bluuebunny/crossref_metadata_2025 huggingface dataset:
DRAFT - Robotic automation of production and the recovery of cell spheroids
Authors: Langer Krzysztof , Jönsson Håkan
Published: February 2019

Droplet microfluidics enables high throughput cell processing, analysis and screening by miniaturizing the reaction vessels to nano-or pico-liter water-in oil droplets, but like many other microfluidic formats, droplet microfluidics have not been interfaced with or automated by laboratory robotics. Here we demonstrate automation of droplet microfluidics based on an inexpensive liquid handling robot for the automated production of human scaffold-free cell spheroids, using pipette actuation and interfacing the pipetting tip with a droplet generating microfluidic chip. In this chip we produce highly mono-disperse 290μm droplets with diameter CV of 1.7%. By encapsulating cells in these droplets we produce cell spheroids in droplets and recover them to standard formats at a throughput of 85000 spheroids per microfluidic circuit per hour. The viability of the cells in spheroids remains high after recovery only decreased by 4% starting from 96% after 16 hours incubation in nanoliter droplets. Scaffold-free cell spheroids and 3D tissue constructs recapitulate many aspects of functional human tissue more accurately than 2D or single cell cultures, but assembly methods for spheroids,e.g. hanging drop micro-plates, has had limited throughput. The increased throughput and decreased cost of our method enables spheroid production at the scale needed for lead discovery drug screening and approaches the cost where these micro tissues could be used as building blocks for organ scale regenerative medicine.
Reliable analysis of clinical tumor-only whole exome sequencing data
Authors: Oh Sehyun , Geistlinger Ludwig , Ramos Marcel , Morgan Martin , Waldron Levi , Riester Markus
Published: February 2019

Background

Allele-specific copy number alteration (CNA) analysis is essential to study the functional impact of single nucleotide variants (SNV) and the process of tumorigenesis. Most commonly used tools in the field rely on high quality genome-wide data with matched normal profiles, limiting their applicability in clinical settings.

Methods

We propose a workflow, based on the open-source PureCN R/Bioconductor package in conjunction with widely used variant-calling and copy number segmentation algorithms, for allele-specific CNA analysis from whole exome sequencing (WES) without matched normals. We use The Cancer Genome Atlas (TCGA) ovarian carcinoma (OV) and lung adenocarcinoma (LUAD) datasets to benchmark its performance against gold standard SNP6 microarray and WES datasets with matched normal samples. Our workflow further classifies SNVs by somatic status and then uses this information to infer somatic mutational signatures and tumor mutational burden (TMB).

Results

Application of our workflow to tumor-only WES data produces tumor purity and ploidy estimates that are highly concordant with estimates from SNP6 microarray data and matched-normal WES data. The presence of cancer type-specific somatic mutational signatures was inferred with high accuracy. We also demonstrate high concordance of TMB between our tumor-only workflow and matched normal pipelines.

Conclusion

The proposed workflow provides, to our knowledge, the only open-source option for comprehensive allele-specific CNA analysis and SNV classification of tumor-only WES with demonstrated high accuracy.
Drosophila p38 MAPK Interacts with BAG-3/starvin to Regulate Age-dependent Protein Homeostasis
Authors: Ryan Sarah M. , Almassey Michael , Burch Amelia M. , Ngo Gia , Martin Julia M. , Myers David , Compton Devin , Barbee Scott , Mortimer Nathan T. , Sanyal Subhabrata , Vrailas-Mortimer Alysia D.
Published: February 2019

As organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with the Chaperone-Assisted Selective Autophagy complex. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex.
White Matter Hyperintensity Quantification in Large-Scale Clinical Acute Ischemic Stroke Cohorts – The MRI-GENIE Study
Authors: Schirmer Markus D. , Dalca Adrian V. , Sridharan Ramesh , Giese Anne-Katrin , Donahue Kathleen L. , Nardin Marco J. , Mocking Steven J. T. , McIntosh Elissa C. , Frid Petrea , Wasselius Johan , Cole John W. , Holmegaard Lukas , Jern Christina , Jimenez-Conde Jordi , Lemmens Robin , Lindgren Arne G. , Meschia James F. , Roquer Jaume , Rundek Tatjana , Sacco Ralph L. , Schmidt Reinhold , Sharma Pankaj , Slowik Agnieszka , Thijs Vincent , Woo Daniel , Vagal Achala , Xu Huichun , Kittner Steven J. , McArdle Patrick F. , Mitchell Braxton D. , Rosand Jonathan , Worrall Bradford B. , Wu Ona , Golland Polina , Rost Natalia S. ,   on behalf of the MRI-GENIE Investigators
Published: February 2019

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery.

In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95) and Pearson correlation of total brain volume (r=0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N=2783) and identify a decrease in total brain volume of -2.4cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing.

Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2,533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.
Infection triggers tumor regression through activation of innate immunity inDrosophila
Authors: Jacqueline Camille , Parvy Jean-Philippe , Faugère Dominique , Renaud François , Missé Dorothée , Thomas Frédéric , Roche Benjamin
Published: February 2019

The pioneering work of Dr. William Coley has shown that infections can stimulate the immune system and improve tumor growth control. However, the immune mechanisms responsible for the protective role of infectious agents have still not been identified. Here, we investigated the role of innate immune pathways in tumor regression by performing experimental infections in genetically modifiedDrosophilathat develop invasive neoplastic tumors. After quantifying tumor size, through image processing, and immune gene expression with transcriptomic analyses, we analyzed the link between tumor size and pathogen-induced immune responses thanks to a combination of statistical and mathematical modeling.Drosophilalarvae infected with a naturally-occurring bacterium showed a smaller tumor size compared to controls and fungus-infected larvae, thanks to an increase expression of Imd and Toll pathways. Our mathematical model reinforces this idea by showing that repeated acute infection could results in an even higher decrease in tumor size. Thus, our study suggests that infectious agents can induce tumor regression through the alteration of innate immune responses. This phenomenon, currently neglected in oncology, could have major implications for the elaboration of new preventive and immunotherapeutic strategies.

One Sentence Summary

Bacterial infections can decrease cancer cell accumulation through stimulation of innate immune responses.
Dynamic Scan Procedure for Detecting Rare-Variant Association Regions in Whole Genome Sequencing Studies
Authors: Li Zilin , Li Xihao , Liu Yaowu , Shen Jincheng , Chen Han , Zhou Hufeng , Morrison Alanna C. , Boerwinkle Eric , Lin Xihong
Published: February 2019

Whole genome sequencing (WGS) studies are being widely conducted to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set based analyses are commonly used to analyze rare variants. However, existing variant-set based approaches need to pre-specify genetic regions for analysis, and hence are not directly applicable to WGS data due to the large number of intergenic and intron regions that consist of a massive number of non-coding variants. The commonly used sliding window method requires pre-specifying fixed window sizes, which are often unknown as a priori, are difficult to specify in practice and are subject to limitations given genetic association region sizes are likely to vary across the genome and phenotypes. We propose a computationally-efficient and dynamic scan statistic method (Scan the Genome (SCANG)) for analyzing WGS data that flexibly detects the sizes and the locations of rare-variants association regions without the need of specifying a prior fixed window size. The proposed method controls the genome-wise type I error rate and accounts for the linkage disequilibrium among genetic variants. It allows the detected rare variants association region sizes to vary across the genome. Through extensive simulated studies that consider a wide variety of scenarios, we show that SCANG substantially outperforms several alternative rare-variant association detection methods while controlling for the genome-wise type I error rates. We illustrate SCANG by analyzing the WGS lipids data from the Atherosclerosis Risk in Communities (ARIC) study.
Delivering on the Vision of Bench to Bedside: A Rare Disease Funding Community Collaboration to Develop Effective Therapies for Neurofibromatosis Type 1 Tumors
Authors: Rosa Salvatore La , Browder Vidya , Bakker Annette C. , Blakeley Jaishri O. , Verma Sharad K. , Wong Ling M. , Morris Jill A. , Bora Naba
Published: February 2019

The time from target identification to new drug approval is often measured in decades. This can be even more challenging for rare diseases. Indeed, 95% of rare diseases do not have a specific therapy approved. Coordinated efforts to support research along the drug development pipeline can provide long term and comprehensive support to enable scientific breakthroughs for rare diseases. However, this requires coordination across multiple stakeholders. The present article analyzes the funding efforts of four major federal and philanthropic organizations to accelerate the advancement of MEK inhibitors to human clinical trials for NF1-associated tumors.
Harnessing phenotypic networks and structural equation models to improve genome-wide association analysis
Authors: Momen Mehdi , Campbell Malachy T. , Walia Harkamal , Morota Gota
Published: February 2019

