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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 50,150 bioRxiv papers from 233,741 authors.

Most downloaded bioRxiv papers, since beginning of last month

48,856 results found. For more information, click each entry to expand.

46701: Seasonality dynamics of avian influenza occurrences in Central and West Africa
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Posted to bioRxiv 08 Aug 2014

Seasonality dynamics of avian influenza occurrences in Central and West Africa
5 downloads ecology

Trevon Fuller, Mariette Ducatez, Kevin Njabo, Emanuel Couacy-Hymann, Tony Chasar, G L Aplogan, Sirena Lao, F Awoume, A Tehou, Q Langeois, Scott Krauss, Thomas B Smith

Understanding seasonal cycles of viruses originating in wildlife can provide insight into their likelihood of persistence in animal populations and inform policies to limit spillover to human populations. Avian influenza virus (AIV) is an important zoonotic agent causing seasonal occurrence of avian influenza (AI) in wild birds in temperate areas. Although the seasonality of AIV transmission in tropical birds is largely unknown, peaks of influenza activity in human populations in the tropics coincide with the rainy season. To assess the seasonality of AI in tropical birds, from 2010-14, we sampled 40,099 birds at 32 sites in Central Africa (Cameroon, Central African Republic, Congo-Brazzaville, and Gabon) and West Africa (Benin, Côte d'Ivoire, and Togo). Although AIV was not isolated by egg culture, in Central Africa, detection rates by real-time RT-PCR were 3.57% for passerine songbirds and 8.74% for Anatid ducks. RT-PCR positivity in resident birds increased when Palearctic migrants arrived in Central Africa. At sampling sites with two annual wet seasons, the positive rate in wild birds was greatest during the big rainy season in September–October. This study provides the first evidence that AI is present in Central African birds and identifies environmental factors associated with cases.

46702: Dimorphic development in Streblospio benedicti: genetic analysis of morphological differences between larval types
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Posted to bioRxiv 02 Sep 2014

Dimorphic development in Streblospio benedicti: genetic analysis of morphological differences between larval types
5 downloads developmental biology

Christina Zakas, Matthew V Rockman

The marine polychaete Streblospio benedicti exhibits two distinct larval types, making it a model for the study of developmental evolution. Females produce either large eggs or small ones, which develop into distinct lecithotrophic or planktotrophic larvae with concomitant morphological and life-history differences. Here, we investigate the inheritance of key morphological traits that distinguish the larval types. We use genetic crosses to establish the influence of maternal and zygotic differences on larval phenotypes. We find a large maternal effect on larval size and the number of larval chaetae, while the number and length of these chaetae are also strongly influenced by zygotic genotype. Interestingly, the distribution of larval phenotypes produced by these crosses suggests traits intermediate to the two parental types should not be uncommon. Yet, despite gene flow between the types in natural populations, such intermediates are rarely found in nature, suggesting that selection may be maintaining distinct larval modes.

46703: Transmission patterns of hyper-endemic multi-drug resistant Klebsiella pneumoniae in a Cambodian neonatal unit: a longitudinal study with whole genome sequencing
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Posted to bioRxiv 28 Nov 2017

Transmission patterns of hyper-endemic multi-drug resistant Klebsiella pneumoniae in a Cambodian neonatal unit: a longitudinal study with whole genome sequencing
5 downloads epidemiology

Pieter W. Smit, Nicole Stoesser, Sreymom Pol, Esther van Kleef, Mathupanee Oonsivilai, Pisey Tan, Leakhena Neou, Claudia Turner, Paul Turner, Ben S. Cooper

