is not without risk for early stage career researchers or other researchers in vulnerable positions. We have discussed this in our preprint journal club and in my opinion early stage career researchers (PhD candidates, post-docs) should not sign public comments by default. If they want to disclose their identity, I’d recommend to directly contact the authors with their feedback by email. 

One way to protect young researchers would be to co-review and co-sign with a senior scientist. Another opportunity is the cross-commenting on peer review reports that several journals are implementing. One could imagine that multiple reviewers draft a single review report and sign this together. This generates a review report with an author list, which has the advantage that the comments cannot be traced back to a single person. The downside is that such a collaborative review may require substantially more effort and time.

Finally…

As said in the intro, signing peer review reports is an experiment. So far, I am pleased with the results and I will continue. There may, however, be some unwanted side-effects that will stop my experiment. In the meantime, I hope that reviewers realize that signing review reports is often an option and that they give it some serious thoughts.

(11 votes)

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We offer one fully-funded postdoctoral position up to five years in the Laboratory of Genome Integrity located at the main campus of the National Institutes of Health (NIH/NCI, Bethesda, MD).Our laboratory uses human and mouse embryonic stem cells (ESCs) as well as mouse embryos to understand the molecular mechanisms underlying the maintenance/exit of pluripotency and self-renewal. Understanding cell plasticity, pluripotency and differentiation to get a better comprehension of embryonic development, cell transformation and cancer are our scientific interests.

Areas of Expertise:

1) Embryonic stem cells 2) Embryology 3) Pluripotency 4) Somatic cell reprogramming 5) CRISPR-based screenings 6) Differentiation 7) Cell plasticity 8) DNA damage.

The applicant should have or about to have a PhD in Developmental Biology, Genetics or similar, and must have demonstrated expertise in mouse embryology and in vitro embryo manipulation. Knowledge on mammalian tissue culture, molecular biology and/or next generation sequencing technologies and computational biology will be considered as an advantage. The applicant will have the opportunity to develop his/her research program or lead ongoing projects.

We seek a highly motivated, interactive, creative individual, eager to learn and develop new technologies and complex cell systems based on live cell/embryo imaging, 3D modelling and CRISPR-based editing interested in understanding how a single cell can develop into a complex multicellular organism in vitro and in vivo.

Please send a brief cover letter, CV and at least two reference letters via e-mail to:

Sergio Ruiz Macias (NIH/NCI) [E]

Laboratory of Genome Integrity

Center for Cancer Research

National Cancer Institute, NIH

Building 37, Room 1108

Bethesda, Maryland 20892

sergio.ruizmacias@nih.gov

Further information about our lab and publications can be found at:

https://ccr.cancer.gov/Laboratory-of-Genome-Integrity/sergio-ruiz-macias

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Welcome to our monthly trawl for developmental biology (and related) preprints. 

January was notable for the number of preprints on Xenopus development, plus a trio on Piezo channels, two on ctenophores, and a preprint on preprints that has also been preLighted (very meta).

The preprints were hosted on bioRxiv, PeerJ, and arXiv. Let us know if we missed anything, and use these links to get to the section you want:

Developmental biology

| Patterning & signalling

| Morphogenesis & mechanics

| Genes & genomes

| Stem cells, regeneration & disease modelling

| Plant development

Evo-devo & evo

Cell biology

Modelling

Tools & resources

Research practice & education

Why not…

Developmental biology

| Patterning & signalling

Parallel control of mechanosensory hair cell orientation by the PCP and Wnt pathways
Joaquin Navajas Acedo, Matthew G Voas, Richard L Alexander, Thomas Woolley, Jay Unruh, Hua Li, Cecilia Moens, Tatjana Piotrowski

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling
Beatriz Garcia-Diaz, Corinne Bachelin, Fanny Coulpier, Gaspard Gerschenfeld, Cyrille Deboux, Violetta Zujovic, Patrick Charnay, Piotr Topilko, Anne Baron-Van Evercooren

Nestin in immature embryonic neurons regulates axon growth cone morphology and Sema3a sensitivity
Christopher J Bott, Colin G Johnson, Chan Choo Yap, Noelle D Dwyer, Karen Newell-Litwa, Bettina Winckler

BDNF/TrkB.T1 signaling is a novel mechanism for astrocyte morphological maturation
Leanne M Holt, Natasha L Pacheco, Raymundo Hernandez, Muhannah Hossain, Michelle L Olsen

BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids
Nathalie Duval, Celia Vaslin, Tiago Costa Barata, Stephane Nedelec, Vanessa Celine Ribes

Otx2 signals from the choroid plexus to regulate adult neurogenesis
Anabelle Planques, Vanessa Oliveira Moreira, Chantal Dubreuil, Alain Prochiantz, Ariel A Di Nardo

Lineage tracing analysis of cone photoreceptor-associated cis-regulatory elements in the developing chicken retina.
Estie Schick, Sean McCaffery, Erin Keblish, Cassandra Thakurdin, Mark Emerson

Fetal stage melanopsin (OPN4) and GNAQ (Gαq) signaling regulates vascular development of the eye
Shruti Vemaraju, Gowri Nayak, William E Miller, David R Copenhagen, Richard A Lang

Cell type composition and circuit organization of neocortical radial clones
Cathryn R Cadwell, Federico Scala, Paul G Fahey, Dmitry Kobak, Fabian H Sinz, Per Johnsson, Shuang Li, R. James Cotton, Rickard Sandberg, Philipp Berens, Xiaolong Jiang, Andreas S Tolias

mTOR suppresses macroautophagy during postnatal development of the striatum.
Ori Lieberman, Irena Pigulevskiy, Michael Post, David Sulzer, Emanuela Santini

Multiple sources of Shh are critical for the generation and scaling of ventral spinal cord oligodendrocyte precursor populations.
Lev Starikov, Andreas H Kottmann

The transcription factor TCF7L2 functions as a terminal selector in thalamic and habenular regions of the brain
Marcin Andrzej Lipiec, Kamil Kozinski, Tomasz Zajkowski, Michal Dabrowski, Chaitali Chakraborty, Angel Toval, Jose Ferran, Andrzej Nagalski, Marta Barbara Wisniewska

Large scale analysis of the diversity and complexity of the adult spinal cord neurotransmitter typology
Andrea Pedroni, Konstantinos Ampatzis

Early-generated interneurons regulate neuronal circuit formation during early postnatal development
Chang-Zheng Wang, Jian Ma, Shao-Na Jiang, Tian-Qi Chen, Ye-Qian Xu, Zu-Liang Yuan, Xiao-Yi Mao, Shu-Qing Zhang, Lin-Yun Liu, Yinghui Fu, Yong-Chun Yu

Neural differentiation is increased by GSK-3β inhibition and decreased by tankyrase inhibition in human neural precursor cells
Michael Telias, Dalit Ben-Yosef

Redox signaling via lipid peroxidation regulates retinal progenitor cell differentiation
Shahad Albadri, Federica Naso, Carole Gauron, Carola Parolin, Karine Duroure, Jessica Fiori, Carla Boga, Sophie Vriz, Natalia Calonghi, Filippo Del Bene

Cell Fate Determining Molecular Switches and Signaling Pathway in Pax7-expressing Somitic Mesoderm
Cheuk Wang Fung, Zhu Han, Shaopu Zhou, Zhenguo Wu, Angela R Wu

Positional information encoded in the dynamic differences between neighbouring oscillators during vertebrate segmentation.
Marcelo Boareto, Tomas Tomka, Dagmar Iber

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development
Teresa G Krieger, Carla M Moran, Alberto Frangini, W Edward Visser, Erik Schoenmakers, Francesco Muntoni, Chris Clark, David Gadian, Wui K Chong, Adam Kuczynski, Mehul Dattani, Greta Lyons, Alexandra Efthymiadou, Faraneh Varga-Khadem, Benjamin D Simons, Krishna Chatterjee, Frederick J Livesey

Thyroid hormone regulates distinct paths to maturation in pigment cell lineages
Lauren Saunders, Abhishek Mishra, Andrew J Aman, Victor Lewis, Matthew B Toomey, Jonathan Packer, Jose McFaline-Figueroa, Xiaojie Qiu, Joseph C Corbo, Cole Trapnell, David M Parichy

Fate plasticity and reprogramming in genetically distinct populations of Danio leucophores
Victor Lewis, Lauren Saunders, Tracy A Larson, Emily Bain, Samantha Sturiale, Dvir Gur, Sarwat Chowdhury, Jessica Flynn, Michael Allen, Dimitri Deheyn, Jennifer Lee, Julian Simon, Jennifer Lippincott-Schwartz, David Raible, David Parichy

Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant
Elvira Diamantopolou, Sarah Baxendale, Antonio de la Vega de Léon, Anzar Asad, Celia J Holdsworth, Leila Abbas, Valerie J Gillet, Giselle R. Wiggin, Tanya T Whitfield

A new transgenic reporter line reveals Wnt-dependent Snail2 re-expression and cranial neural crest differentiation in Xenopus
Jiejing Li, Mark Perfetto, Christopher Materna, Rebecca Li, Hong Thi Tran, Kris Vleminckx, Melinda K. Duncan, Shuo Wei

Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development.
Marshall Lukacs, Tia Roberts, Praneet Chaturvedi, Rolf Stottmann

SWI/SNF component BAF250a coordinates OCT4 and WNT signaling pathway to control cardiac lineage differentiation
Ienglam Lei, Shuo Tian, Victor Chen, Yong Zhao, Zhong Wang

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest
Gustavo A. Gomez, Maneeshi S Prasad, Man Wong, Rebekah M Charney, Patrick Shelar, Nabjot Sandhu, James Hackland, Jacqueline C Hernandez, Alan W Leung, Martin I. Garcia-Castro

Hedgehog signaling controls progenitor differentiation timing
Megan Rowton, Andrew D. Hoffmann, Jeffrey D. Steimle, Suzy Hur, Xinan Holly Yang, Alexander Guzzetta, Sonja Lazarevic, Chul Kim, Nikita Deng, Emery Lu, Jessica Jacobs-Li, Shuhan Yu, Mervenaz Koska, Erika Hanson, Carlos Perez-Cervantes, Sunny Sun-Kin Chan, Kohta Ikegami, Daniel J. Garry, Michael Kyba, Ivan P. Moskowitz

