bluuebunny/crossref_metadata_2025 huggingface dataset:
Antennal scales improve signal detection efficiency in moths
Authors: Wang Qike , Shang Yidan , Hilton Douglas S. , Inthavong Kiao , Zhang Dong , Elgar Mark A.
Published: March 2018

The elaborate bipectinate antennae of male moths are thought to increase their sensitivity to female sex pheromones, and so should be favoured by selection. Yet simple filamentous antennae are the most common structure among moths. The stereotypic arrangements of scales on the surface of antennae may resolve this paradox. We use computational fluid dynamics techniques to model how scales on the filamentous antennae of moths affect the passage of different particles in the airflow across the flagellum in both small and large moths. We found that the scales provide an effective solution to improve the efficacy of filamentous antennae, by increasing the concentration of nanoparticles, which resemble pheromones, around the antennae. The smaller moths have a greater increase in antennal efficiency than larger moths. The scales also divert microparticles, which resemble dust, away from the antennal surface, thereby reducing contamination. The positive correlations between antennal scale angles and sensilla number across Heliozelidae moths are consistent with the predictions of our model.
Olfaction written in bone: cribriform plate size parallels olfactory receptor gene repertoires in Mammalia
Authors: Bird Deborah J. , Murphy William J. , Fox-Rosales Lester , Hamid Iman , Eagle Robert A. , Van Valkenburgh Blaire
Published: March 2018

The evolution of mammalian olfaction is manifested in a remarkable diversity of gene repertoires, neuroanatomy and skull morphology across living species. Olfactory receptor genes (ORGs), which initiate the conversion of odorant molecules into odour perceptions and help an animal resolve the olfactory world, range in number from a mere handful to several thousand genes across species. Within the snout, each of these ORGs is exclusively expressed by a discrete population of olfactory sensory neurons (OSNs), suggesting that newly evolved ORGs may be coupled with new OSN populations in the nasal epithelium. Because OSN axon bundles leave high-fidelity perforations (foramina) in the bone as they traverse the cribriform plate (CP) to reach the brain, we predicted that taxa with larger ORG repertoires would have proportionately expanded footprints in the CP foramina. Previous work found a correlation between ORG number and absolute CP size that disappeared after accounting for body size. Using updated, digital measurement data from high-resolution CT scans and re-examining the relationship between CP and body size, we report a striking linear correlation between relative CP area and number of functional ORGs across species from all mammalian superorders. This correlation suggests strong developmental links in the olfactory pathway between genes, neurons and skull morphology. Furthermore, because ORG number is linked to olfactory discriminatory function, this correlation supports relative CP size as a viable metric for inferring olfactory capacity across modern and extinct species. By quantifying CP area from a fossil sabertooth cat (Smilodon fatalis), we predicted a likely ORG repertoire for this extinct felid.
Different alleles of the same gene vary in pleiotropy, often mediated through currency metabolite production
Authors: Alzoubi Deya , Desouki Abdelmoneim Amer , Lercher Martin J.
Published: March 2018

A major obstacle to the mapping of genotype-phenotype relationships is pleiotropy, the tendency of mutations to affect seemingly unrelated traits. Pleiotropy has major implications for evolution, development, ageing, and disease. Except for disease data, pleiotropy is almost exclusively estimated from full gene knockouts. However, most deleterious alleles segregating in natural populations do not fully abolish gene function, and the degree to which a polymorphism reduces protein function may influence the number of traits it affects. Utilizing genome-scale metabolic models forEscherichia coliand the baker’s yeastSaccharomyces cerevisiae, we show that most fitness-reducing full gene knockouts of metabolic genes have pleiotropic effects,i.e., they compromise the production of multiple biomass components. Alleles of the same gene with increasingly reduced enzyme function typically affect an increasing number of biomass components. This increasing pleiotropy is often mediated through effects on the generation of currency metabolites such as ATP or NADPH. We conclude that the physiological effects observed in full gene knockouts will in most cases not be representative for alleles with only partially reduced enzyme capacity or expression level.
MiR-505-3p, a New Repressor of Puberty Onset in Female Mice
Authors: Tong Li , Wang Maochun , Zhou Yuxun , Li Yu , Chen Li , Xu Fuyi , Li Kai , Xiao Junhua
Published: March 2018

Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty-related QTL on chromosome X in female mice to a 1.7 Mb region and deduced that miR-505-3p was the functional gene.

In a GT1-7 cell line with stable overexpression of miR-505-3p (pGT1-7), both ribosomes and ribosome biogenesis pathways were affected, and the expression of some puberty-related genes was down-regulated. The amount of mRNA and protein products of theSrsf1gene decreased by 50 percent, and the expression of puberty-related genes was rescued by the overexpression ofSrsf1. With the down regulation ofSrsf1expression through shRNA, the mRNA accumulation of puberty-related genes decreased simultaneously in the GT1-7 cell line. The results of RIP-seq showed that SF2, the protein of theSrsf1gene, primarily bound ribosome protein (RP) mRNAs in GT1-7 cells.

miR-505-3p knockout female mice showed earlier vaginal opening, higher serum gonadotrophin levels and higher expression of puberty-related andSrsf1genes in the hypothalamus than their wild-type littermates. B6 female mice with ectopic expression of miR-505-3p in the hypothalamus showed significant growth retardance and later VO than wild types.

