bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental evolution for niche breadth in bacteriophage T4 highlights the importance of structural genes
Authors: Pham Jenny Y. , Ogbunugafor C. Brandon , Nguyen Ba Alex N. , Hartl Daniel L. 
Published: June 2019

AbstractEcologists have long studied the evolution of niche breadth, including how variability in environments can drive the evolution of specialism and generalism. This concept is of particular interest in viruses, where niche-breadth evolution may explain viral disease emergence, or underlie the potential for therapeutic measures like phage therapy. Despite the significance and potential applications of virus-host interactions, the genetic determinants of niche-breadth evolution remain unexplored in many bacteriophage. In this study, we present the results of an evolution experiment with a model bacteriophage system,Escherichia virus T4, in several host environments: exposure toE. coliC, exposure toE. coliK-12, and exposure to bothE. coliC andE. coliK-12. This experimental framework allowed us to investigate the phenotypic and molecular manifestations of niche-breadth evolution. First, we show that selection on different hosts led to measurable changes in phage productivity in all experimental populations. Second, whole—genome sequencing of experimental populations revealed signatures of selection. Finally, clear and consistent patterns emerged across the host environments, especially the presence of new mutations in phage structural genes. A comparison of mutations found across functional gene categories revealed that structural genes acquired significantly more mutations than other categories. Our findings suggest that structural genes—those that provide morphological and biophysical integrity to a virus—are central determinants in bacteriophage niche breadth.
Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein
Authors: Lu Daniel R. , Wu Hao , Driver Ian , Ingersoll Sarah , Sohn Sue , Wang Songli , Li Chi-Ming , Phee Hyewon 
Published: June 2019

AbstractThe therapeutic expansion of Foxp3+ regulatory T cells (Tregs) shows promise for treating autoimmune and inflammatory disorders. Yet, how this treatment affects the heterogeneity and function of Tregs is not clear. Using single-cell RNA-seq analysis, we characterized 31,908 Tregs from the mice treated with a half-life extended mutant form of murine IL-2 (IL-2 mutein, IL-2M) that preferentially expanded Tregs, or mouse IgG Fc as a control. Cell clustering analysis revealed that IL-2M specifically expands multiple sub-states of Tregs with distinct expression profiles. TCR-profiling with single-cell analysis uncovered Treg migration across tissues and transcriptional changes between clonally related Tregs following IL-2M treatment. Finally, we identified IL-2M-expanded Tnfrsf9+Il1rl1+ Tregs with superior suppressive function, highlighting the potential of IL-2M to expand highly suppressive Foxp3+ Tregs.One Sentence SummarySingle-cell analysis revealed that IL-2 mutein treatment expanded multiple sub-states of Tregs with a highly suppressive function in mice.
lncRNAKB: A comprehensive knowledgebase of long non-coding RNAs
Authors: Seifuddin Fayaz , Singh Komudi , Suresh Abhilash , Chen Yun-Ching , Chaitankar Vijender , Tunc Ilker , Ruan Xiangbo , Li Ping , Chen Yi , Cao Haiming , Lee Richard S. , Goes Fernando , Zandi Peter P. , Jafri M. Saleet , Pirooznia Mehdi 
Published: June 2019

ABSTRACTWe have assembled a comprehensivelongnon-codingRNAknowledgebase (lncRNAKB) of 77,199 annotated human lncRNAs (224,286 transcripts) by methodically integrating widely used lncRNAs resources. To facilitate functional characterization of lncRNAs, we employed Genotype-Tissue Expression (GTEx) project to provide tissue-specific gene expression profiles of lncRNAs in 31 solid organ tissues. Additional information includes network analysis to identify co-expressed gene modules to potentially delineate lncRNA function. Tissue-specificity, phylogenetic conservation scores and coding potential for lncRNAs are included. Finally, using whole genome sequencing data from GTEx, expression quantitative trait loci (cis-eQTL) regulated lncRNAs were calculated in all tissues. lncRNAKB is available athttp://www.lncrnakb.org.
Pseudomonas aeruginosaethanol oxidation by AdhA in low oxygen environments
Authors: Crocker Alex W. , Harty Colleen E. , Hammond John H. , Willger Sven D. , Salazar Pedro , Jacobs Nicholas J. , Hogan Deborah A. 
Published: June 2019

