Here are the highlights form the current issue of Development:

Making matrix in the inner ear

The tectorial membrane (TM) is an extracellular matrix (ECM) that overlies the organ of Corti in the inner ear and is crucial for our sense of hearing. It is composed of collagen fibrils embedded in a tectorin-based matrix. The precise alignment of the collagen fibrils across the TM is a feature considered critical for hearing, but very little is known about how this pattern is generated. On p. 3978, Richard Goodyear and colleagues undertake a detailed analysis of TM development in mice and begin to investigate the mechanisms underlying collagen-fibril orientation. They find that the presence of a tectorin-based matrix is essential for the normal co-alignment and orientation of the first-forming collagen fibrils, and that collagen-fibril orientation does not seem to depend on stretch of the ECM caused by growth of the underlying epithelium. Rather, the authors identify an influence of the planar cell polarity machinery, generally associated with cell-cell alignment, on collagen fibril orientation – although the molecular mechanisms underlying this remain unclear. These data provide first insights into how TM patterning is achieved, and point to an intriguing interplay between planar cell polarity and collagen-fibril organisation.

Gastruloids: mimicking early embryonic polarisation in vitro

Embryonic patterning is dependent on the establishment of the anteroposterior (AP) and dorsoventral axes early in development. In mammalian embryos, these axes are established by a breaking of symmetry in the epiblast, which involves signals from the extra-embryonic tissues. However, the molecular mechanisms that control this process are still not fully understood. On p. 3894, David Turner, Alfonso Martinez Arias and colleagues use gastruloids, three-dimensional aggregates of mouse embryonic stem cells, as a tool to unravel the signalling pathways that establish AP polarity in mammalian embryos. The authors demonstrate that these gastruloids can develop an AP axis in the absence of extra-embryonic tissue, instead depending on precisely timed interactions between Wnt and Nodal signalling. They also show that BMP signalling is dispensable for AP axis formation. This research demonstrates the powerful potential of gastruloids as a tool to understand the molecular mechanisms that underpin early embryonic development. Together, their results suggest that extra-embryonic tissues do not induce axis formation per se, but rather bias the critical symmetry-breaking event in embryo development, furthering our understanding of the molecular control of embryonic patterning.

Atg16 in the intestine: more than autophagy

The core autophagy protein Atg16L1 has been identified as a genetic risk factor in inflammatory bowel disease, but how it plays this role has remained unclear. On p. 3990, Gábor Juhász and colleagues interrogate the role of Atg16, the Drosophila orthologue of human ATG16L1, in intestinal homeostasis and inflammation. Using mutants that affect either the N-terminal autophagic domain or the C-terminal WD40 domain, they observe defects in intestinal morphology and an impaired stress response in Atg16 WD40 mutants. In Atg16 WD40 mutant intestines, the differentiation of enteroendocrine (EE) cells is impaired, leading to an accumulation of pre-EE cells, and this results from reduced Slit/Robo signalling (a pathway known to regulate EE cell number). The failure of EE differentiation is accompanied by an inflammatory response, but appears to be independent of autophagy: autophagy is not altered in Atg16 WD40 mutants, and mutants affecting the autophagy domain alter neither Slit/Robo signalling nor EE differentiation. Finally, the authors show that Atg16 binds to the GTPase Rab19 – also a genetic risk factor for inflammatory bowel disease – and the two cooperate in regulating intestinal homeostasis. This work provides insight into the molecular control of intestinal homeostasis and implies a link between impaired cell differentiation and intestinal pathologies in humans.

PLUS:

An interview with Christiane Nüsslein-Volhard

Christiane Nüsslein-Volhard is Director Emeritus at the Max Planck Institute for Developmental Biology in Tübingen, Germany. In 1995, she was awarded the Nobel Prize for Physiology and Medicine, along with Eric Wieschaus and Edward Lewis, for her work on the genetic control of embryogenesis using the fruit fly Drosophila melanogaster. In the 1990s, she transitioned her lab to working with zebrafish (Danio rerio), using similar forward genetic approaches to those that had proved so successful in Drosophila to uncover key regulators of vertebrate development. We met with Christiane at the recent International Society for Developmental Biology (ISDB) meeting in Singapore, to talk about her research, the impact of the Nobel Prize and the challenges of being a ‘woman in science’. See the Spotlight article.