These results suggest that miR-505-3p may regulate puberty onset via theSrsf1gene and RP expression, which reveals a new regulatory pathway in mammalian puberty onset involving microRNA, SF2 and ribosome proteins.

Author summary

In this study, we identified miR-505-3p in a puberty-related QTL on the X chromosome as a female puberty onset repressor using a positional cloning strategy.

GT1-7 cell lines stably overexpressing miR-505-3p (pGT1-7) showedKiss1andGnRHdown-regulation. We also identifiedSrsf1as the functional target gene of miR-505-3p in GT1-7 cells. Compared to wild-type mice, miR-505-3p knockout female mice showed puberty onset four days sooner, along with the overexpression of miR-505-3p in the hypothalamus 2 days later. Thus, miR-505-3p is a new repressor of puberty onset in female mice.
Automated sequential chromogenic IHC double staining with two HRP substrates
Authors: Petersen Kenneth H , Lohse Jesper , Ramsgaard Lasse
Published: March 2018

Automated IHC double staining using DAB and HRP Magenta is illustrated utilizing a new acid block with sulfuric acid to prevent cross-reactivity. Residual cross-reactivity in double staining is determined to arise from chromogenic-bound antibodies and amplification system during the first part of the double staining.
PKD2 influence uric acid levels and gout risk by interacting with ABCG2
Authors: Dong Zheng , Zhou Jingru , Jiang Shuai , Li Yuan , Zhao Dongbao , Yang Chengde , Ma Yanyun , He Hongjun , Ji Hengdong , Jin Li , Zou Hejian , Wang Jiucun
Published: March 2018

Background

Uric acid is the final product of purine metabolism and elevated serum urate levels can cause gout. Conflicting results were reported for the effect of PKD2 on serum urate levels and gout risk. Therefore, our study attempted to state the important role of PKD2 in influencing the pathogenesis of gout.

Method

SNPs in PKD2 (rs2725215 and rs2728121) and ABCG2 (rs2231137 and rs1481012) were tested in approximately 5,000 Chinese individuals.

Results

Two epistatic interactions between loci in PKD2 (rs2728121) and ABCG2 (rs1481012 and rs2231137) showed distinct contributions to uric acid levels with Pint values of 0.018 and 0.004, respectively, and the associations varies by gender and BMI. The SNP pair of rs2728121 and rs1481012 justly played roles in uric acid in females (Pint = 0.006), while the other pair did in males (Pint = 0.017). Regarding BMI, the former SNP pair merely contributed in overweigh subjects (Pint = 0.022) and the latter one did in both normal and overweigh individuals (Pint = 0.013 and 0.047, respectively). Furthermore, the latter SNP pair was also associated with gout pathology (Pint = 0.001), especially in males (Pint = 0.001). Finally, functional analysis showed potential epistatic interactions in those genes region and PKD2 mRNA expression had a positive correlation with ABCG2’s (r = 0.743, P = 5.83e-06).

Conclusion

Our study for the first time identified that epistatic interactions between PKD2 and ABCG2 influenced serum urate concentrations and gout risk, and PKD2 might affect the pathogenesis from elevated serum urate to hyperuricemia to gout by modifying ABCG2.
Electron cryo-microscopy structure of the canonical TRPC4 ion channel
Authors: Vinayagam Deivanayagabarathy , Mager Thomas , Apelbaum Amir , Bothe Arne , Merino Felipe , Hofnagel Oliver , Gatsogiannis Christos , Raunser Stefan
Published: March 2018

Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of zebrafish TRPC4 in its unliganded (apo), closed state at an overall resolution of 3.6 Å. The structure reveals the molecular architecture of the cation conducting pore, including the selectivity filter and lower gate. The cytoplasmic domain contains two key hubs that have been shown to interact with modulating proteins. Structural comparisons with other TRP channels give novel insights into the general architecture and domain organization of this superfamily of channels and help to understand their function and pharmacology.
Hydrodynamic cavitation as an energy efficient process to increase biochar surface area and porosity: a case study
Authors: Albanese Lorenzo , Baronti Silvia , Liguori Francesca , Meneguzzo Francesco , Barbaro Pierluigi , Vaccari Francesco Primo
Published: March 2018