AbstractPseudomonas aeruginosahas a broad metabolic repertoire that facilitates its co-existence with different microbes. Many microbes secrete products thatP. aeruginosacan then catabolize, including ethanol, a common fermentation product. Here, we show that under oxygen limiting conditionsP. aeruginosautilizes AdhA, an NAD-linked alcohol dehydrogenase, as a previously undescribed means for ethanol catabolism. In a rich medium containing ethanol, AdhA, but not the previously described PQQ-linked alcohol dehydrogenase, ExaA, oxidizes ethanol and leads to the accumulation of acetate in culture supernatants. AdhA-dependent acetate accumulation, and the accompanying decrease in pH, promotesP. aeruginosasurvival in LB-grown stationary phase cultures. The transcription ofadhAis elevated by hypoxia and in anoxic conditions, and we show that it is regulated by the Anr transcription factor. We have shown thatlasRmutants have higher levels of Anr-regulated transcripts in low oxygen conditions compared to their wild type counterparts. Here, we show that alasRmutant, when grown with ethanol, has an even larger decrease in pH than WT that is dependent on bothanrandadhA. The large increase in AdhA activity similar to that of a strain expressing a hyperactive Anr-D149A variant. Ethanol catabolism inP. aeruginosaby AdhA supports growth on ethanol as a sole carbon source and electron donor in oxygen-limited settings and in cells growing by denitrification in anoxic conditions. This is the first demonstration of a physiological role for AdhA in ethanol oxidation inP. aeruginosa.ImportanceEthanol is a common product of microbial fermentation, and thePseudomonas aeruginosaresponse to and utilization of ethanol is relevant to our understanding of its role in microbial communities. Here, we report that the putative alcohol dehydrogenase, AdhA, is responsible for ethanol catabolism and acetate accumulation in low oxygen conditions and that it is regulated by Anr.
Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014
Authors: Sommer Grit , Schindler Matthias , Redmond Shelagh , Pfeiffer Verena , Konstantinoudis Garyfallos , Ammann Roland A. , Ansari Marc , Hengartner Heinz , Michel Gisela , Kuehni Claudia E. ,   for the Swiss Paediatric Oncology Group (SPOG)
Published: June 2019

STRUCTURED ABSTRACTBackgroundIncidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.MethodsWe extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends in annual age-standardised incidence using JoinPoint regression models.ResultsOver the study period from 1985-2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p<0.001). Using the 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.ConclusionTrends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and at least partly due to changes in risk factors.HighlightsIn Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.Increase in incidence was mainly caused by brain tumours and leukaemias.Improved registration and diagnostics may have increased brain tumour incidence.Increasing trend for leukaemias may be real, but reasons remain elusive.
Limited thermal plasticity and geographic divergence in the ovipositor of Drosophila suzukii
Authors: Varón-González Ceferino , Fraimout Antoine , Delapré Arnaud , Debat Vincent , Cornette Raphaël 
Published: June 2019