Loss of YAP/TAZ impaired the proliferation and differentiation ability of neural progenitor cells
Shanshan Kong

Follicle-stimulating hormone and luteinizing hormone increase Ca2+ in the granulosa cells of mouse ovarian follicles
Jeremy R. Egbert, Paul G. Fahey, Jacob Reimer, Corie M. Owen, Alexei V. Evsikov, Viacheslav O. Nikolaev, Oliver Griesbeck, Russell S. Ray, Andreas S. Tolias, Laurinda A. Jaffe

APC2 is Critical for Ovarian WNT Signalling Control, Fertility and Tumour Suppression
Noha-Ehssan Mohamed, Trevor Hay, Karen Reed, Matthew Smalley

PSMC3 is required for spermatogonia niche establishment in mouse spermatogenesis
Maria Cristina Pranchevicius, Luciana Previato, Rodrigo O. de Castro, Roberto J Pezza

Ensuring meiotic DNA break formation in the mouse pseudoautosomal region
Laurent Acquaviva, Michiel Boekhout, Mehmet E. Karasu, Kevin Brick, Florencia Pratto, Megan van Overbeek, Liisa Kauppi, R. Daniel Camerini-Otero, Maria Jasin, Scott Keeney

Fetus-derived IGF2 matches placental development to fetal demand
Ionel Sandovici, Aikaterini Georgopoulou, Antonia S Hufnagel, Samira N Schiefer, Fatima Santos, Katharina Hoelle, Brian Y.H. Lam, Giles S.H. Yeo, Keith Burling, Jorge Lopez-Tello, Moritz Reiterer, Abigail L. Fowden, Graham J. Burton, Amanda N. Sferruzzi-Perri, Cristina M. Branco, Miguel Constancia

HMGB1 orchestrates uterine macrophage trafficking to safeguard embryo implantation
Shizu Aikawa, Wenbo Deng, Xiaohuan Liang, Jia Yuan, Amanda Bartos, Xiaofei Sun, SK Dey

Multiple human adipocyte subtypes and mechanisms of their development
So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Ryan M.J. Genga, Alper Kucukural, Lawrence Lifshitz,Rene Maehr, Manuel Garber, Silvia Corvera

Enhancing Cardiac Reprogramming by Suppressing Specific C-C Chemokine Signaling Pathways
Yijing Guo, Ienglam Lei, Shuo Tian, Wenbin Gao, Karatas Hacer, Yangbing Li, Shaomeng Wang, Liu Liu, Zhong Wang

NOTCH assembles a transcriptional repressive complex containing NuRD and PRC1 to repress genes involved in cell proliferation and differentiation.
Cecile M Doyen, David Depierre, Ahmad Yatim, Alex Heurteau, Jean Daniel Lelievre, Yves Levy, Olivier Cuvier, Monsef Benkirane

Cdk1 in germline and the dose of somatic EGFR signaling determine the rate of transit amplification
Purna Sham Gadre, Shambhabi Chatterjee, Bhavna Varshney, Chetan Chandra Joshi, Samir Gupta, Nitin Nitsure, Krishanu Ray

Lactate and glycerol-3-phosphate metabolism cooperatively regulate growth and redox balance during Drosophila melanogaster larval development
Hongde Li, Kasun Buddika, Maria C. Sterrett, Cole R. Julick, Rose C. Pletcher, Chelsea J. Gosney, Anna K. Burton, Jonathan A. Karty, Kristi L. Montooth, Nicholas S. Sokol, Jason M. Tennessen

A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila
Christopher M Uyehara, Daniel J McKay

| Morphogenesis & mechanics

Epithelial invagination by vertical telescoping
Jingjing Li, Andrew D. Economou, Jeremy B A Green

Buckling of epithelium growing under spherical confinement
Anastasiya Trushko, Ilaria Di Meglio, Aziza Merzouki, Carles Blanch-Mercader, Shada Abuhattum, Jochen Guck, Kevin Alessandri, Pierre Nassoy, Karsten Kruse, Bastien Chopard, Aurelien Roux

Tissue shape determines actin-dependent nuclear migration mechanisms in neuroepithelia
Iskra Yanakieva, Anna Erzberger, Marija Matejcic, Carl D Modes, Caren Norden

Piezo1 is required for outflow tract and aortic valve development.
Adele Faucherre, Hamid Moha ou Maati, Nathalie Nasr, Amelie Pinard, Alexis Theron, Gaelle Odelin, Jean Pierre Desvignes, David Salgado, Gwenaelle Collod Beroud, Jean Francois Avierinos, Guillaume Lebon, Stephane Zaffran, Chris Jopling

Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis
Anne Laure Duchemin, Helene Vignes, Julien Vermot

Yorkie controls tube length and apical barrier integrity in the developing Drosophila airways
Dimitrios K Papadopoulos, Pavel Tomancak, Vasilios Tsarouhas, Christos Samakovlis, Elisabeth Knust, Kassiani Skouloudaki

Cytokinetic furrowing and abscission dynamics during brain development revealed by live imaging
Katrina C McNeely, Jessica Neville Little, Noelle D Dwyer

Cdc42 promotes epithelial morphogenesis by coupling Par-complex and Crumbs recruitment via Par6-aPKC
Francisca Nunes De Almeida, Rhian Faye Walther, Mary Toulantis Presse, Evi Vlassaks, Franck Pichaud

E-cadherin endocytosis is modulated by p120-catenin through the opposing actions of RhoA and Arf1
Joshua Greig, Natalia A. Bulgakova

Delta/Notch signaling controls neuroepithelial morphogenesis in the zebrafish spinal cord
Priyanka Sharma, Vishnu Muraleedharan Saraswathy, Li Xiang, Maximilian Furthauer

A contractile acto-myosin belt promotes growth anisotropy during the early stages of pectoral fin development in zebrafish.
Elena Kardash, Hanh Nguyen, Martin Behrndt, Carl-Philipp Heisenberg, Nadine Peyrieras, Marcos Gonzalez-Gaitan

Mechanical instabilities of aorta drive blood stem cell production: a live study
Nausicaa Poullet, Ivan Golushko, Vladimir Lorman, Jana Travnickova, Dmitryi Chalin, Sergei Rochal, Andrea Parmeggiani, Karima Kissa

Cytoplasmic volume and limiting nucleoplasmin scale nuclear size during Xenopus laevis development
Pan Chen, Miroslav Tomschik, Katherine Nelson, John Oakey, Jesse C. Gatlin, Daniel L. Levy

Altering nuclear import in early Xenopus laevis embryos affects later development
Predrag Jevtic, Daniel L. Levy

Development and maintenance of synaptic structure is mediated by the alpha-tubulin acetyltransferase MEC-17/αTAT1
Jean-Sébastien Teoh, Wenyue Wang, Gursimran Chandhok, Roger Pocock, Brent Neumann

The Role of the Wnt/PCP Formin Daam1 in Renal Ciliogenesis
Mark E Corkins, Vanja Krneta-Stankic, Malgorzata Kloc, Pierre D. McCrea, Andrew B. Gladden, Rachel K. Miller

RHO-1 and the Rho GEF RHGF-1 interact with UNC-6/Netrin signaling to regulate growth cone protrusion and microtubule organization in C. elegans
Mahekta Rajeshkumar Gujar, Aubrie Stricker, Erik A. Lundquist

Abl signaling shapes the intrinsic fluctuations of actin to direct growth of a pioneer axon in Drosophila
Akanni Clarke, Philip McQueen, Hsiao-Yu Fang, Ramakrishnan Kannan, Victor Wang, Evan McCreedy, Stephen Wincovitch, Edward Giniger

Cyto-architecture constrains a photoactivation induced tubulin gradient in the syncytial Drosophila embryo
Sameer Thukral, Bivash Kaity, Bipasha Dey, Swati Sharma, Amitabha Nandi, Mithun Mitra, Richa Rikhy

In vivo optochemical control of cell contractility at single cell resolution by Ca2+ induced myosin activation
Deqing Kong, Zhiyi Lv, Matthias Häring, Fred Wolf, Joerg Grosshans

Cell cycle dynamics during diapause entry and exit in an annual killifish revealed by FUCCI technology
Alessandro Cellerino, Luca Dolfi, Roberto Ripa, Adam Antebi, Dario Riccardo Valenzano

Novel signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size
Yara Eid Mutlak, Dina Aweida, Alexandra Volodin, Bar Ayalon, Nitsan Dahan, Anna Parnis, Shenhav Cohen

Observing the origins of human brain development: Automated processing of fetal fMRI
Saige Rutherford, Pascal Sturmfels, Mike Angstadt, Jasmine Hect, Jenna Wiens, Marion I van den Heuval, Dustin Scheinost, Moriah Thomason, Chandra Sripada

Global and regional white matter development in early childhood
Jess E Reynolds, Melody N Grohs, Deborah Dewey, Catherine Lebel

Cerebellar folding is initiated by mechanical constraints on a fluid-like layer without a cellular pre-pattern
Andrew K Lawton, Tyler Engstrom, Daniel Rohrbach, Masaaki Omura, Daniel H Turnbull, Jonathan Mamou, Teng Zhang, Jennifer M Schwarz, Alexandra L Joyner

| Genes & genomes

Early genome activation in Drosophila is extensive with an initial tendency for aborted transcripts and retained introns
Jamie C Kwasnieski, Terry L Orr-Weaver, David P Bartel

Pericentromeric heterochromatin is hierarchically organized and spatially contacts H3K9me2/3 islands located in euchromatic genome
Yuh Chwen G. Lee, Yuki Ogiyama, Nuno M. C. Martins, Brian J. Beliveau, David Acevedo, C.-ting Wu, Giacomo Cavalli, Gary H. Karpen

A single microRNA-Hox gene module controls complex movement in morphologically-distinct developmental forms of Drosophila
Raouf Issa, Joao Picao-Osorio, Nuno Rito, Maria Eugenia Chiappe, Claudio R. Alonso