Plant breeders and breeders alike seek to develop cultivars with maximal agronomic value. The merit of breeding material is often assessed using many, often genetically correlated traits. As intervention on one trait will affect the value of another, breeding decisions should consider the relationships between traits. With the proliferation of multi-trait genome-wide association studies (MTM-GWAS), we can infer putative genetic signals at the multivariate scale. However, a standard MTM-GWAS does not accommodate the network structure of phenotypes, and therefore does not address how the traits are interrelated. We extended the scope of MTM-GWAS by incorporating phenotypic network structures into GWAS using structural equation models (SEM-GWAS). In this network GWAS model, one or more phenotypes appear in the equations for other phenotypes as explanatory variables. A salient feature of SEM-GWAS is that it can partition the total single nucleotide polymorphism (SNP) effects into direct and indirect effects. In this paper, we illustrate the utility of SEM-GWAS using biomass, root biomass, water use, and water use efficiency in rice. We found that water use efficiency is directly impacted by biomass and water use and indirectly by biomass and root biomass. In addition, SEM-GWAS partitioned significant SNP effects influencing water use efficiency into direct and indirect effects as a function of biomass, root biomass, and water use efficiency, providing further biological insights. These results suggest that the use of SEM may enhance our understanding of complex relationships between GWAS traits.
Two novel heteropolymer-forming proteins maintain multicellular shape of the cyanobacteriumAnabaenasp. PCC 7120
Authors: Springstein Benjamin L. , Nürnberg Dennis J. , Woehle Christian , Weissenbach Julia , Theune Marius L. , Helbig Andreas O. , Maldener Iris , Dagan Tal , Stucken Karina
Published: February 2019

Polymerizing and filament-forming proteins are instrumental for numerous cellular processes such as cell division and growth. Their function in stabilization and localization of protein complexes and replicons is achieved by a filamentous structure. Known filamentous proteins assemble into homopolymers consisting of single subunits – e.g. MreB and FtsZ in bacteria – or heteropolymers that are composed of two subunits, e.g. keratin and α/β tubulin in eukaryotes. Here, we describe two novel coiled-coil-rich proteins (CCRPs) in the filament forming cyanobacteriumAnabaenasp. PCC 7120 (hereafterAnabaena) that assemble into a heteropolymer and function in the maintenance of theAnabaenamulticellular shape (termed trichome). The two CCRPs – Alr4504 and Alr4505 (named ZicK and ZacK) – are strictly interdependent for the assembly of protein filamentsin vivoand polymerize nucleotide-independentlyin vitro, similar to known intermediate filament (IF) proteins. A ΔzicKΔzacK double mutant is characterized by a zigzagged cell arrangement and hence a loss of the typical linearAnabaenatrichome shape. ZicK and ZacK interact with themselves, with each other, with the elongasome protein MreB, the septal junction protein SepJ and the divisome associate septal protein SepI. Our results suggest that ZicK and ZacK function in cooperation with SepJ and MreB to stabilize theAnabaenatrichome and are likely essential for the manifestation of the multicellular shape inAnabaena. Our study reveals the presence of filament-forming IF-like proteins whose function is achieved through the formation of heteropolymers in cyanobacteria.
In-silico predictive identification of K-RasG12V inhibitors in natural compounds
Authors: Aliyar Masoud , Aryapour Hassan , Mahdavi Majid
Published: February 2019

As RAS protein is highly significant in signaling pathways, involving cell growth, differentiation and apoptosis; the Ras GTPase proteins play a significant as a master switch in the appearance of many diseases, including 20-30% of all cancers. So, the K-RasG12V mutant was selected as a drug target in present study. This mutant is involved in gastric cancer, lung and pancreatic carcinoma, and colon cancers. So, we employed the structure-based drug design methods and molecular dynamics simulations to undergo virtual screening on natural products small molecules and predicted some new potent therapeutic inhibitors. Finally, ZINC15671852, ZINC85592862, ZINC85567582 and ZINC03616630 final Hits were identified as potent inhibitors from among more than 79,000 bioactive compounds from natural resource. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-P/GBSA) calculation results have also demonstrated that these molecules obtained higher binding free energy than co-crystalized reference ligand.
Sex-biased gene expression is masculinized in asexual females
Authors: Parker Darren J. , Bast Jens , Jalvingh Kirsten , Dumas Zoé , Robinson-Rechavi Marc , Schwander Tanja
Published: February 2019

Males and females feature strikingly different phenotypes, despite sharing most of their genome. The resolution of this apparent paradox is through differential gene expression, whereby genes are expressed at different levels in each sex. This resolution, however, is likely to be incomplete, leading to conflict between males and females over the optimal expression of genes. We test the hypothesis that gene expression in females is constrained from evolving to its optimum level due to sexually antagonistic selection on males, by examining changes sex-biased gene expression in five obligate asexual species of stick insect, which do not produce males. We predicted that the transcriptome of asexual females would be feminized as asexual females do not experience any sexual conflict. Contrary to our prediction we find that asexual females feature masculinized gene expression, and hypothesise that this is due to shifts in female optimal gene expression levels following the suppression of sex.
Phospho-sRNA-seq reveals extracellular mRNA/lncRNA fragments as potential biomarkers in human plasma
Authors: Giraldez Maria D. , Spengler Ryan M. , Etheridge Alton , Goicochea Annika Jane , Tuck Missy , Choi Sung Won , Galas David J. , Tewari Muneesh
Published: February 2019