AbstractPhenotypic plasticity has been repeatedly suggested to facilitate adaptation to new environmental conditions, as in invasions. Here we investigate this possibility by focusing on the worldwide invasion of Drosophila suzukii: an invasive species that has rapidly colonized all continents over the last decade. This species is characterized by a highly developed ovipositor, allowing females to lay eggs through the skin of ripe fruits. Using a novel approach based on the combined use of SEM and photogrammetry, we quantified the ovipositor size and 3D shape, contrasting invasive and native populations raised at three different developmental temperatures. We found a small but significant effect of temperature and geographic origin on the ovipositor shape, showing the occurrence of both geographic differentiation and plasticity to temperature. The shape reaction norms are in turn strikingly similar among populations, suggesting very little difference in shape plasticity among invasive and native populations, and therefore rejecting the hypothesis of a particular role for plasticity of the ovipositor in the invasion success. Overall, the ovipositor shape seems to be a fairly robust trait, indicative of stabilizing selection. The large performance spectrum rather than the flexibility of the ovipositor would thus contribute to the success of D. suzukii worldwide invasion.
Metabolic pathway rerouting inParaburkholderia rhizoxinicaevolved long-overlooked derivatives of coenzyme F420
Authors: Braga Daniel , Last Daniel , Hasan Mahmudul , Guo Huijuan , Leichnitz Daniel , Uzum Zerrin , Richter Ingrid , Schalk Felix , Beemelmanns Christine , Hertweck Christian , Lackner Gerald 
Published: June 2019

AbstractCoenzyme F420is a specialized redox cofactor with a highly negative redox potential. It supports biochemical processes like methanogenesis, degradation of xenobiotics or the biosynthesis of antibiotics. Although well-studied in methanogenic archaea and actinobacteria, not much is known about F420in Gram-negative bacteria. Genome sequencing revealed F420biosynthetic genes in the Gram-negative, endofungal bacteriumParaburkholderia rhizoxinica, a symbiont of phytopathogenic fungi. Fluorescence microscopy, high-resolution LC-MS, and structure elucidation by NMR demonstrated that the encoded pathway is active and yields unexpected derivatives of F420(3PG-F420). Further analyses of a biogas-producing microbial community showed that these derivatives are more widespread in nature. Genetic and biochemical studies of their biosynthesis established that a specificity switch in the guanylyltransferase CofC re-programmed the pathway to start from 3-phospho-D-glycerate, suggesting a rerouting event during the evolution of F420biosynthesis. Furthermore, the cofactor activity of 3PG-F420was validated, thus opening up perspectives for its use in biocatalysis. The 3PG-F420biosynthetic gene cluster is fully functional inEscherichia coli, enabling convenient production of the cofactor by fermentation.
Reprogramming of 24nt siRNAs in rice gametes
Authors: Li Chenxin , Xu Hengping , Fu Fang-Fang , Russell Scott D. , Sundaresan Venkatesan , Gent Jonathan I. 
Published: June 2019

ABSTRACTGametes constitute a critical stage of the plant life cycle, during which the genome undergoes reprogramming in preparation for embryogenesis. Here we characterized the small RNA transcriptomes of egg cells and sperm cells from rice to elucidate genome-wide distributions of 24nt siRNAs, which are a hallmark of RNA-directed DNA methylation (RdDM) in plants and are typically concentrated at boundaries of heterochromatin. We found that 24nt siRNAs were depleted from heterochromatin boundaries in both gametes, reminiscent of siRNA patterns in DDM1-type nucleosome remodeler mutants. In sperm, 24nt siRNAs were spread across broad heterochromatic regions, while in eggs, 24nt siRNAs were concentrated at a smaller number of heterochromatic loci throughout the genome, which were shared with vegetative tissues and sperm. In both gametes, patterns of CHH methylation, typically a strong indicator of RdDM, were similar to vegetative tissues, although lower in magnitude. These findings indicate that the small RNA transcriptome undergoes large-scale re-programming in both male and female gametes, which is not correlated with recruitment of DNA methyltransferases in gametes and suggestive of unexplored regulatory activities of gamete small RNAs in seeds after fertilization.
The Endless Frontier? The Recent Upsurge of R&D Productivity in Pharmaceuticals
Authors: Pammolli Fabio , Righetto Lorenzo , Abrignani Sergio , Pani Luca , Pelicci Pier Giuseppe , Rabosio Emanuele 
Published: June 2019

