Biology

Microglia exit the CNS in spinal root avulsion

PLOS Biology (new articles) - 21 hours 54 min ago

by Lauren A. Green, Julia C. Nebiolo, Cody J. Smith

Microglia are central nervous system (CNS)-resident cells. Their ability to migrate outside of the CNS, however, is not understood. Using time-lapse imaging in an obstetrical brachial plexus injury (OBPI) model, we show that microglia squeeze through the spinal boundary and emigrate to peripheral spinal roots. Although both macrophages and microglia respond, microglia are the debris-clearing cell. Once outside the CNS, microglia re-enter the spinal cord in an altered state. These peripheral nervous system (PNS)-experienced microglia can travel to distal CNS areas from the injury site, including the brain, with debris. This emigration is balanced by two mechanisms—induced emigration via N-methyl-D-aspartate receptor (NMDA) dependence and restriction via contact-dependent cellular repulsion with macrophages. These discoveries open the possibility that microglia can migrate outside of their textbook-defined regions in disease states.
Categories: Biology, Journals

Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion

PLOS Biology (new articles) - 21 hours 54 min ago

by Christian Flueck, Laura G. Drought, Andrew Jones, Avnish Patel, Abigail J. Perrin, Eloise M. Walker, Stephanie D. Nofal, Ambrosius P. Snijders, Michael J. Blackman, David A. Baker

Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falciparum phosphodiesterase β (PDEβ) hydrolyses both cAMP and cGMP and is essential for blood stage viability. Conditional gene disruption causes a profound reduction in invasion of erythrocytes and rapid death of those merozoites that invade. We show that this dual phenotype results from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA). Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, more than half of which conform to a PKA substrate consensus sequence. We conclude that PDEβ plays a critical role in governing correct temporal activation of PKA required for erythrocyte invasion, whilst suppressing untimely PKA activation during early intra-erythrocytic development.
Categories: Biology, Journals

Uncovering and resolving challenges of quantitative modeling in a simplified community of interacting cells

PLOS Biology (new articles) - 21 hours 54 min ago

by Samuel F. M. Hart, Hanbing Mi, Robin Green, Li Xie, Jose Mario Bello Pineda, Babak Momeni, Wenying Shou

Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in parameter quantification and offer means to overcome these challenges, using a case example in which we quantitatively predict the growth rate of a cooperative community. Specifically, the community consists of two Saccharomyces cerevisiae strains, each engineered to release a metabolite required and consumed by its partner. The initial model, employing parameters measured in batch monocultures with zero or excess metabolite, failed to quantitatively predict experimental results. To resolve the model–experiment discrepancy, we chemically identified the correct exchanged metabolites, but this did not improve model performance. We then remeasured strain phenotypes in chemostats mimicking the metabolite-limited community environments, while mitigating or incorporating effects of rapid evolution. Almost all phenotypes we measured, including death rate, metabolite release rate, and the amount of metabolite consumed per cell birth, varied significantly with the metabolite environment. Once we used parameters measured in a range of community-like chemostat environments, prediction quantitatively agreed with experimental results. In summary, using a simplified community, we uncovered and devised means to resolve modeling challenges that are likely general to living systems.
Categories: Biology, Journals

Induced aneuploidy in neural stem cells triggers a delayed stress response and impairs adult life span in flies

PLOS Biology (new articles) - 21 hours 54 min ago

by Mihailo Mirkovic, Leonardo G. Guilgur, Alexandra Tavares, Diogo Passagem-Santos, Raquel A. Oliveira

Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time-controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a complex array of karyotypes, and cellular abnormalities. Notably, when other brain-cell lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.
Categories: Biology, Journals

Virgin Galactic reaches space again - this time with a passenger

Genetics - Fri, 2019-02-22 20:54
The first test passenger has gone to the edge of space aboard Virgin Galactic’s Unity space plane, a key milestone in the firm’s quest to send paying customers to space
Categories: Biology

Quantum experiment suggests there really are ‘alternative facts’

Genetics - Fri, 2019-02-22 19:02
A complex probe of the foundations of quantum mechanics suggests that the nature of reality depends on who is looking – there are no objective facts we can agree on
Categories: Biology

Four stars full of burnt nuclear ash are speeding through the galaxy

Genetics - Fri, 2019-02-22 17:16
When a star goes supernova it is usually destroyed in a powerful explosion, but four stars have survived to tell the tale and are running away fast
Categories: Biology