The effectivity of biochar as soil amendment is depending by its physical and chemical characteristics that are related to the type and the features of the thermal production process, such as peak temperature, heating rate, holding time, as well as from the used feedstocks. The textural characteristics of biochar in term of surface area, pore size and pore volume distribution, important for the physicochemical properties of the material, are critically dependent on the production process and the feedstock type. In this study, based on a single biochar type and a single experiment, for the first time controlled hydrodynamic cavitation was proven as a fast and effective way to enhance the biochar surface area by as much as 120%, while preserving or improving the respective chemical composition, showing far higher efficiency than the conventional increase of the peak pyrolysis temperature.
idtracker.ai: Tracking all individuals in large collectives of unmarked animals
Authors: Romero-Ferrero Francisco , Bergomi Mattia G. , Hinz Robert , Heras Francisco J. H. , de Polavieja Gonzalo G.
Published: March 2018

Our understanding of collective animal behavior is limited by our ability to track each of the individuals. We describe an algorithm and software, idtracker.ai, that extracts from video all trajectories with correct identities at a high accuracy for collectives of up to 100 individuals. It uses two deep networks, one detecting when animals touch or cross and an-other one for animal identification, trained adaptively to conditions and difficulty of the video.
Evolution of the mutational process under relaxed selection inCaenorhabditis elegans
Authors: Saxena Ayush Shekhar , Salomon Matthew P. , Matsuba Chikako , Yeh Shu-Dan , Baer Charles F.
Published: March 2018

The mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.

Deleterious mutations are a ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups ofCaenorhabditis elegansmutation accumulation (MA) lines that differ in their starting mutation loads. “First-Order MA” (O1MA) lines maintained under minimal selection for ∼250 generations were divided into high-fitness and low-fitness groups and sets of “second-order MA” (O2MA) lines derived from each O1MA line were maintained for ∼150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate (µbs), but no effect of initial fitness, whereas the indel rate is greater in high-fitness O2MA lines. Overall,µbsis positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 Kb GC content. However, probability of mutation is well-predicted by the three-nucleotide motif. ∼90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the “drift barrier” model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic.
Bicoid gradient formation mechanism and dynamics revealed by protein lifetime analysis
Authors: Durrieu Lucia , Kirrmaier Daniel , Schneidt Tatjana , Kats Ilia , Raghavan Sarada , Knop Michael , Saunders Timothy E , Hufnagel Lars
Published: March 2018

Embryogenesis relies on instructions provided by spatially organized signaling molecules known as morphogens. Understanding the principles behind morphogen distribution and how cells interpret locally this information remains a major challenge in developmental biology. Here we introduce morphogen-age measurements as a novel approach to retrieve key parameters in morphogen dynamics. Using a tandem fluorescent timer (tFT) as a protein-age sensor we find a gradient of increasing age of Bicoid (Bcd) along the anterior-posterior (AP) axis in the early Drosophila embryo. Quantitative analysis retrieves parameter that are most consistent with the synthesis-diffusion-degradation (SDD) model underlying Bcd-gradient formation, and rule out some other hypotheses for gradient formation. Moreover, we show that the timer can detect transitions in the dynamics associated with syncytial cellularization. Our results provide new insight into Bcd gradient formation, and demonstrate how morphogen age-information can complement knowledge about movement, abundance and distribution, which should be widely applicable for other systems.
Electrocortical Evidence for Long-Term Incidental Spatial Learning Through Modified Navigation Instructions
Authors: Wunderlich Anna , Gramann Klaus
Published: March 2018

The use of Navigation Assistance Systems for spatial orienting has become increasingly popular. Such automated navigation support, however, comes with a reduced processing of the surrounding environment and often with a decline of spatial orienting ability. To prevent such deskilling and to support spatial learning, the present study investigated incidental spatial learning by comparing standard navigation instructions with two modified navigation instruction conditions. The first modified instruction condition highlighted landmarks and provided additional redundant information regarding the landmark (contrast condition), while the second highlighted landmarks and included personal relevant information regarding the landmark (personal-reference condition). Participants’ spatial knowledge of the previously unknown virtual city was tested three weeks later. Behavioral and electroencephalographic (EEG) data demonstrated enhanced memory performance for participants in the modified navigation instruction conditions without further differentiating between modified instructions. Recognition performance of landmarks was better and the late positive complex of the event-related potential (ERP) revealed amplitude differences reflecting an increased amount of recollected information for modified navigation instructions. The results indicate a significant long-term spatial learning effect when landmarks are highlighted during navigation instructions.
An eQTL landscape of kidney tissue in human nephrotic syndrome
Authors: Gillies Christopher E. , Putler Rosemary , Menon Rajasree , Otto Edgar , Yasutake Kalyn , Nair Viji , Hoover Paul , Lieb David , Li Shuqiang , Eddy Sean , Fermin Damian ,   Nephrotic Syndrome Study Network (NEPTUNE), Hacohen Nir , Kiryluk Krzysztof , Wen William , Kretzler Matthias , Sampson Matthew G.
Published: March 2018

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTLs studies of human kidney. Here, we used whole genome sequencing (WGS) and microdissected glomerular (GLOM) & tubulointerstitial (TI) transcriptomes from 187 patients with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures.

Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n=136) and TI (n=166). We used the Bayesian “Deterministic Approximation of Posteriors” (DAP) to fine-map these signals, eQtlBma to discover GLOM-or TI-specific eQTLs, and single cell RNA-Seq data of control kidney tissue to identify cell-type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IGAN) GWAS to perform a transcriptome-wide association study (TWAS).

We discovered 894 GLOM eQTLs and 1767 TI eQTLs at FDR <0.05. 14% and 19% of GLOM & TI eQTLs, respectively, had > 1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM-specific and TI-specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IGAN TWAS identified significant GLOM & TI genes, primarily at the HLA region.

In this study of NS patients, we discovered GLOM & TI eQTLs, identified those that were tissue-specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are publicly available for browsing and download at http://nephqtl.org.
PaintOmics 3: a web resource for the pathway analysis and visualization of multi-omics data
Authors: Hernández-de-Diego Rafael , Tarazona Sonia , Martínez-Mira Carlos , Balzano-Nogueira Leandro , Furió-Tarí Pedro , Pappas Georgios J , Conesa Ana
Published: March 2018

The increasing availability of multi-omic platforms poses new challenges to data analysis. Joint visualization of multi-omics data is instrumental to understand interconnections across molecular layers and to fully leverage the biology discovery power offered by the multi-omics approach.

We present here PaintOmics 3, a web-based resource for the integrated visualization of multiple omic data types onto KEGG pathway diagrams. PaintOmics 3 combines server-end capabilities for data analysis with the potential of modern web resources for data visualization, providing researchers with a powerful framework for interactive exploration of their multi-omics information.

Unlike other visualization tools, PaintOmics 3 covers a complete pathway analysis workflow, including automatic feature name/identifier conversion, multi-layered feature matching, pathway enrichment, network analysis, interactive heatmaps, trend charts, etc. It accepts a wide variety of omic types, including transcriptomics, proteomics and metabolomics, as well as region-based approaches such as ATAC-seq or ChIP-seq data. The tool is freely available at http://bioinfo.cipf.es/paintomics/.
Effects of CEPA and 1-MCP on flower bud differentiation of apple cv. ‘Nagafu No.2’ grafted on different rootstocks
Authors: Li Wenfang , Chen Baihong , Mao Juan , Li Xinwen , Su Jing , Dawuda Mohammed Mujitaba , Ma Zonghuan , Zuo Cunwu , An Zeshan
Published: March 2018

The apple (Malus domestica Borkh.) has a relatively long juvenile period which prevent the fruit breeding. The understanding of the flowering system is important to improve breeding efficiency in the apple. In this context, 2-year-old “Fuji” apple cv. “Nagafu No.2” trees that were grafted on dwarf self-rooted rootstock M.26, vigorous rootstock M. sieversii and interstock M.26/M. sieversii, respectively. Spraying with clean water (as controls), 800 mg·L−1 2-Chloroethylphosphonic acid (CEPA) and 2 μL·L−1 1-methylcyclopropene (1-MCP). The results showed that CEPA significantly repressed the vegetative growth attributed to the increase of the ABA and ZT synthesis, and the decrease of IAA synthesis in leaves and buds. However, there was no significant difference or significant inverse effect between 1-MCP and control. Furthermore, CEPA promoted flower formation, increased the flowering rate and advanced the blossom period for 2 days compared with the control, which accompanied by the accumulation of soluble sugar, glucose and sucrose, and the increase of α-amylase (α-AMY) and sucrose phosphate synthase (SPS) activities, and the decrease of the starch contents and sucrose synthase (SS) activities in leaves and buds. However, the blossom period was delayed for 2 days after spraying with 1-MCP. Finally, the expression of TFL1 was significantly repressed while the AP1 was significantly promoted in buds from M.26 and M.26/M. sieversii after spraying with CEPA, while the effect was not significant from M. sieversii. However, the expression levels of TFL1 and AP1 were not significantly different from the control after the application of 1-MCP. In spite of this, CEPA was more susceptible to easy-flowering M26, followed by M26/M. sieversii, and still less susceptible to difficult-flowering rootstock M. sieversii.

Abbreviations

1-MCP

1-methylcyclopropene

α-amylase

(α-AMY)

ABA

abscisic acid

CEPA

2-Chloroethylphosphonic acid

CTK

cytokinins

ETH

ethylene

GA

gibberellin

SPS

sucrose phosphate synthase

SS

sucrose synthase

ZT

zeatin.
Evolutionary analysis implicates RNA polymerase II pausing and chromatin structure in nematode piRNA biogenesis
Authors: Beltran T. , Barroso C. , Birkle T.Y. , Stevens L. , Schwartz H. T. , Sternberg P.W. , Fradin H. , Gunsalus K. , Piano F. , Cotton J. , Martínez-Pérez E. , Blaxter M. , Sarkies P.
Published: March 2018