Post-translational modifications of Drosophila melanogaster HOX protein, Sex combs reduced
Anirban Banerjee, Anthony Percival-Smith

The regulatory function of dIno80 correlates with its DNA binding activity
Shruti Jain, Jayant Maini, Ankita Narang, Souvik Maiti, Vani Brahmachari

Multilevel regulation of the glass locus during Drosophila eye development
Cornelia Fritsch, F. Javier Bernardo-Garcia, Tim Humberg, Sara Miellet, Silvia Almeida, Armin Huber, Simon Sprecher

Interplay of pericentromeric genome organization and chromatin landscape regulates the expression of Drosophila melanogaster heterochromatic genes
Parna Saha, Divya Tej Sowpati, Ishanee Srivastava, Rakesh Mishra

The mir-35 family links maternal germline sex to embryonic viability in C. elegans
Lars Kristian Benner, Katherine Perkins Prothro, Katherine McJunkin

HSB-1 inhibition and HSF-1 overexpression trigger overlapping transcriptional changes to promote longevity in Caenorhabditis elegans
Surojit Sural, Tzu-Chiao Lu, Seung Ah Jung, Ao-Lin Hsu

Organism-wide single-cell transcriptomics of long-lived C. elegans daf-2 mutants reveals tissue-specific reprogramming of gene expression networks
Jessica Preston, Nicholas Stiffler, Maggie Weitzman

Experimentally reduced insulin/IGF-1 signalling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring
Martin I Lind, Sanjana Ravindran, Zuzana Sekajova, Hanne Carlsson, Andrea Hinas, Alexei A Maklakov

An X-specific condensin binds to gene regulatory elements and reduces histone modifications associated with active transcription in C. elegans
Lena Annika Street, Lara Heermans Winterkorn, Chen-Yu Jiao, Sarah Elizabeth Albritton, Mohammed Sadic, Maxwell Kramer, Sevinc Ercan

Mature sperm small RNA profile in the sparrow: implications for transgenerational effects of age on fitness
Wayo Matsushima, Kristiana Brink, Julia Schroeder, Eric Alexander Miska, Katharina Gapp

Preformed Chromatin Topology Assists Transcriptional Robustness of Shh during Limb Development
Christina Paliou, Philine Guckelberger, Robert Schöpflin, Verena Heinrich, Andrea Esposito, Andrea Maria Maria Chiariello, Simona Bianco, Carlo Annunziatella, Johannes Helmuth, Stefan Haas, Ivana Jerković, Norbert Brieske, Lars Wittler, Bernd Timmermann, Mario Nicodemi, Martin Vingron, Stefan Mundlos, Guillaume Andrey

Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification
Ricard Argelaguet, Hisham Mohammed, Stephen Clark, Carine Stapel, Christel Krueger, Chantriolnt Andreas Kapourani, Yunlong Xiang, Courtney Hanna, Sebastien Smallwood, Ximena Ibarra Soria, Florian Buettner, Guido Sanguinetti, Felix Krueger, Wei Xie, Peter Rugg-Gunn, Gavin Kelsey, Wendy Dean, Jennifer Nichols, Oliver Stegle, John C Marioni, Wolf Reik

The phylogenetically distinct early human embryo
Manvendra Singh, Thomas J Widmann, Vikas Bansal, Jose L Cortes, Gerald G Schumann, Stephanie Wunderlich, Ulrich Martin, Jose L Garcia-Perez, Laurence D Hurst, Zsuzsanna Izsvak

N6-methyladenosine dynamics during early vertebrate embryogenesis
Havard Aanes, Dominique Engelsen, Adeel Manaf, Endalkachew Ashenafi Alemu, Cathrine Broberg Vagbo, Leonardo Martin, Mads Lerdrup, Klaus Hansen, Sinnakaruppan Mathavan, Cecilia Winata, Robert B. Darnell, Peter Alestrom, Arne Klungland

Transposable elements drive reorganisation of 3D chromatin during early embryogenesis
Kai Kruse, Noelia Diaz, Rocio Enriquez-Gasca, Xavier Gaume, Maria-Elena Torres-Padilla, Juan M Vaquerizas

Spontaneous retrotranspositions in normal tissues are rare and associated with cell-type-specific differentiation
Xiao Dong, Lei Zhang, Kristina Brazhnik, Moonsook Lee, Xiaoxiao Hao, Alexander Y. Maslov, Zhengdong Zhang, Tao Wang, Jan Vijg

Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability
Aviv Rom, Liliya Melamed, Micah Jonathan Goldrich, Rotem Kadir, Matan Golan, Inbal Biton, Rotem Ben-Tov Perry, Igor Ulitsky

Phase separation during mouse early embryonic development and underlying genetic and epigenetic correlations
Hui Quan, Sirui Liu, Yu Zhang, Wei Xie, Yi Qin Gao

The Prrx1 limb enhancer marks an adult population of injury-responsive, multipotent dermal fibroblasts
Joshua D. Currie, Lidia Grosser, Prayag Murawala, Maritta Schuez, Martin Michel, Elly M. Tanaka, Tatiana Sandoval-Guzman

Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage
Qiang Wu, Ya Guo, Yujia Lu, Jingwei Li, Yonghu Wu, Zhilian Jia

Pioneer and nonpioneer cooperation drives lineage specific chromatin opening
Alexandre Mayran, Kevin Sochodolsky, Konstantin Khetchoumian, Juliette Harris, Yves Gauthier, Amandine Bemmo, Aurelio Balsalobre, Jacques Drouin

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types
Rangarajan D Nadadur, Carlos Perez-Cervantes, Nicolas Lonfat, Linsin A. Smith, Andrew E. O. Hughes, Sui Wang, Joseph C Corbo, Constance L Cepko, Ivan P Moskowitz

Imprinted gene expression at the Dlk1-Dio3 cluster is controlled by both maternal and paternal IG-DMRs in a tissue-specific fashion.
Katherine A Alexander, María J García-García

Placental effects on maternal brain revealed by disrupted placental gene expression in mouse hybrids
Lena Arévalo, Polly Campbell

LINE-1 retrotransposition impacts the genome of human pre implantation embryos and extraembryonic tissues
Martin Munoz-Lopez, Raquel Vilar, Claude Philippe, Raheleh Rahbari, Sandra R. Richardson, Miguel Andres-Anton, Thomas Widmann, David Cano, Jose L. Cortes, Alejandro Rubio-Roldan, Etienne Guichard, Sara R. Heras, Francisco J. Sanchez-Luque, Maria Morell, Elisabet Aguilar, Marta Garcia-Canadas, Laura Sanchez, Angela Macia, Pedro Vilches, Maria Concepcion Nieto-Perez, Antonio Gomez-Martin, Beatriz Gonzalez-Alzaga, Clemente Aguilar- Garduno, Adam D. Ewing, Marina Lacasana, Ignacio S. Alvarez, Richard Badge, Geoffrey J. Faulkner, Gael Cristofari, Jose L. Garcia-Perez

Widespread transcriptional scanning in the testis modulates gene evolution rates
Bo Xia, Yun Yan, Maayan Baron, Florian Wagner, Dalia Barkley, Marta Chiodin, Sang Y. Kim, David L. Keefe, Joseph P. Alukal, Jef D. Boeke, Itai Yanai

Genome-wide association study, replication, and mega-analysis using a dense marker panel in a multi-generational mouse advanced intercross line
Xinzhu Zhou, Celine L. St. Pierre, Natalia M. Gonzales, Riyan Cheng, Apurva S. Chitre, Greta Sokoloff, Abraham A. Palmer

Pou5f3, SoxB1 and Nanog remodel chromatin on High Nucleosome Affinity Regions at Zygotic Genome Activation
Marina Veil, Lev Yampolsky, Bjoern Gruening, Daria Onichtchouk

Integrative methylome and transcriptome analysis of Japanese flounder (Paralichthys olivaceus) skeletal muscle during development
feng he, Jingru Zhang, Shuxian Wu, Yajuan Huang, Haishen Wen, Meizhao Zhang, Jifang Li, Yun Li, Xin Qi

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate
Abhishek Chakraborty, Tuomas Laukka, Matti Myllykoski, Alison Ringel, Matthew Booker, Michael Tolstorukov, Yuzhong Meng, Sam Meier, Rebecca Jennings, Amanda Creech, Zachary Herbert, Jessica Spinelli, Samuel McBrayer, Benjamin Olenchock, Jacob Jaffe, Marcia Haigis, Rameen Beroukhim, Sabina Signoretti, Peppi Koivunen, William G. Kaelin Jr.

| Stem cells, regeneration & disease modelling

A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm
George Britton, Idse Heemskerk, Rachel Hodge, Amina A Qutub, Aryeh Warmflash

Defining reprogramming checkpoints from single-cell analysis of induced pluripotency
Khoa A Tran, Stefan J Pietrzak, Nur Zafirah Zaidan, Alireza Siahpirani, Sunnie Grace McCalla, Gopal Iyer, Sushmita Roy, Rupa Sridharan

Polar-like trophoblast stem cells form an embryonic-abembryonic axis in blastoids.
Javier Frias Aldeguer, Maarten Kip, Judith Vivie, Linfeng Li, Ana Alemany Arias, Jeroen Korving, Frank Darmis, Clemens van Blitterswijk, Alexander van Oudenaarden, Niels Geijsen, Nicolas C Rivron

Self-organization of post-implantation-like embryonic tissues from blastoids
Erik J Vrij, Yvonne Scholte Op Reimer, Javier Frias Aldeguer, Isabel Misteli Guerreiro, Jop Kind, Bon-Kyoung Koo, Clemens van Blitterswijk, Nicolas Rivron

DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency
Katy A McLaughlin, Ilya M Flyamer, John P Thomson, Heidi K Mjoseng, Ruchi Shukla, Iain Williamson, Graeme R Grimes, Robert S Illingworth, Ian R Adams, Sari Pennings, Richard R Meehan, Wendy A Bickmore