How the zebra got its stripes: The problem with 'just-so' stories

Genetics - Fri, 2019-02-22 16:26
The mystery of why zebras have stripes has puzzled biologists for decades, and while we are closing in on the answer, the question isn’t settled yet
Categories: Biology

Liberals who want a Green New Deal must include nuclear power

Genetics - Fri, 2019-02-22 16:17
The congresswoman who sponsored the US Green New Deal suggested the plan won’t include any new money for nuclear power – that’s a mistake, says David Titley
Categories: Biology

Japan’s Hayabusa 2 bags its first sample from the asteroid Ryugu

Genetics - Fri, 2019-02-22 13:35
A Japanese spacecraft has touched down on an asteroid and collected the first of three samples, raising hopes for the space mining industry
Categories: Biology

AIs could debate whether a smart assistant should snitch on you

Genetics - Fri, 2019-02-22 10:00
If a smart home spots cannabis in a teenager’s bedroom, should it tell their parents? Or even the police? One proposal is to let debating AIs decide
Categories: Biology

Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by Fabian Sesterhenn, Marie Galloux, Sabrina S. Vollers, Lucia Csepregi, Che Yang, Delphyne Descamps, Jaume Bonet, Simon Friedensohn, Pablo Gainza, Patricia Corthésy, Man Chen, Stéphane Rosset, Marie-Anne Rameix-Welti, Jean-François Éléouët, Sai T. Reddy, Barney S. Graham, Sabine Riffault, Bruno E. Correia

Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.
Categories: Biology, Journals

Scrutinizing assortative mating in birds

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by Daiping Wang, Wolfgang Forstmeier, Mihai Valcu, Niels Dingemanse, Martin Bulla, Christiaan Both, Renée A. Duckworth, Lynna Marie Kiere, Patrik Karell, Tomáš Albrecht, Bart Kempenaers

It is often claimed that pair bonds preferentially form between individuals that resemble one another. Such assortative mating appears to be widespread throughout the animal kingdom. Yet it is unclear whether the apparent ubiquity of assortative mating arises primarily from mate choice (“like attracts like”), which can be constrained by same-sex competition for mates; from spatial or temporal separation; or from observer, reporting, publication, or search bias. Here, based on a conventional literature search, we find compelling meta-analytical evidence for size-assortative mating in birds (r = 0.178, 95% CI 0.142–0.215, 83 species, 35,591 pairs). However, our analyses reveal that this effect vanishes gradually with increased control of confounding factors. Specifically, the effect size decreased by 42% when we used previously unpublished data from nine long-term field studies, i.e., data free of reporting and publication bias (r = 0.103, 95% CI 0.074–0.132, eight species, 16,611 pairs). Moreover, in those data, assortative mating effectively disappeared when both partners were measured by independent observers or separately in space and time (mean r = 0.018, 95% CI −0.016–0.057). Likewise, we also found no evidence for assortative mating in a direct experimental test for mutual mate choice in captive populations of Zebra finches (r = −0.020, 95% CI −0.148–0.107, 1,414 pairs). These results highlight the importance of unpublished data in generating unbiased meta-analytical conclusions and suggest that the apparent ubiquity of assortative mating reported in the literature is overestimated and may not be driven by mate choice or mating competition for preferred mates.
Categories: Biology, Journals

Single-cell transcriptomics reveals gene expression dynamics of human fetal kidney development

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by Mazène Hochane, Patrick R. van den Berg, Xueying Fan, Noémie Bérenger-Currias, Esmée Adegeest, Monika Bialecka, Maaike Nieveen, Maarten Menschaart, Susana M. Chuva de Sousa Lopes, Stefan Semrau

The current understanding of mammalian kidney development is largely based on mouse models. Recent landmark studies revealed pervasive differences in renal embryogenesis between mouse and human. The scarcity of detailed gene expression data in humans therefore hampers a thorough understanding of human kidney development and the possible developmental origin of kidney diseases. In this paper, we present a single-cell transcriptomics study of the human fetal kidney. We identified 22 cell types and a host of marker genes. Comparison of samples from different developmental ages revealed continuous gene expression changes in podocytes. To demonstrate the usefulness of our data set, we explored the heterogeneity of the nephrogenic niche, localized podocyte precursors, and confirmed disease-associated marker genes. With close to 18,000 renal cells from five different developmental ages, this study provides a rich resource for the elucidation of human kidney development, easily accessible through an interactive web application.
Categories: Biology, Journals