Piwi-interacting RNAs (piRNAs) control transposable elements widely across metazoans but have rapidly evolving biogenesis pathways. In Caenorhabditis elegans, almost all piRNA loci are found within two 3Mb clusters on Chromosome IV. Each piRNA locus possesses an upstream motif that recruits RNA polymerase II to produce a ∼28 nt precursor transcript. Here, we use comparative epigenomics across nematodes to gain insight into piRNA biogenesis. We show that the piRNA upstream motif is derived from core promoter elements controlling snRNA biogenesis. We describe two alternative modes of piRNA organisation in nematodes: in C. elegans and closely related nematodes, piRNAs are clustered within repressive H3K27me3 chromatin, whilst in other species, typified by Pristionchus pacificus, piRNAs are distributed genome-wide within introns of actively transcribed genes. In both groups, piRNA production depends on downstream sequence signals associated with RNA polymerase II pausing, which synergise with the chromatin environment to control piRNA precursor transcription.
Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
Authors: de Vos Ivo J.H.M. , Tao Evelyn Yaqiong , Ong Sheena Li Ming , Goggi Julian L. , Scerri Thomas , Wilson Gabrielle R. , Low Chernis Guai Mun , Wong Arnette Shi Wei , Grussu Dominic , Stegmann Alexander P.A. , van Geel Michel , Janssen Renske , Amor David J. , Bahlo Melanie , Dunn Norris R. , Carney Thomas J. , Lockhart Paul J. , Coull Barry J. , van Steensel Maurice A.M.
Published: March 2018

Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation inMMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murineMMP14mutations, does not affect MMP14’s transport to the cell membrane. Instead, it partially impairs MMP14’s proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14’s catalytic activity is the prime determinant of disease severity. Given the limitations of ourin vitroassays in addressing the consequences of MMP14 dysfunction, we generated a novelmmp14a/bknockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density due to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.
Measuring Endoplasmic Reticulum Signal Sequences Translocation Efficiency Using the Xbp1 Arrest Peptide
Authors: Kriegler Theresa , Magoulopoulou Anastasia , Marchal Rocio Amate , Hessa Tara
Published: March 2018

Secretory proteins translocate across the mammalian ER membrane co-translationally via the ribosome-sec61 translocation channel complex. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER-targeting signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation initiation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient, versus inefficient (poorly hydrophobic) signal sequences, using an assay based on Xbp1 peptide-mediated translational arrest. With this method we were able to measure the functional efficiency of ER signal sequences. We show that an efficient signal sequence experiences a two-phases event in which the nascent chain is pulled from the ribosome during its translocation, thus resuming translation and yielding full-length products. Conversely, the inefficient signal sequence experiences a single weaker pulling event, suggesting inadequate engagement by the translocation machinery of these marginally hydrophobic signal sequences.
Escher-FBA: A web application for interactive flux balance analysis
Authors: Rowe Elliot , Palsson Bernhard O. , King Zachary A.
Published: March 2018

Background

Flux balance analysis (FBA) is a widely-used method for analyzing metabolic networks. However, most existing tools that implement FBA require downloading software and writing code. Furthermore, FBA generates predictions for metabolic networks with thousands of components, so meaningful changes in FBA solutions can be difficult to identify. These challenges make it difficult for beginners to learn how FBA works.

Results

To meet this need, we present Escher-FBA, a web application for interactive FBA simulations within a pathway visualization. Escher-FBA allows users to set flux bounds, knock out reactions, change objective functions, upload metabolic models, and generate high-quality figures without downloading software or writing code. We provide detailed instructions on how to use Escher-FBA to replicate several FBA simulations that generate real scientific hypotheses.

Conclusions

We designed Escher-FBA to be as intuitive as possible so that users can quickly and easily understand the core concepts of FBA. The web application can be accessed at https://sbrg.github.io/escher-fba.
Comprehensive profiling of the fission yeast transcription start site activity during stress and media response
Authors: Thodberg Malte , Thieffry Axel , Bornholdt Jette , Boyd Mette , Holmberg Christian , Azad Ajuna , Workman Christopher T. , Chen Yun , Ekwall Karl , Nielsen Olaf , Sandelin Albin
Published: March 2018

Fission yeast, Schizosaccharomyces pombe, is an attractive model organism for transcriptional and chromatin biology research. Such research is contingent on accurate annotation of transcription start sites (TSSs). However, comprehensive genome-wide maps of TSSs and their usage across commonly applied laboratory conditions and treatments for S. pombe are lacking. To this end, we profiled TSS activity genome-wide in S. pombe cultures exposed to heat shock, nitrogen starvation, hydrogen peroxide and two commonly applied media, YES and EMM2, using Cap Analysis of Gene Expression (CAGE). CAGE-based annotation of TSSs is substantially more accurate than existing PomBase annotation; on average, CAGE TSSs fall 50-75 bp downstream of PomBase TSSs and co-localize with nucleosome boundaries. In contrast to higher eukaryotes, S. pombe does not show sharp and dispersed TSS distributions. Our data recapitulate known S. pombe stress expression response patterns and identify stress- and mediaresponsive alternative TSSs. Notably, alteration of growth medium induces changes of similar magnitude as some stressors. We show a link between nucleosome occupancy and genetic variation, and that the proximal promoter region is genetically diverse between S. pombe strains. Our detailed TSS map constitute a central resource for S. pombe gene regulation research.
smCounter2: an accurate low-frequency variant caller for targeted sequencing data with unique molecular identifiers
Authors: Xu Chang , Gu Xiujing , Padmanabhan Raghavendra , Wu Zhong , Peng Quan , DiCarlo John , Wang Yexun
Published: March 2018