Transcriptional precision and accuracy in development: from measurements to models and mechanisms

During development, genes are transcribed at specific times, locations and levels. In recent years, the emergence of quantitative tools has significantly advanced our ability to measure transcription with high spatiotemporal resolution in vivo. Here, Angela DePace and co-workers highlight recent studies that have used these tools to characterize transcription during development, and discuss the mechanisms that contribute to the precision and accuracy of the timing, location and level of transcription. See the Review.

Cortical interneuron development: a tale of time and space

Cortical interneurons are a diverse group of neurons that project locally and are crucial for regulating information processing and flow throughout the cortex. Recent studies in mice have advanced our understanding of how these neurons are specified, migrate and mature. Here, John Rubenstein and colleagues evaluate new findings that provide insights into the development of cortical interneurons and that shed light on when their fate is determined, on the influence that regional domains have on their development, and on the role that key transcription factors and other crucial regulatory genes play in these events. See the Review.

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Dear Colleagues,

The 2nd NEUBIAS school for Bioimage Analysts will be organized in Jan. 2018 in Szeged, Hungary, and the registration is now open (Organizers: Jean-Yves Tinevez & Kota Miura). Please visit the linked URL below for more details. This school is the most advanced among three levels of NEUBIAS school. Deadline for the registration is Nov. 9th.

The school is part of one week-conference, and there will be another school in parallel: “Early Career Investigator (ECI) school” In this school, you can learn how to program ImageJ macro and MATLAB script for bioimage analysis.

After these schools, there is 3-days symposium. Anyone can join and there is no selection for this meeting. School participants are free to attend this symposium.

Analyst School: http://goo.gl/qdWc6t
ECI school: http://goo.gl/Tfmwjx
Symposium: http://goo.gl/pHU3Pz

We are looking forward to seeing you in Szeged!

Sincerely,
Jean-Yves Tinevez and Kota Miura

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The lab of Savraj Grewal (University of Calgary, Canada) is looking to recruit new postdocs and grad students.

Our lab investigates how growth is controlled during animal development. We use a combination of molecular and genetic approaches to investigate the cell-cell signalling pathways and the genetic mechanisms that govern the control of cell, tissue and body growth in Drosophila. Our main focus to-date has been the conserved insulin and TOR kinase pathways, and understanding how they regulate cellular and animal metabolism to drive growth. Further information on our research can be found here. Recent publications can be found here.

POSTDOCS: applicants with a Ph.D. and strong background in developmental biology, genetics, or molecular biology are encouraged to apply. Interested individuals should send a CV and a short statement of research interests to grewalss@ucalgary.

GRAD STUDENTS: applicants with a strong undergraduate degree in any area related to the biological sciences are encouraged to apply. Interested individuals should send a CV and  a short statement of research interests to grewalss@ucalgary.

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The Marine Biological Laboratory seeks a motivated Postdoctoral Scientist to join the laboratories of Kristin Gribble and David Mark Welch in the Josephine Bay Paul Center. The successful candidate will develop genome editing techniques, including CRISPR/Cas9, in rotifers, a novel aquatic invertebrate model system for studies of aging, neurobiology, developmental biology, ecology, and evolution. Specific goals of the project include designing guide RNAs, optimizing microinjection methodologies, phenotyping and genotyping mutant strains, and screening genes of interest.

Basic Qualifications:

Applicants should have a Ph.D. in biology, cell/molecular biology, biochemistry, or a related field. This position requires proficiency in basic molecular biology techniques, microscopy, microinjection, and CRISPR/Cas9 methodology. We are seeking an independent, organized, enthusiastic, and productive individual with robust problem solving skills. Excellent written, verbal and interpersonal skills, attention to detail, and a strong work ethic are essential. Position level and salary will depend upon education and experience.

Preferred Qualifications:

The ideal candidate will have working familiarity with RNAi techniques, transgenic protocols, and confocal microscopy. Proficiency in bioinformatics is a plus. Previous experience in established animal model or in non-model systems is preferred.

Special Instructions to Applicants:

Please submit the following three items with your application:

• Cover letter describing your research goals, specific interest in joining our group, and what you would contribute to the project
• CV
• Contact information for 3-4 references

Please apply at: https://mbl.simplehire.com/postings/3824

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A ERC funded postdoctoral position is available in the laboratory of Julien Courchet at the NeuroMyoGene Institute within the University of Lyon, France.