Background: Klebsiella pneumoniae is an important and increasing cause of life-threatening disease in hospitalised neonates. Third generation cephalosporin resistance (3GC-R) is frequently a marker of multi-drug resistance, and can complicate management of infections. 3GC-R K. pneumoniae is hyper-endemic in many developing country settings, but its epidemiology is poorly understood and prospective studies of endemic transmission are lacking. We aimed to determine the transmission dynamics of 3GC-R K. pneumoniae in a newly opened neonatal unit (NU) in Cambodia. Methods: We performed a prospective longitudinal study between September and November 2013. Rectal swabs from 37 consented patients were collected upon NU admission and every three days thereafter. Morphologically different colonies from swabs growing cefpodoxime-resistant K. pneumoniae were selected for whole-genome sequencing (WGS). Results: 32/37 (86%) patients screened positive for 3GC-R K. pneumoniae and 93 colonies from 119 swabs were sequenced. Isolates were resistant to a median of six (range 3-9) antimicrobials. WGS revealed high diversity; pairwise distances between isolates from the same patient were either 0-1 SNV or >1,000 SNVs; 19/32 colonized patients harboured K. pneumoniae colonies differing by >1000 SNVs. Diverse lineages accounted for 18 probable importations to the NU and nine probable transmission clusters involving 19/37 (51%) of screened patients. Median cluster size was 5 patients (range 3-9). Conclusions: The epidemiology of 3GC-R K. pneumoniae was characterised by multiple introductions and a dense network of cross-infection, with half of screened neonates part of a transmission cluster. Efforts to reduce the 3GC-R K. pneumoniae disease burden should consider targeting both processes.

46704: Division of labor, bet hedging, and the evolution of mixed biofilm investment strategies
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Posted to bioRxiv 08 Feb 2017

Division of labor, bet hedging, and the evolution of mixed biofilm investment strategies
5 downloads microbiology

Nick Vallespir Lowery, Luke McNally, William C Ratcliff, Sam P Brown

Bacterial cells, like many other organisms, face a tradeoff between longevity and fecundity. Planktonic cells are fast growing and fragile, while biofilm cells are often slower growing but stress resistant. Here we ask: why do bacterial lineages invest simultaneously in both fast and slow growing types? We develop a population dynamical model of lineage expansion across a patchy environment, and find that mixed investment is favored across a broad range of environmental conditions, even when transmission is entirely via biofilm cells. This mixed strategy is favored because of a division of labor, where exponentially dividing planktonic cells can act as an engine for the production of future biofilm cells, which grow more slowly. We use experimental evolution to test our predictions, and show that phenotypic heterogeneity is persistent even under selection for purely planktonic or purely biofilm transmission. Furthermore, simulations suggest that maintenance of a biofilm subpopulation serves as a cost-effective hedge against environmental uncertainty, which is also consistent with our experimental findings.

46705: Name Conditioning in Event-Related Brain Potentials
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Posted to bioRxiv 26 Sep 2017

Name Conditioning in Event-Related Brain Potentials
5 downloads neuroscience

Boris Kotchoubey, Yuri G. Pavlov

Four experiments are reported in which two harmonic tones (CS+ and CS-) were paired with a participant's own name (SON) and different names (DN), respectively. A third tone was not paired with any other stimulus and served as a standard (frequent stimulus) in a three-stimuli oddball paradigm. The larger posterior positivity (P3) to SON than DN, found in previous studies, was replicated in all experiments. Conditioning of the P3 response was albeit observed in two similar experiments (1 and 3), but the obtained effects were weak and not identical in the two experiments. Only Experiment 4, where the number of CS/UCS pairings and the Stimulus-Onset Asynchrony between CS and UCS were increased, showed clear CS+/CS- differences both in time and time-frequency domains. Surprisingly, differential responses to CS+ and CS- were also obtained in Experiment 2, although SON and DN in that experiment were masked and never consciously recognized as meaning words (recognition rate 0/63 participants). The results are discussed in the context of other ERP conditioning experiments and, particularly, the studies of non-conscious effect on ERP. Several further experiments are suggested to replicate and extend the present findings and to remove the remaining methodological limitations.

46706: The dynamics of starvation and recovery
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Posted to bioRxiv 14 Nov 2017

The dynamics of starvation and recovery
5 downloads ecology

Justin D. Yeakel, Christopher P. Kempes, Sidney Redner

The eco-evolutionary dynamics of species are fundamentally linked to the energetic constraints of its constituent individuals. Of particular importance is the interplay between reproduction and the dynamics of starvation and recovery. To elucidate this interplay, we introduce a nutritional state-structured model that incorporates two classes of consumer: nutritionally replete, reproducing consumers, and undernourished, non-reproducing consumers. We obtain strong constraints on starvation and recovery rates by deriving allometric scaling relationships and find that population dynamics are typically driven to a steady state. Moreover, these rates fall within a 'refuge' in parameter space, where the probability of population extinction is minimized. We also show that our model provides a natural framework to predict maximum mammalian body size by determining the relative stability of an otherwise homogeneous population to a competing population with altered percent body fat. This framework provides a principled mechanism for a selective driver of Cope's rule.