Motivation

Low-frequency DNA mutations are often confounded with technical artifacts from sample preparation and sequencing. With unique molecular identifiers (UMIs), most of the sequencing errors can be corrected. However, errors before UMI tagging, such as DNA polymerase errors during end-repair and the first PCR cycle, cannot be corrected with single-strand UMIs and impose fundamental limits to UMI-based variant calling.

Results

We developed smCounter2, a UMI-based variant caller for targeted sequencing data and an upgrade from the current version of smCounter. Compared to smCounter, smCounter2 features lower detection limit at 0.5%, better overall accuracy (particularly in non-coding regions), a consistent threshold that can be applied to both deep and shallow sequencing runs, and easier use via a Docker image and code for read pre-processing. We benchmarked smCounter2 against several state-of-the-art UMI-based variant calling methods using multiple datasets and demonstrated smCounter2’s superior performance in detecting somatic variants. At the core of smCounter2 is a statistical test to determine whether the allele frequency of the putative variant is significantly above the background error rate, which was carefully modeled using an independent dataset. The improved accuracy in non-coding regions was mainly achieved using novel repetitive region filters that were specifically designed for UMI data.

Availability

The entire pipeline is available at https://github.com/qiaseq/qiaseq-dna under MIT license.
Topographic effects on dispersal patterns ofPhytophthora cinnamomiat a stand scale in a Spanish heathland
Authors: Cardillo Enrique , Acedo Angel , Abad Enrique
Published: March 2018

Phytophthora cinnamomiis one of the most important plant pathogens in the world, causing root rot in more than a thousand plant species. This observational study was carried out on aP. cinnamomiinfected heathland ofErica umbellataused as goat pasture. The patterns and shapes of disease foci and their distribution were described in a spatial and temporal context using an aerial photograph record. A set of topographic traits was selected on the basis of a disease dynamic hypothesis and their effects on observed spatial disease patterns were analyzed. Incipient infections situated in flat terrain expanded as compact circular front patterns with a low growth rate. On slopes, disease patches developed more rapidly down slope, forming parabolic shapes. The axis direction of the parabolas was highly correlated with terrain aspect, while the parabolic amplitude was associated with land curvature and slope. New secondary foci appeared over the years producing an accelerated increase of the affected surface. These new foci were observed in sites where disease density was higher or near sites more frequently visited by animals such as the stable or the forage crop. In contrast, a smaller number of disease foci occur in areas which animals are reluctant to visit, such as where they have a short range of vision. Our results suggest that 1) the growth of existingP. cinnamomifoci is controlled by a combination of root-to-root contact and water flows, 2) the increase in the diseased area arises mainly from the multiplication of patches, 3) the formation of new foci is mediated by long-distance transport due to the movement of animals and humans along certain preferential pathways, and 4) geomorphology and topography traits are associated with the epidemiology of this soil-borne pathogen.
Dectin-3 recognizes cryptococcal glucuronoxylomannan to initiate host defense against cryptococcosis
Authors: Huang Hua-Rong , Li Fan , Han Hua , Lv Quan-Zhen , Xu Xia , Li Ning , Wang Shunchun , Xu Jin-Fu , Jia Xin-Ming
Published: March 2018

Cryptococcus neoformansandCryptococcus gattiicause life-threatening meningoencephalitis and pneumonia in immunosuppressed and immunocompetent individuals. Given the structural differences of major polysaccharide glucuronoxylomannan (GXM) betweenC. neoformansandC. gattii, it remains unclear that how innate immune system recognizes GXM. Here, we report that C-type lectin receptor Dectin-3 (MCL encoded by Clec4d) is a direct receptor for GXMs fromC. neoformansserotype AD (C.n-AD) andC. gattiiserotype B (C.g-B). GXMs fromC.n-AD andC.g-B activated both NF-κB and ERK pathways to induce the pro-inflammatory cytokine production, whereas it was completely abolished due to deficiency of Dectin-3 or its downstream adaptor protein CARD9. Upon pulmonaryC.n-AD andC.g-B infection, Dectin-3- and CARD9-deficient mice were highly susceptible and showed augmented lung injury due to impairment of alveolar macrophage accumulation and killing activities. These results demonstrate that Dectin-3 contributes to host immunity againstCryptococcusinfection through selectively recognizingGXM.
CREBBPandWDR 24Affects Quantitative Variation in Red Colouration in the Chicken
Authors: Fogelholm J. , Henriksen R. , Höglund A. , Huq N. , Johnsson M. , Lenz R. , Jensen P. , Wright D.
Published: March 2018