Kidney organoid reproducibility across multiple human iPSC lines and diminished off target cells after transplantation revealed by single cell transcriptomics
Ayshwarya Subramanian, Eriene-Heidi Sidhom, Maheswarareddy Emani, Nareh Sahakian, Katherine Vernon, Yiming Zhou, Maria Kost-Alimova, Astrid Weins, Michal Slyper, Julia Waldman, Danielle Dionne, Lan Nguyen, Jamie L Marshall, Orit Rozenblatt-Rosen, Aviv Regev, Anna Greka

KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control
Navroop K Dhaliwal, Luis E Abatti, Jennifer A Mitchell

Tetraploidy in rodent cardiac stem cells confers enhanced biological properties
Kathleen Broughton, Tiffany Khieu, Nicky Nguyen, Michael Rosa, Sadia Mohsin, Pearl Quijada, Jessica Wang, Oscar Echeagaray, Dieter Kubli, Taeyong Kim, Fareheh Firouzi, Megan Monsanto, Natalie Gude, Robert Adamson, Walter Dembitsky, Michael Davis, Mark Sussman

Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks
Natalie M Clark, Eli Buckner, Adam P Fisher, Emily C Nelson, Thomas T Nguyen, Abigail R Simmons, Maria A de Luis Balaguer, Tiara Butler-Smith, Parnell J Sheldon, Dominique C Bergmann, Cranos M Williams, Rosangela Sozzani

Lipid rafts increase to facilitate ectoderm lineage specification of differentiating embryonic stem cells
Chen Xu, Bo Cao, Ying-dong Huo, Gang Niu, Michael Qiwei Zhang, Zi-lin Mai, Xi-bin Lu, Han-ben Niu, Dan-ni Chen, Yan-xiang Ni

Non-proliferative adult neurogenesis in neural crest-derived stem cells isolated from human periodontal ligament.
Carlos Bueno, Marta Martinez-Morga, Salvador Martinez

Cell division history determines hematopoietic stem cell potency
Fumio Arai, Patrick S Stumpf, Yoshiko M Ikushima, Kentaro Hosokawa, Aline Roch, Matthias P Lutolf, Toshio Suda, Ben D MacArthur

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)
Gobinath Shanmugam, David Crossman, Johnson Rajasingh, Brian Dalley, Jianyi Zhang, Rajasekaran Namakkal-Soorappan

Drosophila ClC-a is required in glia of the stem cell niche for proper neurogenic proliferation and wiring of neural circuits
Haritz Plazaola-Sasieta, Qi Zhu, Hector Gaitan-Penas, Martin Rios, Raul Estevez, Marta Morey

Discovery of Alstrom syndrome gene as a regulator of centrosome duplication in asymmetrically dividing stem cells in Drosophila.
Cuie Chen, Yukiko Yamashita

ABC transporters confer multidrug resistance to Drosophila intestinal stem cells
Hannah Dayton, Jonathan DiRusso, Kristopher Kolbert, Olivia Williamson, Aiste Balciunaite, Edridge D’Souza, Kelly Becker, Elizaveta Hosage, Muneera Issa, Victoria Liu, Raghuvir Viswanatha, Shu Kondo, Michele Markstein

Axin proteolysis by Iduna is required for the regulation of stem cell proliferation and intestinal homeostasis in Drosophila
Yetis Gultekin, Hermann Steller

Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in the adult zebrafish
Nicholas J Silva, Mikiko Nagashima, Jingling Li, Laura Kakuk-Atkins, Milad Ashrafzadeh, David R Hyde, Peter F Hitchcock

HSA+ immature cardiomyocytes persist in the adult heart and expand after ischemic injury
Mariana Valente, Tatiana Pinho Resende, Diana Santos Nascimento, Odile Burlen-Defranoux, Benoit Dupont, Ana Cumano, Perpetua Pinto-do-O

Cell non-autonomous functions of S100a4 drive fibrotic tendon healing
Jessica Ackerman, Valentina Studentsova, Katherine Best, Emma Knapp, Alayna Loiselle

Scarless whole-body regeneration in the absence of a blastema requires cell division in the ctenophore Mnemiopsis leidyi.
Julia Ramon Mateu, mark q martindale

Consecutive signaling pathways are activated in progression of Duchenne muscular dystrophy in C. elegans
Heather Geissel, Hannah Steber, Jason Newbern, Alan Rawls, Marco Mangone

A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells
Tomasz Dobrzycki, Monika Krecsmarik, Cansu Koyunlar, Rossella Rispoli, Joke Peulen-Zink, Kirsten Gussinklo, Emma de Pater, Roger Patient, Rui Monteiro

Why does the zebrafish cloche mutant develop lens cataract?
Mason Posner, Matthew S. McDonald, Kelly L. Murray, Andor J. Kiss

Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia
Tatiana V. Tkatchenko, Rupal L. Shah, Takayuki Nagasaki, Andrei V. Tkatchenko

Anterior Cleft Palate due to Cbfb deficiency and its rescue by folic acid
Takashi Yamashiro

Atypical neurogenesis and excitatory-inhibitory progenitor generation in induced pluripotent stem cell (iPSC) from autistic individuals
Dwaipayan Adhya, Vivek Swarup, Roland Nagy, Carole Shum, Paulina Nowosiad, Kamila Jozwik, Irene Lee, David Skuse, Frances A Flinter, Grainne McAlonan, Maria Andreina Mendez, Jamie Horder, Declan Murphy, Daniel H. Geschwind, Jack Price, Jason Carroll, Deepak P. Srivastava, Simon Baron-Cohen

Left Pulmonary Artery in 22q11.2 deletion syndrome. Echocardiographic evaluation in patients without cardiac defects and role of Tbx1 in mice.
Gioia Mastromoro, Giulio Calcagni, Paolo Versacci, Carolina Putotto, Marcello Chinali, Caterina Lambiase, Marta Unolt, Elena Pelliccione, Silvia Anaclerio, Cinzia Caprio, Sara Cioffi, Marchesa Bilio, Anwar Baban, Fabrizio Drago, Maria Cristina Digilio, Bruno Marino, Antonio Baldini

Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse
Sally H Cross, Lisa Mckie, Margaret Keighren, Katrine West, Caroline Thaung, Tracey Davey, Ian J Jackson

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
Jacob A Ross, Yotam Levy, Justin S Kolb, Mark Turmaine, Mark Holt, Michela Ripolone, Maurizio Moggio, Chiara Fiorillo, Johan Lindqvist, Nicolas Figeac, Peter Zammit, Heinz Jungbluth, John Vissing, Nanna Witting, Henk Granzier, Edmar Zanoteli, Edna C Hardeman, Carina Wallgren-Pettersson, Julien Ochala

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome
Eduardo Soares, Quan Xu, Qingqing Li, Jieqiong Qu, Yuxuan Zheng, Hetty H. M. Raeven, Karina Brandao, Isabelle Petit, Willem M.R. van den Akker, Daniel Aberdam, Fuchou Tang, Huiqing Zhou

Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy
Emily Jones, Zoe Matthews, Lejla Gul, Padhmanand Sudhakar, Agatha Treveil, Devina Divekar, Jasmine Buck, Tomasz Wrzesinski, Matthew Jefferson, Stuart Armstrong, Lindsay Hall, Alastair Watson, Simon Carding, Wilfried Haerty, Federica Di Palma, Ulrike Mayer, Penny Powell, Isabelle Hautefort, Tom Wileman, Tamas Korcsmaros

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter
Prisca Leferink, Stephanie Dooves, Anne Hillen, Kyoko Watanabe, Gerbren Jacobs, Lisa Gasparotto, Paulien Cornelissen-Steijger, Marjo van der Knaap, Vivi Heine

Development of Human Neuroblastomas in Mouse-Human Neural Crest Chimeras
Malkiel A. Cohen, Shupei Zhang, Satyaki Sengupta, Haiting Ma, Brendan Horton, George W. Bell, Rani E. George, Stefani Spranger, Rudolf Jaenisch

Tissue nonspecific alkaline phosphatase improves bone quality but does not alleviate craniosynostosis in the FGFR2C342Y/+ mouse model of Crouzon syndrome
Hwa Kyung Nam, Sara Dean Schutte, Nan Hatch

Isogenic human iPSC pairs reveal a neuronal subtype-specific and genetic background-independent mechanism of SCN1A epilepsy
Yunyao Xie, Nathan N Ng, Olga S Safrina, Carmen M Ramos, Kevin C Ess, Philip H Schwartz, Martin A Smith, Diane K O’Dowd

Postnatal development of skeletal muscle in IUGR pigs: morphofunctional phenotype and molecular mechanisms
Fernanda Almeida, Andreia Pereira, Fernando Felicioni, André Caldeira-Brant, Diogo Magnabosco, Fernando Bortolozzo, Stephen Tsoi, Michael Dyck, Walter Dixon, Patricia Martinelli, Erika Jorge, Helio Chiarini-Garcia

CIC-DUX4 expression drives the development of small round cell sarcoma in transgenic zebrafish: a new model revealing a role for ETV4 in CIC-mediated sarcomagenesis
Sarah Watson, Genevieve C Kendall, Dinesh Rakheja, Matthew E McFaul, Bruce W Draper, Franck Tirode, Olivier Delattre, James F Amatruda

| Plant development

Wheat VRN1 and FUL2 play critical and redundant roles in spikelet meristem identity and spike determinacy
Chengxia Li, Huiqiong Lin, Andrew Chen, Meiyee Lau, Judy Jernstedt, Jorge Dubcovsky

Systemic signalling through TCTP1 controls lateral root formation in Arabidopsis
Remi Branco, Josette Masle

Distinct ROPGEFs successively drive polarization and outgrowth of root hairs
Denninger Philipp, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, Dietmar Gerald Mehlhorn, Lisa Yasmin Asseck, Claire Elizabeth Stanley, Nana Friderike Keinath, Jan Felix Evers, Christopher Grefen, Guido Grossmann

Shoot-to-root translocation of the jasmonate precursor 12-oxo-phytodienoic acid (OPDA) coordinates plant growth responses following tissue damage
Adina Schulze, Marlene Zimmer, Stefan Mielke, Hagen Stellmach, Charles W Melnyk, Bettina Hause, Debora Gasperini