Our group studies the molecular mechanisms underlying axon outgrowth and neural circuits formation in the mouse cerebral cortex. Our current research is supported by an ERC Starting Grant and funds from AFM-telethon to explore how a dynamic regulation of the energy metabolism is involved in axon morphogenesis and cortex development. We focus on a previously identified kinase pathway controlling terminal axon branching through the regulation of mitochondria trafficking and distributing in developing axons (Cell 2013). Building on this previous research, the proposed project will use a combination of whole cell metabolomics, real-time fluorescent videomicroscopy and live 2-photon imaging to characterize some of the molecular mechanisms involved in the local regulation of mitochondria function in developing axon in vivo.

The selected candidate will join a young research team within a dynamic and collaborative scientific environment at the newly created NeuroMyoGene Institute (INMG). The candidate will have access to state-of-the-art facilities for imaging and metabolic analyses, including high quality confocal and 2-photon microscopes, animal phenotyping centers and a seahorse analyzer. Our institute is located in a newly renovated laboratory space in the Rockefeller faculty of Medicine in close proximity to the Neuroscience and the Cancer Research Centers.

Applicants should have a PhD degree or equivalent with a strong background and practical experience in neurobiology, confocal microscopy and/or real-time imaging. Previous experience working with rodent models is required. Training in techniques relevant to cell signaling, metabolic regulation and optogenetics would be an asset. We are looking for a highly motivated candidate with a strong attitude towards independent work and good interpersonal and communication skills. Excellent written and spoken English skills are essential. Ability to speak French in not mandatory.

The initial appointment is one year and can be renewed for 2 additional years. Salary including benefits will depend on previous experience according to guidelines at the University of Lyon. Applications will be reviewed on a rolling basis until position is filled. Selected candidates will be invited for an interview early 2018. Project start date is expected during the first semester of 2018.

Interested candidates should contact Dr Julien Courchet (julien.courchet@inserm.fr) with their CV, a summary of their previous research (< 1 page), a brief statement of their research interests and career goals, as well as the contact information for at least 3 references.

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The MRC Weatherall Institute of Molecular Medicine (WIMM) has fully funded 4-year Prize PhD (DPhil) Studentships available to start in October 2018. These Studentships are open to outstanding students of any nationality who wish to train in experimental and/or computational biology.

The Institute is a world leading molecular and cell biology centre that focuses on research with application to human disease. It includes the recently opened MRC WIMM Centre for Computational Biology and houses over 500 research and support staff in 50 research groups working on a range of fields in Haematology, Gene Regulation & Epigenetics, Stem Cell Biology, Computational Biology, Cancer Biology, Human Genetics, Infection & Immunity. The Institute is committed to training the next generation of scientists in these fields through its Prize PhD Studentship Programme.

The fully funded studentships include a stipend of £18,000 per annum and cover University and College fees.

Further information on the studentships, how to apply, and the projects available can be found at:

http://www.imm.ox.ac.uk/wimm-prize-studentships-2018

Closing date for submission of applications:  Monday, 8 January 2018, 12 noon UK time.

Interviews will take place the week commencing 22 January 2018.

Pure Computational Biology Project Leaders

Hashem Koohy – Machine-learning in gene function, transcription regulation and immunology

Ed Morrissey – Quantitative biology of cell fate

Aleksandr Sahakyan – Regulatory chromosomal domains and genome architecture

Supat Thongjuea – Computational biology of single-cell transcription and gene regulation 