46707: A Cytoplasmic GOLD Protein Controls Cell Polarity
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Posted to bioRxiv 27 Jul 2018

A Cytoplasmic GOLD Protein Controls Cell Polarity
5 downloads cell biology

Christopher J Stefan, Deike J Omnus, Angela Cadou, Gary HC Chung, Jakob M Bader

Phosphoinositide lipids provide spatial landmarks during polarized secretion. Here, we elucidate a role for phosphatidylinositol 4-phosphate (PI4P) metabolism in the control of cell polarity. In budding yeast, PI4P is enriched at the plasma membrane of growing daughter cells. Upon heat shock however, PI4P rapidly increases at the plasma membrane in mother cells resulting in a more uniform PI4P distribution. Rather than phosphoinositide kinase activation, PI4P hydrolysis is impaired to generate the heat-induced PI4P signal in mother cells. This fine tune control of PI4P metabolism is mediated through attenuation of the Osh3 protein that binds and presents PI4P to a phosphoinositide phosphatase. Importantly, Osh3 undergoes phase transitions upon environmental stress conditions, resulting in intracellular aggregates and reduced cortical localization. The chaperone Hsp104 co-assembles with intracellular Osh3 granules, but is not required for their formation. Interestingly, the Osh3 GOLD domain, also present in the ER-localized p24 cargo adaptor family, is sufficient to form stress granules. Accordingly, GOLD-mediated phase transitions may provide a general mechanism to modulate secretion and growth upon transient changes in physiological and environmental conditions.

46708: Evolutionary and Functional Implications of Hypervariable Loci Within the Skin Virome
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Posted to bioRxiv 28 Sep 2016

Evolutionary and Functional Implications of Hypervariable Loci Within the Skin Virome
5 downloads microbiology

Geoffrey D. Hannigan, Qi Zheng, Jacquelyn S Meisel, Samuel Minot, Frederick D Bushman, Elizabeth A Grice

Localized genomic variability is crucial for the ongoing conflicts between infectious microbes and their hosts. An understanding of evolutionary and adaptive patterns associated with genomic variability will help guide development of vaccines and anti-microbial agents. While most analyses of the human microbiome have focused on taxonomic classification and gene annotation, we investigated genomic variation of skin-associated viral communities. We evaluated patterns of viral genomic variation across 16 healthy human volunteers. HPV and Staphylococcus phages contained 106 and 465 regions of diversification, or hypervariable loci, respectively. Propionibacterium phage genomes were minimally divergent and contained no hypervariable loci. Genes containing hypervariable loci were involved in functions including host tropism and immune evasion. HPV and Staphylococcus phage hypervariable loci were associated with purifying selection. Amino acid substitution patterns were virus dependent, as were predictions of their phenotypic effects. We identified diversity generating retroelements as one likely mechanism driving hypervariability. We validated these findings in an independently collected skin metagenomic sequence dataset, suggesting that these features of skin virome genomic variability are widespread. Our results highlight the genomic variation landscape of the skin virome and provide a foundation for better understanding community viral evolution and the functional implications of genomic diversification of skin viruses.

46709: Collective excitability in a mesoscopic neuronal model of epileptic activity
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Posted to bioRxiv 12 Jul 2017

Collective excitability in a mesoscopic neuronal model of epileptic activity
5 downloads neuroscience

Maciej Jedynak, Antonio Javier Pons, Jordi Garcia-Ojalvo

The brain can be understood as a collection of interacting neuronal oscillators, but the extent to which its sustained activity is due to coupling among brain areas is still unclear. Here we study the joint dynamics of two cortical columns described by Jansen-Rit neural mass models, and show that coupling between the columns gives rise to stochastic initiations of sustained collective activity, which can be interpreted as epileptic events. For large enough coupling strengths, termination of these events results mainly from the emergence of synchronization between the columns, and thus is controlled by coupling instead of noise. Stochastic triggering and noise-independent durations are characteristic of excitable dynamics, and thus we interpret our results in terms of collective excitability.