Molecular framework for TIR1/AFB-Aux/IAA-dependent auxin sensing controlling adventitious rooting in Arabidopsis
Abdellah Lakehal, Salma Chaabouni, Emilie Cavel, Rozenn Le Hir, Alok Ranjan, Zahra Raneshan, Ondrej Novak, Daniel I Pacurar, Irene Perrone, Francois Jobert, Laurent Gutierrez, Laszlo Bako, Catherine Bellini

Potential involvement of root auxins in drought tolerance by modulating nocturnal and daytime water use in wheat
Walid Sadok, Remy Schoppach

Members of the Arabidopsis auxin receptor gene family are essential early in embryogenesis and have broadly overlapping functions
Michael J Prigge, Nikita Kadakia, Kathleen Greenham, Mark Estelle

The striking flower-in-flower phenotype of Arabidopsis thaliana Nossen (No-0) is caused by a novel LEAFY allele
Anne Mohrholz, Hequan Sun, Nina Gloeckner, Sabine Hummel, Uener Kolukisaoglu, Korbinian Schneeberger, Klaus Harter

REC8-cohesin, chromatin and transcription orchestrate meiotic recombination in the Arabidopsis genome
Christophe Lambing, Andrew J. Tock, Kyuha Choi, Stephanie D. Topp, Pallas C. Kuo, Alexander R. Blackwell, Xiaohui Zhao, Kim Osman, James D. Higgins, F. Chris H. Franklin, Ian R. Henderson

Paternally-acting canonical RNA-directed DNA methylation pathway genes sensitize Arabidopsis endosperm to paternal dosage
Rajavasireddy P Satyaki, Mary Gehring

Elucidating small RNA pathways in Arabidopsis thaliana egg cells
Stefanie Sprunck, Marc Urban, Nicholas Strieder, Maria Lindemeier, Andrea Bleckmann, Maurits Evers, Thomas Hackenberg, Christoph Moehle, Thomas Dresselhaus, Julia C. Engelmann

Regulation of Parent-of-Origin Allelic Expression in Arabidopsis thaliana endosperm
Karina S. Hornslien, Jason R. Miller, Paul E. Grini

A hypomorphic allele of telomerase reverse transcriptase uncovers the minimal functional length of telomeres in Arabidopsis.
James M. Watson, Johanna Trieb, Martina Troestl, Kyle Renfrew, Terezie Mandakova, Dorothy E Shippen, Karel Riha

A cis-carotene derived apocarotenoid regulates etioplast and chloroplast development
Christopher I Cazzonelli, Xin Hou, Yagiz Alagoz, John Rivers, Namraj Dhami, Jiwon Lee, Shashikanth Marri, Barry J Pogson

Environmental and epigenetic regulation of Rider retrotransposons in tomato
Matthias Benoit, Hajk-Georg Drost, Marco Catoni, Quentin Gouil, Sara Lopez-Gomollon, David Charles Baulcombe, Jerzy Paszkowski

Plant seeds are primed by herbivore-induced plant volatiles
Abhinav Kumar Maurya, Leila Pazouki, Christopher Frost

From spatio-temporal morphogenetic gradients to rhythmic patterning at the shoot apex
Carlos Samuel Galvan-Ampudia, Guillaume Cerutti, Jonathan Legrand, Romain Azais, Géraldine Brunoud, Steven Moussu, Christian Wenzl, Jan Lohmann, Christophe Godin, Teva Vernoux

WUSCHEL acts as a rheostat on the auxin pathway to maintain apical stem cells in Arabidopsis
Yanfei Ma, Andrej Miotk, Zoran Sutikovic, Anna Medzihradszky, Christian Wenzl, Olga Ermakova, Christophe Gaillochet, Joachim Forner, Goedze Utan, Klaus Brackmann, Carlos S. Galvan-Ampudia, Teva Vernoux, Thomas Greb, Jan U. Lohmann

Genome-Wide Association Study and Pathway-Level Analysis of Kernel Color in Maize
Brenda F. Owens, Deepu Mathew, Christine Diepenbrock, Tyler Tiede, Di Wu, Maria Mateos-Hernandez, Michael A. Gore, Torbert Rocheford

The genetics and genome-wide screening of regrowth loci, a key component of perennialism in Zea diploperennis
Anjun Ma, Yinjie Qiu, Tajbir Raihan, Subha Dahal, Yongbin Zhuang, Aravind Galla, Donald L. Auger, Yang Yen

Evo-devo & evo

β-catenin has an ancestral role in cell fate specification but not cell adhesion
Miguel Salinas-Saavedra, Athula Wikramanayake, mark Q martindale

Differential expression of BMP antagonists, gremlin and noggin in hydra: antagonism between Wnt and BMP pathways
Lakshmi Surekha Krishnapati, Samiksha Khade, Diptee Trimbake, Rohan Patwardhan, Siva Kumar Nadimpalli, Surendra Ghaskadbi

Evolutionary loss of foot muscle during development with characteristics of atrophy and no evidence of cell death
Mai P Tran, Rio Tsutsumi, Joel M Erberich, Kevin D Chen, Michelle D Flores, Kimberly L Cooper

Evolution of the embryonic cis-regulatory landscapes between divergent Phallusia and Ciona ascidians.
Alicia Madgwick, Marta Silvia Magri, Christelle Dantec, Damien Gailly, Ulla-Maj Fiuza, Leo Guignard, Sabrina Hettinger, Jose Luis Gomez-Skarmeta, Patrick Lemaire

Bacterial community dynamics during embryonic and larval development of three confamilial echinoids
Tyler Carrier,  ProfileAdam Reitzel

Mice carrying a humanized Foxp2 knock-in allele show region-specific shifts of striatal Foxp2 expression levels
Christiane Schreiweis, Theano Irinopoulou, Beate Vieth, Lilia Laddada, Franck Oury, Eric Burguiere, Wolfgang Enard, Matthias Groszer

Krüppel-like factor gene function in the ctenophore Mnemiopsis suggests an ancient role in promoting cell proliferation in metazoan stem cell niches
Jason S Presnell, William E Browne

RNAi screen in Tribolium reveals involvement of F-BAR proteins in myoblast fusion and visceral muscle morphogenesis in insects
Dorothea Schultheis, Jonas Schwirz, Manfred Frasch

A large-scale systemic RNAi screen in the red flour beetle Tribolium castaneum identifies novel genes involved in insect muscle development
Dorothea Schultheis, Matthias Weißkopf, Christoph Schaub, Salim Ansari, Van-Anh Dao, Daniela Grossmann, Upalparna Majumdar, Muhammad Salim Hakeemi, Nicole Troelenberg, Tobias Richter, Christian Schmitt-Engel, Jonas Schwirz, Nadi Ströhlein, Matthias Teuscher, Gregor Bucher, Manfred Frasch

The visual system of the genetically tractable crustacean Parhyale hawaiensis: diversification of eyes and visual circuits associated with low-resolution vision
Ana Patricia Ramos, Ola Gustafsson, Nicolas Labert, Iris Salecker, Dan Eric Nilsson, Michalis Averof

The Evolution of Placental Invasion and Cancer Metastasis are Causally Linked
Kshitiz Gupta, Junaid Afzal, Jamie D. Maziarz, Archer Hamidzadeh, Cong Liang, Eric M. Erkenbrack, Hong Nam, Jan-Dirk Haeger, Christiane Pfarrer, Thomas Hoang, Troy Ott, Thomas Spencer, Mihaela Pavlicev, Doug Antczak, Andre Levchenko, Gunter P. Wagner

Loss of a glutaredoxin gene underlies parallel evolution of trichome pattern in Antirrhinum
Ying Tan, Matthew Barnbrook, Yvette Wilson, Attila Molnar, Andrew Hudson

Recent origin of an XX/XY sex-determination system in the ancient plant lineage Ginkgo biloba
He Zhang, Rui Zhang, Xianwei Yang, Kai-Jie Gu, Wenbin Chen, Yue Chang, Qiwu Xu, Qun Liu, Yating Qin, Xiaoning Hong, Ping-Ping Yin, Inge Seim, Han-Yang Lin, Wen-Hao Li, Jinfu Tian, Shanshan Li, Longqi Liu, Junnian Liu, Shanshan Liu, Xiaoshan Su, Congyan Wang, Fu-Ming Zhang, Song Ge, Cheng-Xin Fu, Simon Ming-Yuen Lee, Yiji Xia, Jian Wang, Huanming Yang, Guangyi Fan, Xun Xu, Yun-Peng Zhao, Xin Liu

A simple genetic architecture and low constraint allows rapid floral evolution in a diverse and recently radiating plant genus
Jamie L. Kostyun, Matthew J. S. Gibson, Christian M. King, Leonie C. Moyle

Sulcal organization in the medial frontal cortex reveals insights into primate brain evolution
CELINE AMIEZ, Jerome Sallet, William D. Hopkins, Adrien Meguerditchian, Fadila Hadj-Bouziane, Suliann BenHamed, Charles R.E. Wilson, Emmanuel Procyk, Michael Petrides

Molecular evolution across developmental time reveals rapid divergence in early embryogenesis
Asher D Cutter, Rose H Garrett, Stephanie Mark, Wei Wang, Lei Sun

Evolution of the D. melanogaster chromatin landscape and its associated proteins
Elise Parey, Anton Crombach

Birth-and-death evolution of the fatty acyl-CoA reductase (FAR) gene family and diversification of cuticular hydrocarbon synthesis in Drosophila
Cedric Finet, Kailey Slavik, Jian Pu, Sean B. Carroll, Henry Chung

Studying the dawn of de novo gene emergence in mice reveals fast integration of new genes into functional networks
Chen Xie, Cemalettin Bekpen, Sven Künzel, Maryam Keshavarz, Rebecca Krebs-Wheaton, Neva Skrabar, Kristian Karsten Ullrich, Diethard Tautz

Premeiotic and meiotic failures lead to hybrid male sterility in the Anopheles gambiae complex
Jiangtao Liang, Igor V. Sharakhov

Mosaic origin of the eukaryotic kinetochore
Jolien JE van Hooff, Eelco Tromer, Geert Kops, Berend Snel