Molecular and Cell Biology Project Leaders

Ahmed Ahmed – Experimental therapeutics

Chris Babbs – Causes of congenital anaemia

Oliver Bannard – B cell biology

Andrew Blackford – DNA damage and disease

Walter Bodmer – Colorectal cancer, stem cells, differentiation & drug response

Marella De Bruijn – Developmental haematopoiesis

Zam Cader – Stem cell neurological disease models

Vincenzo Cerundolo – Tumour immunology, vaccine strategies

David Clynes – DNA damage, repair and cancer

Simon Davis – T-cell biology

Hal Drakesmith – Iron and infection

Christian Eggeling – Super-resolution microscopy in immunology

Ben Fairfax – Inflammation, genetics and cancer therapeutics

Marco Fritzsche – Biophysical immunology

Lars Fugger – Multiple sclerosis

Tudor Fulga – MicroRNAs in development and disease

Richard Gibbons – Chromatin, epigenetics & transcription

Anne Goriely – De novo mutations and human disease

Doug Higgs – Gene regulation and epigenetics

Ling-Pei Ho – Lung immunology

Georg Hollander – T cell development and thymus organogenesis

David Jackson – Lymphatic trafficking in inflammation and cancer

Peter McHugh – DNA repair

Adam Mead – Normal and leukaemic haematopoietic stem cell biology

Claus Nerlov – Tissue stem cell genetics

Graham Ogg – Translational skin research

Catherine Porcher – Transcription factors and blood development

Jan Rehwinkel – Innate detection of viruses

Irene Roberts – Trisomy 21, haematopoiesis and leukaemia

Tatjana Sauka-Spengler – Neural crest gene regulatory networks

Alison Simmons – Innate immunity & Crohn’s disease

Alain Townsend – Influenza and ebola, vaccination and treatment

Paresh Vyas – Leukaemic stem cells

Andrew Wilkie – Sperm and craniofacial mutations

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The Karam Teixeira laboratory (https://www.gen.cam.ac.uk/research-groups/karam-teixeira) at the University of Cambridge (Department of Genetics) is looking to recruit an outstanding Postdoctoral scientist to investigate the molecular mechanisms sheltering totipotency and controlling germline stem cell behavior in vivo. Using the Drosophila germline as a model for studying stem cells, we employ an integrated approach, combining high-throughput molecular analysis (next-generation sequencing) and computational investigation with developmental, microscopy, and genetic analyses (including CRISPR-Cas9 gene editing, tissue-specific RNAi knockdown, etc). We were previously able to assemble the complete genetic framework controlling germline stem cell self-renewal and differentiation in vivo, revealing conserved new aspects of stem cell biology (Teixeira et al, Nature Cell Biology, 2015; Sanchez et al, Cell Stem Cell, 2016). Moving forward, our goal is to build a refined molecular understanding of how protein synthesis control – a new frontier in gene regulation – governs stem cell fate transitions in vivo. Our lab is generously funded by the Wellcome Trust.

Candidates must have experience in a wide range of molecular biology techniques, and prior expertise in next generation sequencing would be an advantage. Experience working with fly genetics is a plus but not required. The successful candidate will be highly motivated, willing to join a young and dynamic research group, have good communication skills, and possess strong problem solving capacities.

How to apply:

To apply online, please follow the link: http://www.jobs.cam.ac.uk/job/15379/

Applications should include a cover letter, Curriculum Vitae, and the contact information of at least two references.

The position start date is flexible. Application deadline: November 17^th, 2017.

For an informal discussion about this position, please contact Dr. Felipe Karam Teixeira (fk319@cam.ac.uk).

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Andras Paldi, Daniel Stockholm, Alice Moussy

How do phenotypic differences between cells of the same clonal origin emerge? How exactly does the transition between the initial and final phenotypes occur? What happens in the cell during the transition? When there are two or more options, how is the choice made between them? How long does it take to acquire a new phenotype? What is the minimal difference required to consider two cells as phenotypically different? To define a cell type, should we consider only morphological, molecular differences or both simultaneously?

Despite the plethora of studies, these simple questions remain unanswered. Most of the studies focus on identifying the essential genes or environmental factors usually at the level of cell populations. The huge amount of molecular data accumulated over the past decades gave us the illusion of knowledge. Knowing the players is obviously essential, but this is only the starting point for the understanding. Unfortunately, our understanding of the process of differentiation remains desperately scarce, as the lack of clear responses to the above listed simple questions shows.

Recently, two important challenges came to modify the perception of differentiation. The first comes from the spectacular development of single-cell technologies. The second is that we have to come to realize how much phenotypic plasticity is a genuine characteristic of cells. The main lesson from the rapid development of single-cell detection techniques is the unambiguous demonstration of how different individual cells are and how poorly population-level averages represent them. The bulk of our knowledge on differentiation comes from studies of cell populations. Perhaps unconsciously, we took for granted that individual cells all follow with small variation the same sequence of events as what we could see at the level of cell populations. The unexpectedly high variation of individual cell phenotypes in populations that were believed to be homogenous (because of the morphological similarity of the cells, their clonal origin, their expression of some markers etc.) draw the attention to the phenotypic plasticity of the cells and to the fact that fate decisions are “taken” by individual cells.