46710: Genetic context and proliferation determine contrasting patterns of copy number amplification and loss for 5S and 45S ribosomal DNA arrays in cancer
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Posted to bioRxiv 23 Jun 2017

Genetic context and proliferation determine contrasting patterns of copy number amplification and loss for 5S and 45S ribosomal DNA arrays in cancer
5 downloads genomics

Meng Wang, Bernardo Lemos

The multicopy 45S ribosomal DNA (45S rDNA) array gives origin to the nucleolus, the first discovered nuclear organelle, site of Poll I 45S rRNA transcription and key regulator of cellular metabolism, DNA repair response, genome stability, and global epigenetic states. The multicopy 5S ribosomal DNA array (5S rDNA) is located on a separate chromosome, encodes the 5S rRNA transcribed by Pol III, and exhibits concerted copy number variation (cCNV) with the 45S rDNA array in human blood. Here we combined genomic data from >700 tumors and normal tissues to provide a portrait of ribosomal DNA variation in human tissues and cancers of diverse mutational signatures. We show that most cancers undergo coupled 5S rDNA array amplification and 45S rDNA loss, with abundant inter-individual variation in rDNA copy number of both arrays, and concerted modulation of 5S-45S copy number in some but not all tissues. Analysis of genetic context revealed associations between the presence of specific somatic alterations, such as P53 mutations in stomach and lung adenocarcinomas, and coupled 5S gain/45S loss. Finally, we show that increased proliferation rates along cancer lineages can partially explain contrasting copy number changes in the 5S and 45S rDNA arrays. We suggest that 5S rDNA amplification facilitates increased ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in highly proliferating tumor cells. Our results highlight the tissue-specificity of concerted copy number variation and uncover contrasting changes in 5S and 45S rDNA copy number along rapidly proliferating cell lineages.

46711: Apontic regulates cell proliferation and development by activating the expression of hedgehog and cyclin E
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Posted to bioRxiv 22 May 2016

Apontic regulates cell proliferation and development by activating the expression of hedgehog and cyclin E
5 downloads developmental biology

Xian-Feng Wang, Qian Cheng, Chong-Lei Fu, Zi-Zhang Zhou, Susumu Hirose, Qing-Xin Liu

Hedgehog (Hh) signaling pathway and Cyclin E are key players in cell proliferation and development. Hyperactivation of hh and cyclin E has been linked to several types of cancer. However, transcriptional regulation of hh and cyclin E are not well understood. Here we show that an evolutionarily conserved transcription factor Apontic (Apt) is an activator of hh and cyclin E in Drosophila. Apt directly promotes the expression of hh and cyclin E through its binding site in the promoter regions of hh and cyclin E during wing development. This Apt-dependent proper expression of hh and cyclin E is required for cell proliferation and development of the wing. Apt-mediated expression of hh and cyclin E can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. The discovery of the coordinated expression of Hh and principal cell-cycle regulator Cyclin E by Apt implicates insight into the mechanism by which deregulated hh and cyclin E promotes tumor formation.

46712: Three-stage processing of category and variation information by entangled interactive mechanisms of peri-occipital and peri-frontal cortices
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Posted to bioRxiv 10 Jan 2018

Three-stage processing of category and variation information by entangled interactive mechanisms of peri-occipital and peri-frontal cortices
5 downloads neuroscience

Hamid Karimi-Rouzbahani

Invariant object recognition, which refers to the ability of precisely and rapidly recognizing objects in the presence of variations, has been a central question in human vision research. The general consensus is that the ventral and dorsal visual streams are the major processing pathways which undertake category and variation encoding in entangled layers. This overlooks the mounting evidence which support the role of peri-frontal areas in category encoding. These recent studies, however, have left open several aspects of visual processing in peri-frontal areas including whether these areas contributed only in active tasks, whether they interacted with peri-occipital areas or processed information independently and differently. To address these concerns, a passive EEG paradigm was designed in which subjects viewed a set of variation-controlled object images. Using multivariate pattern analysis, noticeable category and variation information were observed in occipital, parietal, temporal and prefrontal areas, supporting their contribution to visual processing. Using task specificity indices, phase and Granger causality analyses, three distinct stages of processing were identified which revealed transfer of information between peri-frontal and peri-occipital areas suggesting their parallel and interactive processing of visual information. A brain-plausible computational model supported the possibility of parallel processing mechanisms in peri-occipital and peri-frontal areas. These findings, while advocating previous results on the role of prefrontal areas in object recognition, extend their contribution from active recognition, in which peri-frontal to peri-occipital feedback mechanisms are activated, to the general case of object and variation processing, which is an integral part of visual processing and play role even during passive viewing.