On the value of preprints: An early career researcher perspective

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by Sarvenaz Sarabipour, Humberto J. Debat, Edward Emmott, Steven J. Burgess, Benjamin Schwessinger, Zach Hensel

Peer-reviewed journal publication is the main means for academic researchers in the life sciences to create a permanent public record of their work. These publications are also the de facto currency for career progress, with a strong link between journal brand recognition and perceived value. The current peer-review process can lead to long delays between submission and publication, with cycles of rejection, revision, and resubmission causing redundant peer review. This situation creates unique challenges for early career researchers (ECRs), who rely heavily on timely publication of their work to gain recognition for their efforts. Today, ECRs face a changing academic landscape, including the increased interdisciplinarity of life sciences research, expansion of the researcher population, and consequent shifts in employer and funding demands. The publication of preprints, publicly available scientific manuscripts posted on dedicated preprint servers prior to journal-managed peer review, can play a key role in addressing these ECR challenges. Preprinting benefits include rapid dissemination of academic work, open access, establishing priority or concurrence, receiving feedback, and facilitating collaborations. Although there is a growing appreciation for and adoption of preprints, a minority of all articles in life sciences and medicine are preprinted. The current low rate of preprint submissions in life sciences and ECR concerns regarding preprinting need to be addressed. We provide a perspective from an interdisciplinary group of ECRs on the value of preprints and advocate their wide adoption to advance knowledge and facilitate career development.
Categories: Biology, Journals

Feather arrays are patterned by interacting signalling and cell density waves

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by William K. W. Ho, Lucy Freem, Debiao Zhao, Kevin J. Painter, Thomas E. Woolley, Eamonn A. Gaffney, Michael J. McGrew, Athanasia Tzika, Michel C. Milinkovitch, Pascal Schneider, Armin Drusko, Franziska Matthäus, James D. Glover, Kirsty L. Wells, Jeanette A. Johansson, Megan G. Davey, Helen M. Sang, Michael Clinton, Denis J. Headon

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.
Categories: Biology, Journals

Trpm4 ion channels in pre-Bötzinger complex interneurons are essential for breathing motor pattern but not rhythm

PLOS Biology (new articles) - Fri, 2019-02-22 00:00

by Maria Cristina D. Picardo, Yae K. Sugimura, Kaitlyn E. Dorst, Prajkta S. Kallurkar, Victoria T. Akins, Xingru Ma, Ryoichi Teruyama, Romain Guinamard, Kaiwen Kam, Margaret S. Saha, Christopher A. Del Negro

Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca2+)-activated nonselective cationic current (ICAN) to generate robust neural bursts. Hypothesized to be rhythmogenic, reducing ICAN is predicted to slow down or stop breathing; its contributions to motor pattern would be reflected in the magnitude of movements (output). We tested the role(s) of ICAN using reverse genetic techniques to diminish its putative ion channels Trpm4 or Trpc3 in preBötC neurons in vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased the tidal volume of breaths yet surprisingly increased breathing frequency, often followed by gasping and fatal respiratory failure. Mice transduced with Trpc3-targeted shRNA survived with no changes in breathing. Patch-clamp and field recordings from the preBötC in mouse slices also showed an increase in the frequency and a decrease in the magnitude of preBötC neural bursts in the presence of Trpm4 antagonist 9-phenanthrol, whereas the Trpc3 antagonist pyrazole-3 (pyr-3) showed inconsistent effects on magnitude and no effect on frequency. These data suggest that Trpm4 mediates ICAN, whose influence on frequency contradicts a direct role in rhythm generation. We conclude that Trpm4-mediated ICAN is indispensable for motor output but not the rhythmogenic core mechanism of the breathing central pattern generator.
Categories: Biology, Journals

Dinosaur extinction lines up closely with timing of volcanic eruptions

Genetics - Thu, 2019-02-21 21:00
Many people assume an asteroid triggered the mass extinction that killed the dinosaurs, but geologists say massive volcanic eruptions occurred at the same time
Categories: Biology

Why Samsung’s folding smartphone might prove more than just a fad

Genetics - Thu, 2019-02-21 18:46
With the Galaxy Fold, Samsung has become the first major manufacturer to launch a phone with a folding screen – it might just be useful enough to tempt consumers
Categories: Biology