A chromosome-level genome of black rockfish, Sebastes schlegelii, provides insights into the evolution of live birth
Yan He, Yue Chang, Lisui Bao, Mengjun Yu, Rui Li, Jingjing Niu, Guangyi Fan, Weihao Song, Inge Seim, Yating Qin, Xuemei Li, Jinxiang Liu, Xiangfu Kong, Meiting Peng, Minmin Sun, Mengya Wang, Jiangbo Qu, Xuangang Wang, Xiaobing Liu, Xiaolong Wu, Xi Zhao, Xuliang Wang, Yaolei Zhao, Jiao Guo, Yang Liu, Kaiqiang Liu, Yilin Wang, He Zhang, Longqi Liu, Mingyue Wang, Haiyang Yu, Xubo Wang, Jie Cheng, Zhigang Wang, Xun Xu, Jian Wang, Huanming Yang, Simon Ming-Yuen Lee, Xin Liu, Quanqi Zhang, Jie Qi

De novo assembly of the Mongolian gerbil genome and transcriptome
Shifeng Cheng, Yuan Fu, Yaolei Zhang, Wenfei Xian, Hongli Wang, Benedikt Grothe, Xin Lu, Xun Xu, Achim Klug, Elizabeth A McCullagh

Cell biology

Reconstruction of Par polarity in apolar cells reveals a dynamic process of cortical polarization
Kalyn Kono, Shigeki Yoshiura, Ikumi Fujita, Yasushi Okada, Atsunori Shitamukai, Tatsuo Shibata, Fumio Matsuzaki

Centering based on active diffusion in mouse oocytes is non-specific
Alexandra Colin, Nitzan Ratzin, Maria Almonacid, Wylie Ahmed, Timo Betz, Marie-Emilie Terret, Nir Gov, Raphaël Voituriez, Zoher Gueroui, Marie-Helene VERLHAC

The Piezo channel is used by migrating cells to sense compressive load
Nishit Srivastava, David Traynor, Alexandre Kabla, Rob Kay

YAP/TAZ as a Novel Regulator of cell volume
Nicolas Andres Perez Gonzalez, Nash Delta Rochman, Kai Yao, Jiaxiang Tao, Mihn-Tam Tran Le, Shannon Flanary, Lucia Sablich, Ben Toler, Eliana Crentsil, Felipe Takaesu, Bram Lambrus, Jessie Huang, Vivian Fu, Andrew Holland, Steven An, Denis Wirtz, Kun-Liang Guan, Sean Sun

Disassembly of actin and keratin networks by Aurora B kinase at the midplane of cleaving Xenopus laevis eggs
Christine M Field, James F Pelletier, Tim Mitchison

Contractile acto-myosin network on nuclear envelope remnants positions human chromosomes for mitosis
Alexander JR Booth, Zuojun Yue, John K Eykelenboom, Tom Stiff, GW Gant Luxton, Helfrid Hochegger, Tomoyuki U Tanaka

Primary Cilium Disassembly in Mammalian Cells Occurs Predominantly by Whole-Cilium Shedding
Mariya Mirvis, Kathleen A Siemers, William James Nelson, Tim Stearns

Cell-projection pumping: A hydrodynamic cell-stiffness dependent mechanism for cytoplasmic transfer between mammalian cells
Hans Zoellner, Navid Paknejad, James Cornwell, Belal Chami, Yevgeniy Romin, Vitaly Boykov, Sho Fujisawa, Elizabeth Kelly, Garry W Lynch, Glynn Rogers, Katia Manova, Malcolm AS Moore

Mutation Of MLH3 Endonuclease Motif Reveals Integration Between Crossover Pathways In Mammalian Meiosis
Melissa Toledo, Xianfei Sun, Miguel Angel Brieno-Enriquez, Vandana Raghavan, Stephen Gray, Jeffrey Pea, Anita Venkatesh, Lekha Patel, Peter L Borst, Eric Alani, Paula E Cohen

Spatial Regulation of Polo-like Kinase Activity during C. elegans Meiosis by the Nucleoplasmic HAL-2/HAL-3 Complex
Baptiste Roelens, Consuelo Barroso, Alex Montoya, Pedro Cutillas, Weibin Zhang, Alexander Woglar, Chloe Girard, Enrique Martinez-Perez, Anne Villeneuve

Synaptonemal complex proteins direct and constrain the localization of crossover-promoting proteins during Caenorhabditis elegans meiosis
Cori K Cahoon, Jacquellyn M Helm, Diana E Libuda

TMEM98 is a negative regulator of FRAT mediated Wnt/β-catenin signalling
Tanne van der Wal, Jan-Paul Lambooij, Katrin E Wiese, Renée van Amerongen

Phase separation provides a mechanism to reduce noise in cells
Florian Oltsch, Adam Klosin, Frank Julicher, Anthony A. Hyman, Christoph Zechner

Spatial Asymmetries of the Prophase Nucleus Regulate Dynein Recruitment to Ensure Mitotic Fidelity
Vanessa Nunes, Margarida Dantas, Elisa Vitiello, Irene Wang, Nicolas Carpi, Martial Balland, Matthieu Piel, Paulo Aguiar, Helder Maiato, Jorge G Ferreira

Asymmetric clustering of centrosomes defines the early evolution of tetraploid cells
Nicolaas C Baudoin, Kimberly Soto, Olga Martin, Joshua M Nicholson, Jing Chen, Daniela Cimini

Modelling

Neuronal differentiation affects tissue mechanics and progenitor arrangement in the vertebrate neuroepithelium
Pilar Guerrero, Ruben Perez-Carrasco, Marcin Zagorski, David Page, Anna Kicheva, James Briscoe, Karen Page

ya||a: GPU-powered Spheroid Models for Mesenchyme and Epithelium
Philipp Germann, Miquel Marin-Riera, James Sharpe

Competition for Stem Cell Fate Determinants as a Mechanism for Tissue Homeostasis
David J Jörg, Yu Kitadate, Shosei Yoshida, Benjamin D Simons

How to fit in: The learning principles of cell differentiation
Miguel Brun-Usan, Richard Watson

Modeling enamel matrix secretion in mammalian teeth
Teemu J. Hakkinen, S. Susanna Sova, Ian J. Corfe, Leo Tjaderhane, Antti Hannukainen, Jukka Jernvall

A stochastic model of adult neurogenesis coupling cell cycle progression and differentiation
Anna Stopka, Marcelo Boareto

Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers
Ofir Shukron, Vincent Piras, Daan Noordermeer, David Holcman

Dynamical reorganization of transcriptional events governs robust Nanog heterogeneity
Tagari Samanta, Sandip Kar

Interacting cells driving the evolution of multicellular life cycles
Yuanxiao Gao, Arne Traulsen, Yuriy Pichugin

Organ-wide and ploidy-dependent regulations both contribute to cell size determination: evidence from a computational model of tomato fruit
Valentina Baldazzi, Pierre Valsesia, Michel Genard, Nadia Bertin

Coupling water fluxes with cell wall mechanics in a multicellular model of plant development
Ibrahim Cheddadi, Michel Genard, Nadia Bertin, Christophe Godin

A mathematical model of contact inhibition of locomotion: coupling contractility and focal adhesions
Aydar Uatay

A simple mechanochemical model for calcium signalling in embryonic epithelial cells
Katerina Kaouri, Philip K. Maini, Paris Skourides, Neophytos Christodoulou, S. Jonathan Chapman

Theory of mechano-chemical patterning in biphasic biological tissues
Pierre Recho, Adrien Hallou, Edouard Hannezo

The statistics of noisy growth with mechanical feedback in elastic tissues
Ojan Khatib Damavandi, David K. Lubensky

Tools & resources

A 3D-printed hand-powered centrifuge for molecular biology
Gaurav Byagathvalli, Aaron Pomerantz, Soham Sinha, Janet Standeven, M. Saad Bhamla

Microscopy-based chromosome conformation capture enables simultaneous visualization of genome organization and transcription in intact organisms
Andres M Cardozo Gizzi, Diego I. Cattoni, Jean-Bernard Fiche, Sergio Espinola, Julian Gurgo, Olivier Messina, Christophe Houbron, Yuki Ogiyama, Giorgio-Lucio Papadopoulos, Giacomo Cavalli, Mounia Lagha, Marcelo Nollmann

Multi-ATOM: Ultrahigh-throughput single-cell quantitative phase imaging with subcellular resolution
Kelvin Lee, Andy Lau, Anson Tang, Maolin Wnag, Aaron Mok, Bob Chung, Wenwei Yan, Ho Cheung Shum, Kathryn Cheah, Godfrey Chan, Hayden So, Kenneth Wong, Kevin Tsia

Optical clearing of living brains with MAGICAL to extend in vivo imaging
Kouichirou Iijima, Takuto Oshima, Ryosuke Kawakami, Tomomi Nemoto

Optimisation and validation of hydrogel-based brain tissue clearing shows uniform expansion across anatomical regions and spatial scales
Adam L Tyson, Ayesha Akhtar, Laura C Andreae

Magnetic Ultrathin Tissue Sections for Ease of Light and Electron Microscopy
German Koestinger, Daniel During, Simone Rickauer, Vanessa Leite, Homare Yamahachi, Gabor Csucs, Richard HR Hahnloser

Multimodal cell type correspondence by intersectional mFISH in intact tissues
Philip R Nicovich, Michael J Taormina, Christopher A Baker, Thuc Nghi Nguyen, Elliot R Thomsen, Emma Garren, Brian Long, Melissa Gorham, Jeremy Miller, Travis Hage, Alice Bosma-Moody, Gabe J Murphy, Boaz P Levi, Jennie L Close, Bosiljka Tasic, Ed S Lein, Hongkui Zeng

DypFISH: Dynamic Patterned FISH to Interrogate RNA and Protein Spatial and Temporal Subcellular Distribution
Anca F. Savulescu, Robyn Brackin, Emmanuel Bouilhol, Benjamin Dartigues, Jonathan H. Warrell, Mafalda R. Pimentel, Stephane Dallongeville, Jan Schmoranzer, Jean-Christophe Olivo-Marin, Edgar R. Gomes, Macha Nikolski, Musa M. Mhlanga

zGrad: A nanobody-based degron system to inactivate proteins in zebrafish
Naoya Yamaguchi, Tugba Colak-Champollion, Holger Knaut