46713: Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis
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Posted to bioRxiv 07 Nov 2017

Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis
5 downloads genetics

James E. Hicks, Michael A Province

The contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies. In conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them. With millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombinations in a sparse set of markers. We present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model. In simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.

46714: Transient Reduction of DNA Methylation at the Onset of Meiosis in Male Mice
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Posted to bioRxiv 17 Aug 2017

Transient Reduction of DNA Methylation at the Onset of Meiosis in Male Mice
5 downloads molecular biology

Valeriya Gaysinskaya, Brendan F. Miller, Godfried W. van der Heijden, Kasper D. Hansen, Alex Bortvin

The quality of germ cells depends on successful chromatin organization in meiotic prophase I (MPI). To better understand the epigenetic context of MPI we studied the dynamics of DNA methylation in wild-type male mice. We discovered an extended period of genome-wide transient reduction of DNA methylation (TRDM) during early MPI. Our data show that TRDM arises by passive demethylation in the premeiotic S phase highlighting the abundance of hemimethylated DNA in MPI. Importantly, TRDM unmasks a deficit in retrotransposon LINE-1 DNA methylation contributing to its expression in early MPI. We propose that TRDM facilitates meiosis and gamete quality control.

46715: UniLoc: A universal protein localization site predictor for eukaryotes and prokaryotes
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Posted to bioRxiv 25 Jan 2018

UniLoc: A universal protein localization site predictor for eukaryotes and prokaryotes
5 downloads bioinformatics

Hsin-Nan Lin, Ching-Tai Chen, Ting-Yi Sung, Wen-Lian Hsu

There is a growing gap between protein subcellular localization (PSL) data and protein sequence data, raising the need for computation methods to rapidly determine subcellular localizations for uncharacterized proteins. Currently, the most efficient computation method involves finding sequence-similar proteins (hereafter referred to as similar proteins) in the annotated database and transferring their annotations to the target protein. When a sequence-similarity search fails to find similar proteins, many PSL predictors adopt machine learning methods for the prediction of localization sites. We proposed a universal protein localization site predictor - UniLoc - to take advantage of implicit similarity among proteins through sequence analysis alone. The notion of related protein words is introduced to explore the localization site assignment of uncharacterized proteins. UniLoc is found to identify useful template proteins and produce reliable predictions when similar proteins were not available.

46716: Oligogenic Adaptation, Soft Sweeps, and Parallel Melanic Evolution in Drosophila melanogaster
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Posted to bioRxiv 09 Jun 2016

Oligogenic Adaptation, Soft Sweeps, and Parallel Melanic Evolution in Drosophila melanogaster
5 downloads genetics

Héloïse Bastide, Jeremy D. Lange, Justin B Lack, Yassin Amir, John E Pool

Unraveling the genetic architecture of adaptive phenotypic divergence is a fundamental quest in evolutionary biology. In Drosophila melanogaster, high-altitude melanism has evolved in separate mountain ranges in sub-Saharan Africa, potentially as an adaptation to UV intensity. We investigated the genetic basis of this melanism in three populations using a new bulk segregant analysis mapping method. Although hundreds of genes are known to affect cuticular pigmentation in D. melanogaster, we identified only 19 distinct QTLs from 9 mapping crosses, with several QTL peaks being shared among two or all populations. Surprisingly, we did not find wide signals of genetic differentiation (FST) between lightly and darkly pigmented populations at these QTLs, in spite of the pronounced phenotypic difference in pigmentation. Instead, we found small numbers of highly differentiated SNPs at the probable causative genes. A simulation analysis showed that these patterns of polymorphism are consistent with selection on standing genetic variation (leading to "soft sweeps"). Our results thus support a role for oligogenic selection on standing genetic variation in driving parallel ecological adaptation.