AbstractAnalyses of pharmaceutical pipelines of drug development in the 1990-2010 documented progressively increasing attrition rates and duration of clinical trials, leading to a diffuse perception of a “productivity crisis”. We produced a new set of analyses for the last decade, using an extensive data of more than 45,000 projects between 1990 and 2017, and report a recent upsurge of R&D productivity within the industry. First, we investigated how R&D projects are allocated across therapeutic areas and found a polarization towards high-risk/high-reward indications, with a strong focus on oncology. Importantly, attrition rates have been decreasing at all clinical stages in recent years. In parallel, we observed an increase of early failures in preclinical research, and a significant reduction of time required to identify projects to be discontinued. Notably, more recent projects are increasingly based on novel mechanisms of action and target indications with small patient populations. Finally, by analyses of the relative contribution of different institutional types and development companies, we show that the observed increased performance in clinical trials is mostly due to the contribution of biotech-nological companies, while pharmaceutical companies have significantly improved their performances in identifying false positives in preclinical research.
Chloris distichophyllaLag. (Poaceae) as stink bug (Pentatomidae) shelter in soybean and corn off-season in southern Brazil
Authors: Engel Eduardo , Pasini Mauricio P. B. , Hörz Daniele C. , Bortolotto Rafael P. 
Published: June 2019

AbstractThe objective of this study was to evaluate the composition and abundance of dormant bedbugs inChloris distichophyllaLag (Poales: Poaceae) over the soybean and corn off-season. The work was carried out in the municipality of Cruz Alta, over the soybean and corn off-season between 2014 and 2018. Plants ofC. distichophyllawith different clump diameter were sampled, and the bugs contained in them were counted and submitted to data analysis for the evaluation of the composition, structure, and diversity of occurring species. At the end of the experiment, 3543 hibernating adults were counted and divided into six species:Euschistus heros(F.),Dichelops furcatus(F.),Dichelops melacanthusDallas,Edessa meditabunda(F.),Edessa ruformaginata(De Geer) (Hemiptera: Pentatomidae). The speciesE. heroswas the most abundant, followed byD. furcatus. The diameter of the clumps directly affects the population density of the stink bugs. Finally,C. distichophyllais shown as a hibernate favorable to the maintenance of the stink bug populations over the soybean and corn off-season.
Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants
Authors: Donovan Margaret K. R. , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A. 
Published: June 2019

AbstractThe Genotype-Tissue Expression (GTEx) resource has contributed a wealth of novel insights into the regulatory impact of genetic variation on gene expression across human tissues, however thus far has not been utilized to study how variation acts at the resolution of the different cell types composing the tissues. To address this gap, using liver and skin as a proof-of-concept tissues, we show that readily available signature genes based on expression profiles of mouse cell types can be used to deconvolute the cellular composition of human GTEx tissues. We then deconvoluted 6,829 bulk RNA-seq samples corresponding to 28 GTEx tissues and show that we are able to quantify cellular heterogeneity, determining both the different cell types present in each of the tissues and how their proportions vary between samples of the same tissue type. Conducting eQTL analyses for GTEx liver and skin samples using cell type composition estimates as interaction terms, we identified thousands of novel genetic associations that had lower effect sizes and were cell-type-associated. We further show that cell-type-associated eQTLs in skin colocalize with melanoma, malignant neoplasm, and infection signatures, indicating variants that influence gene expression in distinct skin cell types play important roles in skin traits and disease. Overall, our study provides a framework to estimate the relative fractions of different cell types in GTEx tissues using signature genes from mouse cell types and functionally characterize human genetic variation that impacts gene expression in a cell-type-specific manner.
Oncoprotein CoAA repeats interact with RNA polymerase II CTD repeats
Authors: Xiong Shiqin , Brooks Yang S. , Yang Zheqiong , Wu Jiacai , Zhang Liyong , Dynan William S. , Xu Wei , O’Malley Bert W. , Ko Lan 
Published: June 2019