Clearly, a coherent, systemic level explicative frame is needed that can account for the coherent population-level behaviour emerging from highly variable individual cell phenotypes and behaviour.

Our recently published work [1] was motivated by the wish to contribute to this effort. Although we used the extensively studied hematopoietic stem cell model, we were surprised how much these general questions fit to the model. The definition of the hematopoietic stem cell is widely debated, no precise description of the earliest events of differentiation and only very scarce information on the morphological changes during the same period were available. The study of hematopoietic stem cells is made difficult by the lack of exact criteria to identify them. Nonetheless, there is a consensus that CD34+ cell fraction in the umbilical cord blood contains high number of these cells. We decided therefore to privilege an integrated view and work on the whole population of CD34+ cells. Individual cells were randomly sorted from the population at different fixed time-points and their gene expression profile was analysed by single-cell RT-PCR. The structure of the population and its components were identified on the basis of the collected single-cell gene expression data. Parallelly, we set up a time-lapse system that allowed the continuous monitoring of the cells and their progeny during the first 96hrs after stimulation. Adding the continuous observations of the morphological changes and cell division timing of individual cells to the single time-point single-cell molecular analysis sampling of the same population provided a glimpse of the true dynamic nature of cellular fate decision.

The CD34+ cell fraction is traditionally considered as heterogeneous. Indeed, before cytokine stimulation every cell displayed a unique gene expression profile. However, no groups could be identified on the basis of their statistical similarity, this population is not a mixture of a limited number of “cell types”. When cytokines were added to the culture, every cell responded in a unique way. Again, every cell displayed a unique gene expression pattern that was different of the previous seen at t=0 hours. It was characterized by the simultaneous expression of different lineage-specific genes. This state is known as a multi-lineage primed pattern [2, 3]. A second round of change occurred during the second 24 hours. Two days after the stimulation of the cells two distinct transcription patterns emerged. One pattern was typical for myelo-erythroid progenitors, while the second was reminiscent of multipotent cells. Until now, the results overall confirmed the previous studies; the main novelty was the apparent rapidity of transition from the initial to a multilineage primed gene expression pattern and, just 24 hours later, to two distinct profiles. However, these snapshots did not allow us to deduce on the dynamics of the changes.

The real surprise came from the analysis of the time-lapse records. Individual CD34+ cells were placed in microwells and imaged for a week at 1 image/min. The resulting time-lapse records allowed us to record cell cycle lengths and morphological changes of each individual cell within individual clones. After stimulation, the cells usually displayed a polarized shape with a strong protrusion on one side called uropod. The first unexpected observation was to see that the unusual length of the first cell cycle. The cells made more than 50 hours on average to divide. This means, that the first major transcriptional change occurred during the first cell cycle and the second around the end of the first or the very beginning of the second cell cycle. After the first division, we could see two different morphologies; one was strongly polarized with a uropod, the second is spherical. The daughter cells usually inherited the morphology of their mothers. Polarized cells gave two polarized and round cells two round daughters. However, we were surprised to observe that a significant proportion of the cells did not conserve a stable morphology; they switched from one morphology to another and back many times during the cell cycle. The majority of their daughter cells also conserved the fluctuating phenotype

We called these cells “hesitant”. The overall picture suggest that stimulated CD34+ cells, after a brief passage through a multilineage primed state reach (without cell division!) one of the two alternative states characterized by a typical transcription pattern and cellular morphology. However, a significant proportion of cells fluctuate between the two morphologies. Does this morphological instability reflect transcriptome fluctuations? To answer this question, we have isolated individual cells with the three different – stable round, polarized or “hesitant” – behaviours and analysed their gene expression pattern. It appeared that the cells with stable morphology displayed one of the two expression patterns first observed at the 48 hors time point. The “hesitant” cells were characterized by an intermediate profile. The molecular analysis correlated to the time-lapse data suggests therefore that these cells are in an unstable state; their transcriptome undergoes fluctuations that are reflected in their fluctuating morphology also.