Extracellular RNAs (exRNAs) in biofluids have attracted great interest as potential biomarkers. Whereas extracellular microRNAs (miRNAs) in blood plasma are extensively characterized, extracellular messenger RNAs (mRNA) and long noncoding RNAs (lncRNA) are less well-studied. We report that plasma contains fragmented mRNAs and lncRNAs that are largely missed by standard small RNA-seq protocols due to lack of 5’ phosphate or presence of 3’ phosphate. These fragments were revealed using a modified protocol (“phospho-sRNA-seq”) incorporating RNA treatment with T4-polynucleotide kinase, which we compared with standard small RNA-seq for sequencing synthetic RNAs with varied 5’ and 3’ ends, as well as human plasma exRNA. Analyzing phospho-sRNA-seq data using a custom, high-stringency bioinformatic pipeline, we identified mRNA/lncRNA transcriptome fingerprints in plasma, including tissue-specific gene sets. In a longitudinal study of bone marrow transplant patients, bone marrow-and liver-enriched exRNA genes tracked with bone marrow recovery and liver injury, respectively, providing proof-of-concept validation as a biomarker approach. By enabling access to an unexplored realm of mRNA and lncRNA fragments, phospho-sRNA-seq opens up new possibilities for plasma transcriptomic biomarker development.
Meiotic DNA repair in the nucleolus employs a non-homologous end joining mechanism
Authors: Sims Jason , Copenhaver Gregory P. , Schlögelhofer Peter
Published: February 2019

Ribosomal RNA genes are arranged in large arrays with hundreds of rDNA units in tandem. These highly repetitive DNA elements pose a risk to genome stability since they can undergo non-allelic exchanges. During meiosis DNA double strand breaks (DSBs) are induced as part of the regular program to generate gametes. Meiotic DSBs initiate homologous recombination (HR) which subsequently ensures genetic exchange and chromosome disjunction.

InArabidopsis thalianawe demonstrate that all 45S rDNA arrays become transcriptionally active and are recruited into the nucleolus early in meiosis. This shields the rDNA from acquiring canonical meiotic chromatin modifications, meiotic cohesin and meiosis-specific DSBs. DNA breaks within the rDNA arrays are repaired in a RAD51-independent, but LIG4-dependent manner, establishing that it is non-homologous end joining (NHEJ) that maintains rDNA integrity during meiosis. Utilizing ectopically integrated rDNA repeats we validate our findings and demonstrate that the rDNA constitutes a HR-refractory genome environment.
The distribution of fitness effects among synonymous mutations in a gene under selection
Authors: Lebeuf-Taylor E. , McCloskey N. , Bailey S.F. , Hinz A. , Kassen R.
Published: February 2019

The fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitness effects among synonymous mutations for a gene under selection. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. A positive correlation between fitness and the presence of synonymous substitutions across a phylogeny of related Pseudomonads suggests these mutations may be common in nature. Taken together, our results provide the most compelling evidence to date that synonymous mutations with non-neutral fitness effects may in fact be commonplace.
Detecting natural hybridization among Indian major carps through advance morphometric approach
Authors: Dwivedi Arvind Kumar
Published: February 2019

Interspecific natural hybridization is an indicator of altered ecosystem. Habitat destruction increases competition with fish species in close proximity for spawning habitat with overlapping reproductive activities, thereby causing natural hybridization. This study is first investigation on detecting hybrids among Indian major carps (Labeo rohita, Cirrhinus mrigala and Gibelion catla) from the Ganga River by applying a cost-effective method, “Geometric Morphometrics”. The relative warps (RW), principal component analysis (PCA) and canonical variate analysis (CVA) were employed on superimposed images to determine morphometric variations. Deformation grid of RW showed that G. catla and hybrid specimens have a deeper whereas L. rohita and C. mrigala specimens have slender body profile. The PCA showed separation among specimens of four groups (three species and one hybrid) with slight overlap between G. catla and hybrid. CVA extracted Mahalanobis and Procrustes distances among four non-overlapping groups found to be highly significant (P < 0.0001) with hybrid specimens lying between position of L. rohita and G. catla specimens in close proximity to G. catla, suggesting that hybrids are product of crossing between L. rohita and G. catla. The CVA separated four groups with 100.00% classification, indicating that all the three species and hybrid were clearly distinct from each other. In this study, all the four specimens of hybrid were caught from upstream of four barrages (Bijnor, Narora, Kanpur and Farakka) commissioned along the middle and lower stretch of the Ganga River. This suggests that, barrages obstruct upward movement of fish population and impact on reproductive activities, thereby increases possibilities of natural hybridization among these species.
The benefits of insect-swarm hunting in echolocating bats, and its influence on the evolution of bat echolocation signals
Authors: Boonman Arjan , Yovel Yossi , Fenton Brock
Published: February 2019