46717: The healthy ageing gene expression signature for Alzheimer's disease diagnosis: a random sampling perspective
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Posted to bioRxiv 05 Apr 2016

The healthy ageing gene expression signature for Alzheimer's disease diagnosis: a random sampling perspective
5 downloads bioinformatics

Laurent Jacob, Terence P Speed

In a recent publication, Sood et al. presented a set of 150 probe-sets which could be used in a diagnosis of Alzheimer disease (AD) based on gene expression. We reproduce some of their experiments, and show that the performance of their particular set of 150 probe-sets does not stand out compared to that of randomly sampled sets of 150 probe-sets from the same array.

46718: Solution and gas-phase modifiers effect on heme proteins environment and conformational space
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Posted to bioRxiv 27 Jun 2018

Solution and gas-phase modifiers effect on heme proteins environment and conformational space
5 downloads biochemistry

David Butcher, Jaroslava Miksovska, Mark E Ridgeway, Mel A Park, Francisco Fernandez-Lima

The molecular environment is known to impact the secondary and tertiary structure of biomolecules, shifting the equilibrium between different conformational and oligomerization states. In the present study, the effect of solution additives and gas-phase modifiers on the molecular environment of two common heme proteins, bovine cytochrome c and equine myoglobin, is investigated as a function of the time after desolvation (e.g., 100 - 500 ms) using trapped ion mobility spectrometry - mass spectrometry. Changes in the mobility profiles are observed depending on the starting solution composition (i.e., in aqueous solution at neutral pH or in the presence of organic content: methanol, acetone, or acetonitrile) depending on the protein. In the presence of gas-phase modifiers (i.e., N2 containing methanol, acetone, or acetonitrile), a shift in the mobility profiles driven by the gas-modifier mass and size and changes in the relative abundances and number of IMS bands are observed. We attribute these changes in the mobility profiles in the presence of gas-phase modifiers to a clustering/declustering mechanism by which organic molecules adsorb to the protein ion surface and lower energetic barriers for interconversion between conformational states, thus redefining the free energy landscape and equilibria between conformers. These structural biology experiments open new avenues for manipulation and interrogation of biomolecules in the gas-phase with the potential to emulate a large suite of solution conditions, ultimately including conditions that more accurately reflect a variety of intracellular environments.

46719: Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signalling
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Posted to bioRxiv 06 Sep 2018

Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signalling
5 downloads developmental biology

Eva Zacharioudaki, Julia Falo Sanjuan, Sarah Bray

To progress towards differentiation, the progeny of stem cells need to extinguish expression of stem cell maintenance genes. Failures in these mechanisms that suppress stem cell programmes can lead to supernumerary stem cells and drive tumorigenesis. In Drosophila neural stem cell lineages, excessive Notch signalling results in supernumerary stem cells causing hyperplasia. But the onset of hyperplasia is considerably delayed implying there are mechanisms that resist the mitogenic signal. Monitoring live the expression of an early NSC marker, the Notch target gene E(spl)mγ, revealed that the normal process of NSC fate attenuation is still initiated even in the presence of excess Notch activity so that the re-emergence of stem cell properties occurs only in older progeny. Screening for factors responsible, we found that depletion of Mi-2 and other members of the NuRD ATP remodeling complex dramatically enhanced the Notch-induced hyperplasia. Under these conditions, E(spl)mγ was no longer extinguished in the stem cell progeny, but instead remained at high levels. We propose that Mi-2 is required for decommissioning stem cell enhancers in their progeny, enabling the switch towards a more differentiated fate and rendering them insensitive to mitogenic factors such as Notch.

46720: Detecting translational regulation by change point analysis of ribosome profiling datasets
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Posted to bioRxiv 05 Mar 2014

Detecting translational regulation by change point analysis of ribosome profiling datasets
5 downloads bioinformatics

A. Zupanic, C. Meplan, S. N. Grellscheid, J. C. Mathers, T. B. L. Kirkwood, J. E. Hesketh, D. P. Shanley

Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While ribosome density is constant along the length of the mRNA coding region, it can be altered by translational regulatory events. In this study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modelling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq dataset obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artefacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g. premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new gene isoforms.

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