AbstractThe heptad repeating sequence of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II is highly conserved in eukaryotes. In yeast, a CTD code consisting of pairs of heptad repeats is essential for viability. However, the strict requirement of diheptad repeats for the CTD function in transcription and splicing is unexplained. Here we show that CoAA (gene symbol RBM14), an oncoprotein and mammalian transcriptional coactivator, possesses diheptad repeats and directly interacts with the CTD. CoAA comprises 27 copies of tyrosine-rich repeats and regulates pre-mRNA synthesis and alternative splicing. Tyrosine substitutions in either the CoAA repeats or the CTD repeats diminish their interactions. Ser2- or Ser5-phosphorylated CTD peptides exhibit higher binding affinity to CoAA than the corresponding non-phosphorylated CTD peptide. CoAA dynamically interacts with both the CTD and hnRNP M, which is an alternative splicing regulator also comprising diheptad repeats. Arginine methylation of CoAA switches its interaction from the hnRNP M repeats to the CTD repeats. This study provides a mechanism for CoAA at the interface of transcription and alternative splicing, and explains the functional requirement of diheptad repeats in the CTD. In the human genome, tyrosine-rich repeats similar to the CoAA repeats were only found in six oncoproteins including EWS and SYT. We suggest that the diheptad sequence is one of the signature features for the CTD interaction among oncoproteins involved in transcription and alternative splicing. We anticipate that direct RNA Pol II interaction is a mechanism in oncogenesis.
Entorhinal velocity signals reflect environmental geometry
Authors: Munn Robert G K , Mallory Caitlin S , Hardcastle Kiah , Chetkovich Dane M , Giocomo Lisa M 
Published: June 2019

SummaryThe entorhinal cortex contains neural signals for representing self-location, including grid cells that fire in periodic locations and velocity signals that encode an animal’s speed and head direction. Recent work revealed that the size and shape of the environment influences grid patterns. Whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here, we report that changes to the size and shape of the environment result in re-scaling in entorhinal speed codes. Moreover, head direction cells re-organize in an experience-dependent manner to align with the axis of environmental change. A knockout mouse model allows a dissociation of the coordination between cell types, with grid and speed, but not head direction, cells responding in concert to environmental change. These results align with predictions of grid cell attractor models and point to inherent flexibility in the coding features of multiple functionally-defined entorhinal cell types.
Neocortical inhibitory interneuron subtypes display distinct responses to synchrony and rate of inputs
Authors: Tran Matthew M. , Prince Luke Y. , Gray Dorian , Saad Lydia , Chasiotis Helen , Kwag Jeehyun , Kohl Michael M. , Richards Blake A. 
Published: June 2019

AbstractPopulations of neurons in the neocortex can carry information with both the synchrony and the rate of their spikes. However, it is unknown whether distinct subtypes of neurons in the cortical microcircuit are more sensitive to information carried by synchrony versus rate. Here, we address this question using patterned optical stimulation in slices of barrel cortex from transgenic mouse lines labelling distinct interneuron populations: fast-spiking parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. We use optical stimulation of channelrhodopsin-2 (ChR2) expressing excitatory neurons in layer 2/3 in order to encode a random 1-bit signal in either the synchrony or rate of activity in presynaptic cells. We then examine the mutual information between this 1-bit signal and the voltage and spiking responses in PV+ and SST+ interneurons. Generally, we find that both interneuron types carry more information than GFP negative (GFP-) control cells. More specifically, we find that for a synchrony encoding, PV+ interneurons carry more information in the first 5 milliseconds, while both interneuron subtypes carry more information than negative controls in their later response. We also find that for a rate encoding, SST+ interneurons carry more information than either PV+ or negative controls after several milliseconds. These data demonstrate that inhibitory interneuron subtypes in the neocortex have distinct responses to information carried by synchrony versus rates of spiking.