Predation on swarms of prey, especially using visual information, has drawn much interest in studies of collective movement. Surprisingly, in the field of biosonar this aspect of prey detection, which is probably very common, has received little to no attention. Here, we combine computer simulations and actual echo measurements to accurately estimate the echo intensity of insect swarms of different size and density. We show that swarm echo intensity increases with 3dB for every doubling of insect number, irrespective of swarm density. Thus swarms will be much easier to detect than single insects. Many of the insects bats eat are so small that they are only detectable by echolocation at very short distances. By focusing on detection of swarms of insects, a bat may increase its operating range and diversify its diet. Interestingly, interference between the sound waves reflected from a swarm of insects can sometimes result in echoes that are much much weaker than echoes from single insects. We show that bats can reduce this problem by increasing the bandwidth of their echolocation calls. Specifically, a bandwidth of 3-8 kHz would guarantee receiving loud echoes from any angle relative to the swarm. Indeed, many bat species, and specifically bats hunting in open spaces, where swarms are abundant, use echolocation signals with a bandwidth of several kHz. Our results might also explain how the first echolocating bats that probably had limited echolocation abilities, could detect insects through swarm hunting.
In silico analysis ofIDH3Agene revealed Novel mutations associated with Retinitis Pigmentosa
Authors: Mahmoud Thwayba A. , Abdelmoneim Abdelrahman H. , Murshed Naseem S. , Mohammed Zainab O. , Ahmed Dina T. , Altyeb Fatima A. , Mahmoud Nuha A. , Mohammed Mayada A. , Arayah Fatima A. , Mohammed Wafaa I. , Abayazed Omnia S. , Akasha Amna S. , Mustafa Mujahed I. , Hassan Mohamed A.
Published: February 2019

Background

Retinitis Pigmentosa (RP) refers to a group of inherited disorders characterized by the death of photoreceptor cells leading to blindness. The aim of this study is to identify the pathogenic SNPs in the IDH3A gene and their effect on the structure and function of the protein.

Method

we used different bioinformatics tools to predict the effect of each SNP on the structure and function of the protein.

Result

20 deleterious SNPs out of 178 were found to have a damaging effect on the protein structure and function.

Conclusion

this is the first in silico analysis of IDH3A gene and 20 novel mutations were found using different bioinformatics tools, and they could be used as diagnostic markers for Retinitis Pigmentosa.
Metabolomic profiling revels systemic signatures of premature aging induced by Hutchinson-Gilford Progeria Syndrome
Authors: Monnerat Gustavo , Caprini Evaristo Geisa Paulino , Medeiros Evaristo Joseph Albert , dos Santos Caleb Guedes Miranda , Carneiro Gabriel , Maciel Leonardo , Carvalho Vânia Oliveira , Sousa Nogueira Fábio César , Domont Gilberto Barbosa , de Carvalho Antonio Carlos Campos
Published: February 2019

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder. HGPS children present a high incidence of cardiovascular complications along with altered metabolic processes and accelerated aging process. No metabolic biomarker is known and the mechanisms underlying premature aging are not fully understood. The present study analysed plasma from six HGPS patients of both sexes (7.7±1.4 years old; mean±SD) and eight controls (8.6±2.3 years old) by LC-MS/MS in high-resolution non-targeted metabolomics (Q-Exactive Plus). Several endogenous metabolites with statistical difference were found. Multivariate statistics analysis showed a clear separation between groups. Potential novel metabolic biomarkers are identified using the multivariate area under ROC curve (AUROC) based analysis, showing an AUC value higher than 0.80 using only two metabolites, and reaching 1.00 when increasing the number of metabolites in the AUROC model. Targeted metabolomics was used to validate some of the metabolites identified by the non-targeted method. Taken together, changed metabolic pathways in that panel involve sphingolipid, amino acid, and oxidation of fatty acids among others. In conclusion our data show significant alterations in cellular energy use and availability, in signal transduction, and in lipid metabolites, creating new insights on metabolic alterations associated with premature aging.
High transcriptional error rates vary as a function of gene expression level
Authors: Meer K.M. , Nelson P.G. , Xiong K. , Masel J.
Published: February 2019

