Highwire, a conserved axonal E3 ubiquitin ligase, regulates the initiation of axonal degeneration after injury in Drosophila by regulating the levels of the NAD+ biosynthetic enzyme, Nmnat, and the Wnd kinase.
The transcription factor ELF5 is responsible for gene expression patterning underlying molecular subtypes of breast cancer and may mediate acquired resistance to anti-estrogen therapy.
In injured neurons, “leaky” voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na + -loading and “Nav-CLS”, i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I Na-window . A recent computation study revealed that CLS-based I Na-window left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic “smeared” injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For “mild CLS injury”, a prominent feature is slow pump/leak-mediated E Ion oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist “device” could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.
After seven years as the Editor-in-Chief of PLOS Computational Biology, I have decided to step to the side. It's time to bring in new leadership and a new vision. As scientists we generally do not learn a lot of management skills (a mistake in my opinion), but if I have learnt two management skills it is the value of enablement and to start planning for your successor on day one. Well, I did not start on day one, but Ruth Nussinov has been the Deputy Editor-in-Chief since October 2008, and she is an outstanding scientist and editor ideally suited to take over as editor-in-chief. So please welcome Ruth to this leadership role. The journal is in very safe hands. The journal staff, editors, and Ruth have not seen the last of me, however—this is just too much fun. As Founding Editor-in-Chief, I will continue to be involved with the journal, with a focus on special projects, helping Ruth and the team where I can, and, of course, continue as an author of both research articles and front matter, such as the Ten Simple Rules series. In changing roles, I would like to make a few personal comments about the evolution of the journal and where it might go next. When Steven Brenner, Michael Eisen, and I founded the journal, we had a vision for how it would fill a gap between journals supporting purely computational methods and the array of experimental journals with the odd, token computational paper [1]. Thanks to you, the readers and authors, that vision has been realized beyond what we imagined, and I am very proud of how the journal is a voice for our broad and important community and at the same time helps build that community. The appearance of the journal in June 2005 was timely since it both propelled our field of science at a time when it was being recognized as a critical part of the life sciences, and made a strong statement about the importance of open access. I must confess that when we started planning for the journal in 2004, support for open access seemed like the right thing to do, but it was not a major driver for me. That changed when, early on in my tenure, I realized open access is critical to maximizing the rate of scientific discovery. Supporting open access, and the new forms of scholarly communication it fosters, enriched my career and brought me into contact with many amazing people I would not otherwise have met. Emphasizing that enrichment, of the 22 invited lectures I gave in 2011, 18 were evangelizing about the importance of open access and open science, and four were directly related to my science. In my opinion, we have yet to see open access reach its full potential, but we will [2], and our journal will be poised to play an ever-increasing role as an exemplar for what is possible. In short, PLOS and this journal will continue to foster change, which maximizes the accessibility and comprehension of science. I am proud to continue to be a part of that. It only remains for me to thank and acknowledge a variety of people who have all been so critically important in the past seven years. First and foremost are the approximately 150 editors who have worked tirelessly to shape and ensure a high-quality product over the years. There is no journal without community-driven efforts, which offer limited reward beyond a job well done. I can't mention everyone, but I must call out Karl Friston, who between 2005 and 2010 worked tirelessly to make computational neuroscience such a rich part of the journal, and Steven Brenner, Simon Levin, and Sebastian Bonhoeffer, who, since the journal's inception, have always responded with good advice. Thanks are also due to Mark Patterson, who, until late 2011, was Director of Publishing at PLOS. Mark was critical to the success of the journal and to PLOS as a whole. We first began talking about the journal in May 2004, and he listened to, refined, and contributed to a lot of crazy ideas that define what the journal is today. To Catherine Nancarrow, who managed the journal from 2005 to 2010. A nicer and more dedicated person will not be found. In the current era of 140 character snapshots, her emails conferred a quality, beauty, and caring that you just don't see anymore. To Evie Browne, who contributed so much as Publications Assistant and Publications Manager between 2006 and 2009. Her spreadsheet analyses of how the journal was doing were amazing. To Andy Collings, who in various roles from Publications Assistant to Editorial Manager from 2005 to 2012 just made all ideas work, however outside the box they were. To Fran Lewitter, who, as Education Editor since the beginning, has created an important community jewel. To Scott Markel, who has been a voice of reason and an interface to the International Society of Computational Biology (ISCB) over the years. Finally, to all the other staff who have contributed over the past seven years: Emily Stevenson, Johanna Dehlinger, Helen Budd, Sheran Basra, and Cecy Marden, and the amazing current staff of Laura Taylor, Clare Weaver, and Chris Hall, all so well led by Rosemary Dickin and Theo Bloom. PLOS is a family of journals and a family of people; in short, a family organization whose goal is to disseminate science in the most open and useful way possible. It is a successful organization able to recruit the best and most dedicated staff, and to adjust to its growing success and the success of open access itself. The world of scientific publishing will never be the same again because of PLOS and the people who drive it. I am proud to continue to be a member of this amazing family. There is no other publisher like PLOS and no other journal like PLOS Computational Biology.
Self-incompatibility has been considered by geneticists a model system for reproductive biology and balancing selection, but our understanding of the genetic basis and evolution of this molecular lock-and-key system has remained limited by the extreme level of sequence divergence among haplotypes, resulting in a lack of appropriate genomic sequences. In this study, we report and analyze the full sequence of eleven distinct haplotypes of the self-incompatibility locus (S-locus) in two closely related Arabidopsis species, obtained from individual BAC libraries. We use this extensive dataset to highlight sharply contrasted patterns of molecular evolution of each of the two genes controlling self-incompatibility themselves, as well as of the genomic region surrounding them. We find strong collinearity of the flanking regions among haplotypes on each side of the S-locus together with high levels of sequence similarity. In contrast, the S-locus region itself shows spectacularly deep gene genealogies, high variability in size and gene organization, as well as complete absence of sequence similarity in intergenic sequences and striking accumulation of transposable elements. Of particular interest, we demonstrate that dominant and recessive S-haplotypes experience sharply contrasted patterns of molecular evolution. Indeed, dominant haplotypes exhibit larger size and a much higher density of transposable elements, being matched only by that in the centromere. Overall, these properties highlight that the S-locus presents many striking similarities with other regions involved in the determination of mating-types, such as sex chromosomes in animals or in plants, or the mating-type locus in fungi and green algae.
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2 , DDX1 , SLC47A1 , CDK12 , CASP9 , and INO80 . Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis -eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.