Determining targeting specificity of nuclear-encoded organelle proteins with the self-assembling split fluorescent protein toolkit
Mayank Sharma, Carola Kretschmer, Christina Lampe, Johannes Stuttmann, Ralf Bernd Klosgen

De novo assembly, delivery and expression of a 101 kb human gene in mouse cells
Leslie A. Mitchell, Laura H. McCulloch, Sudarshan Pinglay, Henri Berger, Nazario Bosco, Ran Brosh, Milica Bulajic, Emily Huang, James A. Martin, Megan S. Hogan, Esteban Mazzoni, Teresa Davoli, Matthew T. Maurano, Jef D. Boeke

Culturing primary neurons from rat hippocampus and cortex
Madhusmita Priyadarshini Sahu, Outi Nikkila, Seija Lagas, Sulo Kolehmainen, Eero Castren

A gold standard method for human cell quantification after xenotransplantation
Mona Bensalah, Pierre Klein, Ingo Riederer, Soraya Chaouch, Laura Muraine, Wilson Savino, Gillian Sandra Butler-Bowne, Capucine Trollet, Vincent Mouly, Anne Bigot, Elisa Negroni

Stable transgenesis in Astyanax mexicanus using the Tol2 transposase system.
Bethany A Stahl, Robert Peuss, Brittnee McDole, Alexander Kenzior, James B Jaggard, Karin Gaudenz, Jaya Krishnan, Suzanne E McGaugh, Erik R Duboue, Alex C Keene, Nicolas Rohner

The genome of C57BL/6J “Eve”, the mother of the laboratory mouse genome reference strain
Vishal Kumar Sarsani, Narayanan Raghupathy, Ian T Fiddes, Joel Armstrong, Francoise Thibaud-Nissen, Oraya Zinder, Mohan Bolisetty, Kerstin Howe, Doug Hinerfeld, Xiaoan Ruan, Lucy Rowe, Mary Barter, Guruprasad Ananda, Benedict Paten, George M. Weinstock, Gary A. Churchill, Michael V. Wiles, Valerie A. Schneider, Anuj Srivastava, Laura Reinholdt

A genetic system for biasing the sex ratio in mice
Ido Yosef, Liat Edry-Botzer, Rea Globus, Inbar Shlomovitz, Ariel Munitz, Motti Gerlic, Udi Qimron

Identification and mitigation of pervasive off-target activity in CRISPR-Cas9 screens for essential non-coding elements
Josh Tycko, Michael Wainberg, Georgi K Marinov, Oana Ursu, Gaelen T Hess, Braeden K Ego, Aradhana, Amy Li, Alisa Truong, Alexandro E Trevino, Kaitlyn Spees, David Yao, Irene M Kaplow, Peyton G Greenside, David W Morgens, Douglas H Phanstiel, Michael P Snyder, Lacramioara Bintu, William J Greenleaf, Anshul Kundaje, Michael C Bassik

Splice donor site sgRNAs enhance CRISPR/Cas9-mediated knockout efficiency
Ignacio Garcia-Tunon, Veronica Alonso-Perez, Elena Vuelta, Sandra Perez- Ramos, Maria Herrero, Lucia Mendez, Jesus Maria Hernandez-Sanchez, Marta Martin-Izquierdo, Raquel Saldana, Julian Sevilla, Fermin Sanchez-Guijo, Jesus Maria Hernandez-Rivas, Manuel Adolfo Sanchez-Martin

Gene activation by a CRISPR-assistant trans enhancer
Xinhui Xu, Wei Dai, Danyang Wang, Jian Wu, Jinke Wang

Homology-directed repair using transient CRISPR/Cpf1-geminiviral replicon in tomato
Tien Van Vu, Velu Sivankalyani, Eun-Jung Kim, Mil Thi Tran, Jihae Kim, Yeon Woo Sung, Duong Thi Hai Doan, Jae-Yean Kim

Identification of transgene-free CRISPR edited plants of rice and tomato by monitoring DsRED fluorescence in dry seeds
Norma Aliaga Franco, Cunjin Zhang, Silvia Presa, Antonio Granell, David Alabadi, Ari Sadanandom, Miguel A. Blazquez, Eugenio G. Minguet

CRISPR-based platform for multimodal genetic screens in human iPSC-derived neurons
Ruilin Tian, Mariam A Gachechiladze, Connor H Ludwig, Matthew T Laurie, Jason Y Hong, Diane Nathaniel, Anika V Prabhu, Michael S Fernandopulle, Rajan Patel, Michael E Ward, Martin Kampmann

Generating single cell-derived knockout clones in mammalian cells with CRISPR/Cas9

Christopher J Giuliano​, Ann Lin​, Jason Sheltzer

Dynamic pseudo-time warping of complex single-cell trajectories
Van Hoan Do, Mislav Blažević, Pablo Monteagudo, Luka Borozan, Khaled Elbassioni, Sören Laue, Francisca Rojas Ringeling, Domagoj Matijević, Stefan Canzar

TooManyCells identifies and visualizes relationships of single-cell clades
Gregory W Schwartz, Jelena Petrovic, Maria Fasolino, Yeqiao Zhou, Stanley Cai, Lanwei Xu, Warren S Pear, Golnaz Vahedi, Robert B Faryabi

scSLAM-seq reveals core features of transcription dynamics in single cells
Florian Erhard, Marisa AP Baptista, Tobias Krammer, Thomas Hennig, Marius Lange, Panagiota Arampatzi, Christopher Juerges, Fabian J Theis, Antoine-Emmanuel Saliba, Lars Doelken

Geometric Sketching Compactly Summarizes the Single-Cell Transcriptomic Landscape
Brian Hie, Hyunghoon Cho, Benjamin DeMeo, Bryan Bryson, Bonnie Berger

scAlign: a tool for alignment, integration and rare cell identification from scRNA-seq data
Nelson Johansen, Gerald Quon

Scarless Enriched selection of Genome edited Human Pluripotent Stem Cells Using Induced Drug Resistance
Keun-Tae Kim, Ju-Chan Park, Haesung Lee, Hyeon-Ki Jang, Yang Jin, Wankyu Kim, Jeongmi Lee, Hyongbum Henry Kim, Sangsu Bae, Hyuk-Jin Cha

Biased visibility in HiC datasets marks dynamically regulated condensed and decondensed chromatin states genome-wide.
Keerthivasan Raanin Chandradoss, Prashanth Kumar Guthikonda, Srinivas Kethavath, Monika Dass, Harpreet Singh, Rakhee Nayak, Sreenivasulu Kurukuti, Kuljeet Singh Sandhu

Single-molecule long-read sequencing reveals the chromatin basis of gene expression
Yunhao Wang, Anqi Wang, Zujun Liu, Andrew Thurman, Linda S Powers, Meng Zou, Adam Hefel, Yunyi Li, Joseph Zabner, Kin Fai Au

Capturing cell type-specific chromatin structural patterns by applying topic modeling to single-cell Hi-C data
Hyeon-Jin Kim, Galip Gurkan Yardimici, Giancarlo Bonora, Vijay Ramani, Jie Liu, Ruolan Qiu, Choli Lee, Jennifer Hesson, Carol B. Ware, Jay Shendure, Zhijun Duan, William Stafford Noble

TAF-ChIP: An ultra-low input approach for genome wide chromatin immunoprecipitation assay
Junaid Akhtar, Piyush More, Steffen Albrecht, Federico Marini, Apurva Kulkarni, Waldemaar Kaiser, Leszek Wojnowski, Jean-Fred Fontaine, Miguel A Andrade-Navarro, Marion Silies, Christian Berger

Locating a transgene integration site by nanopore sequencing
David Conrad Page, Peter Nicholls, Daniel Winston Bellott, Ting-Jan Cho, Tatyana Pyntikova

Mapping of transgenic alleles in plants using a Nanopore-based sequencing strategy
Shengjun Li, Shangang Jia, Lili Hou, Hanh Nguyen, Shirley Sato, David Holding, Edgar Cahoon, Chi Zhang, Tom Clemente, Bin Yu

Inference of CRISPR Edits from Sanger Trace Data
Timothy Hsiau, David Conant, Travis Maures, Kelsey Waite, Joyce Yang, Reed Kelso, Kevin Holden, Brittany L Enzmann, Rich Stoner

VPAC: Variational projection for accurate clustering of single-cell transcriptomic data
Shengquan Chen, Kui Hua, Hongfei Cui, Rui Jiang

Research practice & education

Tracking the popularity and outcomes of all bioRxiv preprints
Richard J. Abdill, Ran Blekhman

Postdoc X-ray in Europe 2017: work conditions, productivity, institutional support and career outlooks
Maria José Ribeiro, Ana Fonseca, Mariana Moura-Ramos, Marta Costa, Konstantina Kilteni, Lau Moller Andersen, Lisa Harber-Aschan, Joana A. Moscoso, Sonchita Bagchi, European Network of Postdoctoral Associations (ENPA)

A variant of the student’s t-test for data of varying reliability
Suril B Sheth, Bhavin R Sheth

Reaction times and other skewed distributions: problems with the mean and the median
Guillaume A Rousselet, Rand R Wilcox

A Reaction Norm Perspective on Reproducibility
Bernhard Voelkl, Hanno Würbel

Perceptions and Prospects in Life Sciences in a Heterogenous Latin American Population
Leonardo M.R. Ferreira, Giovanni A. Carosso, Bruno Lopez-Videla, Gustavo Vaca Diez, Laura Ines Rivera-Betancourt, Yara Rodriguez, Dalila G. Ordonez, Natalia Montellano Duran, Diana K. Alatriste-Gonzalez, Aldo Vacaflores, Soad Bohorquez, Lilian Gonzalez Auza, Christian Schuetz, Carolina Alexander-Savino, Omar Gandarilla Cuellar, Mohammed Andres Mostajo Radji

Why not…

Recording of “sonic attacks” on U.S. diplomats in Cuba spectrally matches the echoing call of a Caribbean cricket
Alexander L Stubbs, Fernando Montealegre-Z

Enjoy The Violence: Is appreciation for extreme music the result of cognitive control over the threat response system?
Rosalie Ollivier, Louise Goupil, Marco Liuni, Jean-Julien Aucouturier

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A team of preLights selectors respond to a meta-analysis of bioRxiv preprints.