Errors in gene transcription can be costly, and organisms have evolved to prevent their occurrence or mitigate their costs. The simplest interpretation of the drift barrier hypothesis suggests that species with larger population sizes would have lower transcriptional error rates. However, Escherichia coli seems to have a higher transcriptional error rate than species with lower effective population sizes, e.g. Saccharomyces cerevisiae. This could be explained if selection in E. coli were strong enough to maintain adaptations that mitigate the consequences of transcriptional errors through robustness, on a gene by gene basis, obviating the need for low transcriptional error rates and associated costs of global proofreading. Here we note that if selection is powerful enough to evolve local robustness, selection should also be powerful enough to locally reduce error rates. We therefore predict that transcriptional error rates will be lower in highly abundant proteins on which selection is strongest. However, we only expect this result when error rates are high enough to significantly impact fitness. As expected, we find such a relationship between expression and transcriptional error rate for non C➔U errors in E. coli (especially G➔A), but not in S. cerevisiae. We do not find this pattern for C➔U changes in E. coli, presumably because most deamination events occurred during sample preparation, but do for C➔U changes in S. cerevisiae, supporting the interpretation that C➔U error rates estimated with an improved protocol, and which occur at rates comparable to E. coli non C➔U errors, are biological.
B cell tetherin: a flow-cytometric cell-specific assay for response to Type-I interferon predicts clinical features and flares in SLE
Authors: El-Sherbiny Yasser M. , Yusof Md. Yuzaiful Md. , Psarras Antonios , Hensor Elizabeth M. A. , Kabba Kumba Z. , Dutton Katherine , Mohamed Alaa A.A. , Elewaut Dirk , McGonagle Dennis , Tooze Reuben , Doody Gina , Wittmann Miriam , Emery Paul , Vital Edward M.
Published: February 2019

Objective

Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B lineage cell-specific IFN assay might correlate with SLE activity.

Methods

B cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinised for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validatedin vitrothen clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction.

Results

In vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression was selectively responsive to the IFN-I compared to IFN-II and -III. In the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003;SLE/RA: effect size=0.17, p<0.001); plasmablast numbers in rituximab-treated patients (Rho=0.38, p=0.047) and BILAG-2004. Association were equivalent or stronger than interferon score or monocyte tetherin. The validation cohort confirmed this relationship with memory B-cell tetherin predictive of future clinical flares (Hazard Ratio=2.29 (1.01–4.64), p=0.022).

Conclusion

Memory B cell surface tetherin, a reflection of cell-specific IFN response in a convenient flow cytometric assay, was associated with SLE diagnosis, disease activity and predicted flares better than other cell subsets or whole blood assays in independent validation cohorts.
Non-catalytic binding sites induce weaker long-range evolutionary rate gradients than catalytic sites in enzymes
Authors: Sharir-Ivry Avital , Xia Yu
Published: February 2019

Enzymes exhibit a strong long-range evolutionary constraint that extends from their catalytic site and affects even distant sites, where site-specific evolutionary rate increases monotonically with distance. While protein-protein sites in enzymes was previously shown to induce only a weak conservation gradient, a comprehensive relationship between different types of functional sites in proteins and the magnitude of evolutionary rate gradients they induce has yet to be established. Here, we systematically calculate the evolutionary rate (dN/dS) of sites as a function of distance from different types of binding sites on enzymes and other proteins: catalytic sites, non-catalytic ligand binding sites, allosteric binding sites, and protein-protein interaction sites. We show that catalytic binding sites indeed induce significantly stronger evolutionary rate gradient than all other types of non-catalytic binding sites. In addition, catalytic sites in enzymes with no known allosteric function still induce strong long-range conservation gradients. Notably, the weak long-range conservation gradients induced by non-catalytic binding sites on enzymes is nearly identical in magnitude to those induced by ligand binding sites on non-enzymes. Finally, we show that structural determinants such as local solvent exposure of sites cannot explain the observed difference between catalytic and non-catalytic functional sites. Our results suggest that enzymes and non-enzymes share similar evolutionary constraints only when examined from the perspective of non-catalytic functional sites. Hence, the unique evolutionary rate gradient from catalytic sites in enzymes is likely driven by the optimization of catalysis rather than ligand binding and allosteric functions.
Limits to environmental masking of genetic quality in sexual signals
Authors: Howie James Malcolm , Dawson Harry Alexander Cordeaux , Pomiankowski Andrew , Fowler Kevin
Published: February 2019

There is considerable debate over the value of male sexual ornaments as signals of genetic quality. Studies alternately report that environmental variation enhances or diminishes the genetic signal, or leads to crossover where genotypes perform well in one environment but poorly in another. A unified understanding is lacking. We conduct the first experimental test examining the dual effects of distinct low and high genetic quality (inbred versus crossed parental lines) and low, through high, to extreme environmental stress (larval diets) on a condition-dependent male ornament. We find that differences in genetic quality signalled by the ornament (male eyespan inDiasemopsis meigeniistalk-eyed flies) become visible and are amplified under high stress but are overwhelmed in extreme stress environments. Variance among distinct genetic lines increases with environmental stress in both genetic quality classes, but at a slower rate in high quality outcrossed flies. Individual genetic lines generally maintain their ranks across environments, except among high quality lines under low stress conditions, where low genetic variance precludes differentiation between ranks. Our results provide a conceptual advance, demonstrating a unified pattern for how genetic and environmental quality interact. They show when environmental conditions lead to the amplification of differences in signals of genetic quality and thereby enhance the potential indirect genetic benefits gained by female mate choice.
The impact of distillery effluent irrigation on plant-growth-promoting traits and taxonomic composition of bacterial communities in agricultural soil
Authors: Kumari Priyanka , Tripathi Binu M. , Singh Ram N. , Saxena Anil K. , Kaushik Rajeev
Published: February 2019