Plumage colouration in birds is important for a plethora of reasons, ranging from camouflage, sexual signaling, and species recognition. The genes underlying colour variation have been vital in understanding how genes can affect a phenotype. Multiple genes have been identified that affect plumage variation, but research has principally focused on major-effect genes (such as those causing albinism, barring, and the like), rather than the smaller effect modifier loci that more subtly influence colour. By utilizing a domestic x wild advanced intercross with a combination of classical QTL mapping of red colouration as a quantitative trait and a targeted genetical genomics approach, we have identified five separate candidate genes (CREBBP, WDR24, ARL8A, PHLDA3, LAD1) that putatively influence quantitative variation in red colouration in chickens. Such small effect loci are potentially far more prevalent in wild populations, and can therefore potentially be highly relevant to colour evolution.
Human Puf-A, a Novel Component of 90S Pre-ribosome, Links Ribosome Biogenesis to Cancer Progression
Authors: Cho Huan-Chieh , Huang Yenlin , Hung Jung-Tung , Lai Li-Chun , Wang Sheng-Hung , Liu Yun-Hen , Cho I-Ming , Kuo Ming-Wei , Cheng Pei-Yi , Ho Ming-Yi , Lin Rey-Jin , Yu Alice L. , Yu John
Published: March 2018

We describe a novel biogenesis factor of the 90S pre-ribosome, Puf-A, which is a negative transcriptional target of p53. The expression of Puf-A is not only upregulated in advanced human lung cancer and tumors of patients especially with TP53 mutation, but also is highly prognostic for stage I lung cancer. Loss of Puf-A expression prevents KrasG12D/p53-/-–induced tumor progression in the lungs and induces apoptosis in TP53– mutated cancers and c-Myc/p53-/-–transformed cells as well. Overexpression of Puf-A enhances proliferation of normal cells after c-Myc induction and overcomes the cell-cycle checkpoints incurred by p53 expression. Mechanistically, Puf-A interacts with double-stranded structures of the 5.8S sequence within pre-rRNA and maintains the integrity of 90S pre-ribosomes, thereby impacting early ribosome assembly and export of ribosomes from nuclei. Silencing of Puf-A disrupts the assembly of 90S pre-ribosomes and induces the translocation of its associated nucleophosmin (NPM1) from nucleoli to the nucleoplasm, resulting in impairment of ribosome synthesis. Thus, Puf-A is crucial for over-activation of ribosome biogenesis and contributes to tumor progression and cancer growth.
Impulsive choice in mice lacking paternal expression of Grb10 suggests intra-genomic conflict in behavior
Authors: Dent Claire L. , Humby Trevor , Lewis Katie , Ward Andrew , Fischer-Colbrie Reiner , Wilkinson Lawrence S. , Wilkins Jon F , Isles Anthony R.
Published: March 2018

Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events that take place in the mammalian germ line and are thought to have evolved through intra-genomic conflict between parental alleles. We demonstrate, for the first time, oppositional effects of imprinted genes on brain and behavior. Specifically, here we show that mice lacking paternal Grb10 make fewer impulsive choices, with no dissociable effects on a separate measure of impulsive action. Taken together with previous work showing that mice lacking maternal Nesp55 make more impulsive choices this suggests that impulsive choice behavior is a substrate for the action of genomic imprinting. Moreover, the contrasting effect of these two genes suggests impulsive choices are subject to intra-genomic conflict and that maternal and paternal interests pull this behavior in opposite directions. Finally, these data may also indicate that an imbalance in expression of imprinted genes contributes to pathological conditions such as gambling and drug addiction, where impulsive behavior becomes maladaptive.
Binding Affinity Regression Models from Repeats Mutation in Polyglutamine Disease
Authors: Asha P R , Vijaya M S
Published: March 2018

Diagnosing and curing neurodegenarative disorder such as spinocerebellar ataxia is complicated when there is differences in formation of protein sequences and structures. Affinity prediction plays vital role to identify drugs for various genetic disorders. Spinocerebellar ataxia occurs but mainly it occurs due to polyglutamine repeats. This research work aims in predicting the affinity of spinocerebellar ataxia from the protein complexes by extracting the well-defined descriptors. Regression models are built to predict the affinity through machine learning techniques coded in python using the Scikit-Learn framework. Energy complexes and protein sequence descriptors are defined and extracted from the complex and sequences. Results show that the SVR is found to predict the affinity with high accuracy of 98% for spinocerebellar ataxia. This paper also deliberates the results of statistical learning carried out with the same set of complexes with various regression techniques.
Widespread transcriptional scanning in the testis modulates gene evolution rates
Authors: Xia Bo , Yan Yun , Baron Maayan , Wagner Florian , Barkley Dalia , Chiodin Marta , Kim Sang Y. , Keefe David L. , Alukal Joseph P. , Boeke Jef D. , Yanai Itai
Published: March 2018