These are the key observations and the immediate conclusions of this work. However, these observations may contribute to the current tendency to reframe the issue of cell differentiation and stem cells in general. Cell differentiation can be approached using the concepts of stability and change – two complementary concepts widely used in biology. Stem cells may represent a highly unstable cell fraction contrary to the cells with stable differentiated phenotype. Unstable stem cells are actively exploring the space of available phenotypes before getting trapped by one of them. This is a kind of trial-and-error process. Under normal conditions, the unstable period is relatively short lasting; this is why the unstable cells we consider as stem cells are so rare in a normal tissue. However, a substantial change in the environment can destabilize many cells at the same time. This is what we see when CD34+ cells are stressed by the sudden addition of a cytokine cocktail. Due to the progressive adaptation to the new environment, the proportion of the “hesitant” stem cells decreases gradually as they attracted to the more adapted phenotypes. Importantly, this process seems to depend only indirectly on cell divisions. This interpretation is in remarkable agreement with earlier theoretical predictions and experimental work [4-8] and supported by recent experimental observations also [9-12].

Our paper was initially submitted to a well-known journal in stem cell biology. Beyond the disappointment of the rejections (every scientist is used to that), we were surprised by the poor quality of the reviews. The referees raised some technical concerns about the single-cell RT-PCR versus single-cell RNA sequencing, but not a single word about the time-lapse experiments that represented the major part of the paper, nor about the coupling the molecular and cellular scales, which is the true originality of the work. The reviews were very different when the manuscript was submitted to PloS Biology. The comments concerned all aspects of the work and the suggestions truly helped to improve the final version.

It would be naïve to think that a single paper can answer the fundamental questions raised at the beginning of this text. Clearly, we need a fresh view on cell differentiation that goes beyond the simple gathering and classification of molecular data and takes into account the true dynamics.

References

1. Moussy A, Cosette J, Parmentier R, da Silva C, Corre G, Richard A, et al. Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment. PLoS Biol. 2017;15(7):e2001867. doi: 10.1371/journal.pbio.2001867. PubMed PMID: 28749943; PubMed Central PMCID: PMC5531424.
2. Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C, et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes & development. 1997;11(6):774-85. PubMed PMID: 9087431.
3. Pina C, Fugazza C, Tipping AJ, Brown J, Soneji S, Teles J, et al. Inferring rules of lineage commitment in haematopoiesis. Nature cell biology. 2012;14(3):287-94. doi: 10.1038/ncb2442. PubMed PMID: 22344032.
4. Furusawa C, Kaneko K. A dynamical-systems view of stem cell biology. Science. 2012;338(6104):215-7. doi: 10.1126/science.1224311. PubMed PMID: 23066073.
5. Huang S. Non-genetic heterogeneity of cells in development: more than just noise. Development. 2009;136(23):3853-62. doi: 10.1242/dev.035139. PubMed PMID: 19906852; PubMed Central PMCID: PMC2778736.
6. Kupiec JJ. A chance-selection model for cell differentiation. Cell death and differentiation. 1996;3(4):385-90. PubMed PMID: 17180108.
7. Kupiec JJ. A Darwinian theory for the origin of cellular differentiation. Molecular & general genetics : MGG. 1997;255(2):201-8. PubMed PMID: 9236778.
8. Paldi A. Stochastic gene expression during cell differentiation: order from disorder? Cellular and molecular life sciences : CMLS. 2003;60(9):1775-8. doi: 10.1007/s00018-003-23147-z. PubMed PMID: 14523542.
9. Mojtahedi M, Skupin A, Zhou J, Castano IG, Leong-Quong RY, Chang H, et al. Cell Fate Decision as High-Dimensional Critical State Transition. PLoS Biol. 2016;14(12):e2000640. doi: 10.1371/journal.pbio.2000640. PubMed PMID: 28027308; PubMed Central PMCID: PMC5189937.
10. Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351(6269):aab2116. doi: 10.1126/science.aab2116. PubMed PMID: 26541609; PubMed Central PMCID: PMC4816201.
11. Richard A, Boullu L, Herbach U, Bonnafoux A, Morin V, Vallin E, et al. Single-cell-based analysis highlights a surge in cell-to-cell molecular variability preceding irreversible commitment in a differentiation process. . Plos Biology. 2016;(14):e1002585. doi: doi.org/10.1371/journal.pbio.1002585.
12. Velten L, Haas SF, Raffel S, Blaszkiewicz S, Islam S, Hennig BP, et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nature cell biology. 2017;19(4):271-81. doi: 10.1038/ncb3493. PubMed PMID: 28319093.

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Doing a PhD is tough, the data from surveys supports that. However it is not insurmountable, and here we have a collection of some guidance from the Twitter community.  Let us know in the comments if you have any thoughts to add.

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