Long-term irrigation of agricultural fields with distillery effluent (DE) may alter the physical, chemical and biological properties of the soil. Microorganisms are critical to the maintenance of soil health and productivity. However, the impact of DE irrigation on activity and taxonomy of soil microorganisms is poorly understood. Here we studied plant-growth-promoting (PGP) traits and taxonomic composition of bacterial communities in agricultural soil irrigated with DE in conjugation with irrigation water, using cultivation-dependent and - independent methods. Most of the bacterial isolates obtained from DE irrigated soil were found to display PGP traits (phosphate solubilization, siderophore, indolic compounds and ammonia production). Diverse bacterial taxa were found in both culturable bacterial community and 16S rRNA gene clone library, which belonged to bacterial phylaProteobacteria(Alpha-, Beta- and Gamma- subdivisions),Firmicutes, Actinobacteria, Acidobacteria, BacteroidetesandGemmatimonadates. Overall, these results indicate that PGP traits and taxonomic diversity of soil bacterial communities were not severely impacted by DE irrigation.
Virtual Microbes evolve multiple mechanisms to the same end: anticipating a serial transfer protocol
Authors: van Dijk Bram , Meijer Jeroen , Cuypers Thomas D , Hogeweg Paulien
Published: February 2019

Background

Experimental evolution of microbes often involves a serial transfer protocol, where microbes are repeatedly diluted by transfer to a fresh medium, starting a new growth cycle. This protocol has revealed that evolution can be remarkably reproducible, where microbes show parallel adaptations both on the level of the phenotype as well as the genotype. However, these studies also reveal a strong potential for divergent evolution, leading to diversity both between and within replicate populations. We here study howin silicoevolved Virtual Microbe “wild types” (WTs) adapt to a serial transfer protocol to investigate both the generic evolutionary adaptation to such an environment which are independent of prior evolution, and the variety of ways in which the adaptation is implemented at the individual and ecosystem level.

Results

We show that all pre-evolved WTs evolve to anticipate the regularity of the serial transfer protocol by adopting a fine-tuned balance of growth and survival. We find that this anticipation can be done in a variety of ways, either by a single lineage or by several lineages in consort. Interestingly, replicate populations of the same WT initially show similar trajectories, but may subsequently diverge along a growth rate versus yield trade-off.

Conclusions

We find that all ourin silicoWTs show the same anticipation effects — fitting the periodicity of a serial transfer protocol — but do so by a variety of mechanisms. Our results reveal new insights into the dynamics and relevant selection pressures in experimental evolution, but also highlight how, in an eco-evolutionary context, numerous mechanisms can evolve to the same end.
LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation
Authors: Lucas Richard M. , Bauer Claudia S. , Chinnaiya Kavitha , Schwartzentruber Aurélie , MacDonald Ruby , Collins Mark O. , Aasly Jan O. , Brønstad Gunnar , Ferraiuolo Laura , Mortiboys Heather , Vos Kurt J. De
Published: February 2019

Mutations in LRRK2 are the most common cause of dominantly inherited Parkinson’s disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of α-synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein homeostasis, however how PD mutations in LRRK2 may lead to accumulation of ubiquitinated protein aggregates remains unclear.

A main cellular pathway to remove aggregated ubiquitinated proteins is aggrephagy: the histone deacetylase HDAC6 recognizes ubiquitinated misfolded proteins and recruits them to the molecular motor cytoplasmic dynein which transports them to the perinuclear region where they are trapped in aggresomes that are subsequently removed by macroautophagy.

Here we identified HDAC6 as a novel LRRK2 substrate and show that LRRK2 regulates HDAC6-dependent aggresome formation. LRRK2 directly interacted with the HDAC6 deacetylase domains via its Roc domain and phosphorylated HDAC6 on serine-22. Serine-22 phosphorylation of HDAC6 enhanced its interaction with cytoplasmic dynein and stimulated recruitment of ubiquitinated proteins to aggresomes. Knockdown or knockout of LRRK2 impaired HDAC6-mediated aggresome formation. PD mutant LRRK2 G2019S showed reduced interaction with HDAC6 and did not support aggresome formation to the same extend as wild type LRRK2. This was recapitulated in LRRK2 G2019S patient-derived iAstrocytes that showed an aggresome formation defect.