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Analyzing our single-cell transcriptomic maps of human and mouse spermatogenesis, we provide evidence that this widespread transcription serves to maintain DNA sequence integrity in the male germline by correcting DNA damage through 'transcriptional scanning'. Supporting this model, we find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary time-scales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning modulates germline mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for fast evolution in a specific subset.
Topographic diversity of structural connectivity in schizophrenia
Authors: Ruan Hongtao , Luo Qiang , Palaniyappan Lena , Huang Chu-Chung , Zac Lo Chun-Yi , Liu Mu-En , Yang Albert C , Tsai Shih-Jen , Lin Ching-Po , Feng Jianfeng
Published: March 2018

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging (DTI) study, we recruited 77 healthy controls (HC), and 71 patients with DSM-IV diagnosis of schizophrenia (SCZ), and reconstructed the structural connectivity of 90 brain regions covering entire cerebral cortex. We first confirmed the heterogeneity in structural connectivity by showing a reduced inter-individual similarity in SCZ compared with HC. Moreover, we found it was not possible to cluster patients into subgroups with shared patterns of dysconnectivity, indicating a high degree of mechanistic divergence in schizophrenia. Instead of the strength of connectivity between any particular brain regions, we investigated the diversity (or statistically, the variance) of the topographic distribution of the strength was reduced. HC had higher topographic diversity in whole brain structural connectivity compared to the patient group

(P = 2 × 10−6, T = 4.96, Cohen′S d = 0.87). In 62 of the 90 brain regions, the topographic diversity was significantly reduced in patients compared to controls after FDR correction (<0.05). When topographic diversity was used as a discriminant feature for classification between patients and controls, we significantly (P = 4.29 × 10−24) improved the classification accuracy to 79.6% (sensitivity 78.3%, specificity 81.3%). This finding suggests highly individualized pattern of structural dysconnectivity underlying the heterogeneity of schizophrenia converges to a convergent common pathway as reduced topographic diversity for the clinical construct of the disease.
Identifying G protein-coupled receptor dimers from crystal packings
Authors: Stenkamp Ronald E.
Published: March 2018

Dimers of G protein-coupled receptors are believed to be important for signaling with their associated G proteins. Low resolution electron microscopy shows rhodopsin dimers in native retinal membranes, and CXCR4 dimers are found in several different crystal structures. Evidence for dimers of other GPCRs is more indirect. An alternative to computational modeling studies is to search for parallel dimers in the packing environments of the reported crystal structures of GPCRs. Two major structural types of GPCR dimers exist (as predicted by others), but there is considerable structural variation within each cluster. The different structural variants described here might reflect different functional properties and should provide a range of model structures for computational and experimental examination.

Synopsis

Analysis of intermolecular interactions in G protein-coupled receptor crystal structures shows two major types of dimers.
Covert spatial selection in primate basal ganglia
Authors: Arcizet Fabrice , Krauzlis Richard J.
Published: March 2018

The basal ganglia are important for action selection. They are also implicated in perceptual and cognitive functions that seem far removed from motor control. Here, we tested whether the role of the basal ganglia in selection extends to non-motor aspects of behavior by recording neuronal activity in the caudate nucleus while animals performed a covert spatial attention task. We found that caudate neurons strongly select the spatial location of the relevant stimulus throughout the task even in the absence of any overt action. This spatially selective activity was dependent on task and visual conditions, and could be dissociated from goal-directed actions. Caudate activity was also sufficient to correctly identify every epoch in the covert attention task. These results provide a novel perspective on mechanisms of attention by demonstrating that the basal ganglia are involved in spatial selection and tracking of behavioral states even in the absence of overt orienting movements.
Inter- and intra-specific genomic divergence inDrosophila montanashows evidence for cold adaptation
Authors: Parker D. J. , Wiberg R. A. W. , Trivedi U. , Tyukmaeva V. I. , Gharbi K. , Butlin R. K. , Hoikkala A. , Kankare M. , Ritchie M. G.
Published: March 2018

The genomes of species that are ecological specialists will likely contain signatures of genomic adaptation to their niche. However, distinguishing genes related to their ecological specialism from other sources of selection and more random changes is a challenge. Here we describe the genome ofDrosophila montana, the most extremely cold-adapted Drosophila species. We describe the genome, which is similar in size and gene content to most Drosophila species. We look for evidence of accelerated divergence from a previously sequenced relative, and do not find strong evidence for divergent selection on coding sequence variation. We use branch tests to identify genes showing accelerated divergence in contrasts between cold- and warm adapted species and identify about 250 genes that show differences, possibly driven by a lower synonymous substitution rate in cold-adapted species. Divergent genes are involved in a variety of functions, including cuticular and olfactory processes. We also re-sequenced three populations ofD. montanarepresenting its ecological and geographic range. Outlier loci were more likely to be found on the X chromosome and there was a greater than expected overlap between population outliers and those genes implicated in cold adaptation between Drosophila species, implying some continuity of selective process at these different evolutionary scales.