Gautam Dey, Zhang-He Goh, Lars Hubatsch, Maiko Kitaoka, Robert Mahen, Máté Palfy, Connor Rosen and Samantha Seah*

*all authors contributed equally; cross-posted from here.

The growing adoption of preprints over the last five years in the biological sciences has driven discussion within the academic community about the merits, goals, and potential downsides of disseminating work prior to peer review. However, the community has lacked a systematic bibliometric analysis (Figure 1) of preprints in which to root these discussions. Abdill and Blekhman¹ have generated an analysis of the data to identify trends in preprint usage, popularity, and outcomes, and created the website rxivist.org to facilitate future analysis and to provide an alternative platform for discovering actively discussed preprints.

As members of the preLights community who support the increased uptake of – and discussion about – preprints in the life sciences, we have taken this opportunity to reflect on how preprint success can be measured, and what the data provided by Abdill and Blekhman tell us about preprints in the life sciences.

 

What makes a preprint successful?

Citation rates have long served as the bibliometric gold standard for measuring the scientific impact of publications. However, follow-up studies and reviews can take years to make their own appearance in the literature, meaning that the impact of any one study based on citations can only be assessed in the long term (read: years to decades).

Standing in sharp contrast to this slow, cumulative view of scientific impact, the core goal of preprints is to accelerate the dissemination of scientific observations – to promote discussion, collaboration, and quick follow-up. In this sense, the ability of a preprint to reach the scientific community quickly and effectively is perhaps the ultimate measure of its success.

This alternate perspective justifies Abdill and Blekhman’s use of preprint downloads, Twitter activity and eventual publication outcomes as key quantitative metrics of preprint success, but these naturally raise some questions as well. Is using Twitter to define “popularity” acceptable? Our experience suggests Twitter is indeed the dominant social media platform for spreading preprints – but this does raise the possibility of excluding communities of scientists, and their opinions, based on a lack of Twitter presence. Our hope is that preprint curation platforms (such as preLights) will play an ever more important role in dissemination.

As with all bibliometric methods, it is important to keep in mind the potential for manipulation or misuse – as summarised in Goodhart’s Law, when a measure becomes a target, it ceases to be a good measure². While we applaud the introduction of quantitative measures for preprint “success” in the rxivist project and the enablement of detailed analyses conducted by the authors, we are mindful that a small number of metrics should not be used to define a preprint without critical engagement and evaluation.

Social media and the dissemination of science

The use of Twitter activity as a metric for popularity of preprints on the rxivist website helps flag some issues of interest. First, biases in research communication using social media are poorly understood. For example, among scientists active on Twitter, there is widespread variation in the number of their Twitter followers³. As such, the interests of a single popular scientific influencer could potentially drive far greater disparities than are reflected in quality.

Second, preprinting opens up a space – until recently unexplored – for community engagement, spanning the gap between the dissemination of the authors’ unfiltered data and ideas, and the final peer-approved version. The bulk of this engagement takes place on social media platforms like Twitter. While the informal, loose, and relatively egalitarian structure of communicating this way can be immensely liberating, it is also easy to get lost in the noise, or to simply be overwhelmed by information overload. It is possible to go to sleep in the UK and miss a wide-ranging and critical discussion about a preprint taking place in US time zones – by the time you wake up, Twitter has moved on to the next big thing. In a world of science dissemination via social media, preprint curation and journal club initiatives (and the biorXiv comments section) must take on a critical role – that of providing a stable platform for sustained, publicly recorded engagement while remaining responsive to the abbreviated timescales driven by social media.

What happens, then, after the first few weeks, when the tweetstorms have settled, and the commentaries have been posted? We explore this in more detail below.

Time to publication

The eventual publication outcomes of preprints – their appearance in some peer-reviewed journal – feature heavily in the metrics utilised by Abdill and Blekhman. The authors found that two-thirds of bioRxiv preprints posted between 2013 and the end of 2016 were eventually published in peer-reviewed form. This high rate indicates that authors tend to post quality preprints, therefore initial fears that work not meeting certain scientific standards might ‘clog’ bioRxiv appear to be unfounded. The median time from the posting of a preprint on bioRxiv to its final publication in a peer-reviewed journal was just under six months, although this varied substantially, depending on the eventual journal of publication (Figure 2). In terms of accelerating science, pushing forward the public dissemination of new information by an average of six months could be considered a significant success- especially for early-career researchers, for whom six months represents a large fraction of their total career progress. Having their work and ideas publicly available enables them to receive feedback earlier and prepare effectively for career transitions.

However, as Abdill and Blekhman point out, “time-to-publication” is influenced by a plethora of factors, including journal behavior, when preprints are posted in the publication process, and whether preprints are ever published at all.

It’s worth noting that the two “slowest” and the two “fastest” journals (in terms of time from bioRxiv posting to final publication) both fall within the field of genetics and genomics – Genetics and G3 on the “fast” end and Nature Genetics and Genome Research on the “slow” end. This suggests that field-specific attitudes and norms about preprint usage do not drive the difference in publication times by journal.

Preprints can be posted at many stages of the publication process. More field-specific data on when authors typically post preprints would help us understand how authors are utilising preprints – are they sharing work as close to publication as possible, or aiming to get feedback on their work prior to submitting it to a journal? Although the total number of infractions appears to be small, it’s worth noting that some authors appear to be flaunting the bioRxiv guidelines that state that preprints must be uploaded prior to acceptance in a journal.

Publication as a readout of preprint quality

The authors find a significant correlation between preprint download counts and the impact factor of the eventual journal of publication. This suggests that the popularity of a preprint reflects the eventual perceived impact and quality of the work, and that there is some informal consensus among the scientific community about the scientific quality of both published and unpublished preprints. However, the authors rightly point out that publication, particularly in a high profile journal, may actually drive further downloads. Additionally, both metrics are susceptible to biases that distort the connection between popularity and quality – name recognition of the principal investigator, or “hot” topics within a field, for example. Therefore, further validation will be needed to determine how precisely this measure correlates with the scientific utility of a preprint. For instance, it will be interesting to examine whether the number of downloads a preprint receives in its first month holds predictive value for eventual publication.

On the other end of the scale, what about preprints that are never published in peer-reviewed form? Missing links to final publications in the rxivist website and analysis may be partly a technical issue – changes in authors or preprint title make it difficult for automated formats to match preprints to their final publications – but this is unlikely to account for many preprints. Instead, of greater concern is whether these unpublished preprints are of lower quality and are constructed on the back of poor science that would not pass the stringency of peer review. We argue that a lack of final publication should not be held as an indictment of the quality of a preprint. First, preprints help to communicate results more rapidly, particularly in instances where matching a manuscript to typical journal expectations may be difficult or impossible – for example, following the departure of the primary author from a lab. Second, preprints can serve as useful repositories of negative results, which often remain unpublished – after all, “a negative result is still a result”. Therefore, preprints communicating preliminary or shorter stories can prompt discussion and study in the field and be as successful as those that lead to full publication, especially if they invalidate previous hypotheses or drive changes in research that lead in different directions.

Conclusion

The explosive rise of bioRxiv preprints in the life sciences since 2013 has clearly demonstrated the importance of increased speed and visibility through the publishing process. Leveraging social media has also been key to this process. The rxivist project is a laudable effort to collect and collate data on preprint usage, which can in turn be used to measure the influence and uptake of preprints in the life sciences, while he rxivist website makes this data easily accessible and allows others to easily interact with the metadata. We believe the data indicate that preprints are generally successful and that their increasing adoption is a positive trend for not just the life sciences, but science as a whole. While the metrics for preprints diverge from those used for standard peer-reviewed publications, this appropriately reflects the difference between the standards and goals for preprints and that of peer-reviewed journal articles. We thank the authors of the rxivist project for their work, and are excited to watch as our understanding of preprint publishing continues to grow in the future.

References

1. Abdill, R. J. & Blekhman, R. Tracking the popularity and outcomes of all bioRxiv preprints. bioRxiv 515643 (2019). doi:10.1101/515643
2. Biagioli, M. Watch out for cheats in citation game. Nature 535, 201–201 (2016).
3. Côté, I. M. & Darling, E. S. Scientists on Twitter: Preaching to the choir or singing from the rooftops? FACETS 3, 682–694 (2018).

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In the latest episode of Genetics Unzipped, Kat Arney is exploring some more of the leading 100 ideas in genetics. She’s been digging around in the genetic vegetable patch in search of flavourful GM tomatoes, chunky onion genomes and Mendelian peas.

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3 year-POSTDOC + Starting grant (OPEN-CALL BEATRIU de PINOS program) to join our lab on EvoDevoGenomics in Barcelona

We are seeking candidates to join our lab to study our favorite chordate model Oikopleura dioica, in which we are currently interested in heart and muscle development, tail elongation and the impact of gene loss on the evolution of gene regulatory signalling networks. Click here for a tour “A day in our lab” posted in The Node

We have also engaged a new EcoEvoDevo line investigating if the developmental mechanisms of marine embryos are ready to respond to climate change, including biotoxins derived from algal blooms. Click here for a tour on this new EcoEvoDevo adventure.

Our approaches include RNAseq, CRISPR, RNAi, Fluorescent-Microscopy

DEADLINE call: March 4th 2019 (contact for enquiries as soon as possible canestro@ub.edu)

REQUIREMENT: to have defended the PhD within the period January 1st 2011 – December 31st 2016

DURATION:  3 years: starting not later than February 2020

FUNDING: 132.300€ total gross salary for 3 years + 12.000€ research funds

CONTACT: Interested candidates, please send an email to Cristian Cañestro (canestro@ub.edu), including a brief letter of interest, a brief CV, including list of publications with their impact, and technical skills for post-doc applications, and official scores for doctoral candidates, all together in ONE single pdf file.

More info please visit our web: http://bit.ly/2S1PNa8

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