In conclusion our data reveal HDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.
Distinct subdivisions of human medial parietal cortex are recruited differentially for memory recall of places and people
Authors: Silson Edward H , Steel Adam , Kidder Alexis , Gilmore Adrian W , Baker Chris I
Published: February 2019

Human medial parietal cortex (MPC) is implicated in multiple cognitive processes including memory recall, visual scene processing and navigation. It is also considered a core component of the default mode network. Here, we combine fMRI data across three independent experiments to demonstrate distinct subdivisions of MPC that are selectively recruited during memory recall of either specific places or specific people. First, distinct regions of MPC were identified on the basis of differential functional connectivity with medial and lateral regions of anterior ventral temporal cortex (VTC). Second, these same medial regions exhibited differential responses to the visual presentation of different stimulus categories, with clear preferences for scenes and faces, respectively. Third, and most critically, these regions were selectively recruited during either place or people memory recall. These subdivisions also showed a striking relationship with ventral and dorsal divisions of the default mode network. Taken together, these data reveal distinct subdivisions within MPC for the recall of places and people and moreover, suggest that the organizing principle defining the medial-lateral axis of VTC is reflected in MPC, but in the context of memory recall.
Faizal & Shabana Foundation: a venture philanthropic approach to education
Authors: Sahasranamam Sreevas , Mitra Sumit
Published: February 2019

Learning outcomes

Learning outcomes are as follows: understand venture philanthropy in India; discuss in what ways venture philanthropy is different from charity; identify the aims of venture philanthropy and the strategy adopted to achieve those objectives; analyze the role of the unique structuring of a venture philanthropy working in tandem with the government to achieve its objectives; identify the nature and source of dilemmas of disengagement from a project by the venture philanthropist; and understand the role of antecedents and outcomes on how a firm views its social impact initiative (in the Indian context).

Case overview/synopsis

The Faizal and Shabana Foundation (F&SF) made one of the largest philanthropic investments in Kerala, India for the redevelopment of Government Vocational Higher Secondary School for Girls, Nadakkavu. The foundation applied a strategic approach to their philanthropic investment making it a unique case of venture philanthropy. The uniqueness of this case lies in the fact that, this is one among those rare cases where venture philanthropy has been successfully implemented within a government educational context. This case highlights how a private philanthropic organization went about executing a project and faced several challenges of scaling up the redevelopment model to other government schools. The other salient aspect is that this case delves into the dilemma faced by a philanthropist of either using the existing model for scaling up or adopting a totally different model.

Complexity academic level

Undergraduate and postgraduate business management courses.

Supplementary materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS: 11: Strategy.
Spatial analysis of the factors influencing housing quality for renters in a traditional Nigerian city
Authors: Olowu Falilat Yetunde , Jaiyeoba Emmanuel Babatunde , Agbabiaka Hafeez Idowu , Daramola Olawunmi Johnson
Published: February 2019

Purpose

Rental housing is an important form of accommodation; evaluating its quality will improve the quality of designs, standard living of renters, new dimension to policy guiding rental housing and enhance the values of rental houses. This study aims to examine the factors influencing rental housing quality in Ile-Ife, Nigeria.

Design/methodology/approach

Multi-stage sampling procedure was used to select tenants for the study. Residential areas were stratified into three densities: high, medium and low. Out of the 18 residential areas identified, six, eight and four were in the high, medium and low densities, respectively. Five residential areas were selected based on high concentrations of rental housing. The selected areas are Mokuro and Iloro (high density), Ife City and Eleyele (medium density) and Aladanla (low density). Systematic sampling technique was used to select 550 buildings where an adult tenant was selected per building for questionnaire administration.

Findings

The results of the principal component analysis established that four factors were generated for the high-density, nine factors for the medium-density and five factors for low-density areas as the major factors influencing rental housing quality. The variation in the number of factors generated and the percentage variance explained by the factors could be associated to the peculiarities across the densities in terms of the socioeconomic characteristics and housing characteristics of the renters.

Originality/value

This study examined the factors influencing housing quality for renters in Ile-Ife, Nigeria. It provides information on the three residential densities in terms of the variation in their housing morphology. The study went further to establish the relationship among the three musketeers such as socioeconomic characteristic of renters, housing characteristics and housing quality, under three dimensions environmental, internal building and external Building. Therefore, the contribution of this study strengthens the position that a minimum standard and schedule of upgrade and maintenance should be meted out for landlords to carry out repairs at interval, so as to make the housing unit and environment habitable for tenants.
Fineman and vulnerability
Authors: Cummins Ian
Published: February 2019

Purpose

The purpose of this paper is to argue that the work of the American feminist political and legal philosopher, Martha Fineman can be the basis for a shift away from the proceduralism and managerialism that has come to dominate social work practice.

Design/methodology/approach

This paper’s work is based on the application of Fineman’s work to social welfare settings.

Findings

Fineman’s work calls for a radical rethinking of our notions of autonomy and vulnerability.

Originality/value

This paper applies Fineman’s work to this field.