bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic starvation induces non-canonical pro-death stress granules
Authors: Reineke Lucas C. , Cheema Shebna A. , Dubrulle Julien , Neilson Joel R.
Published: May 2018

Stress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including eIF2α phosphorylation, inhibition of the RNA helicase eIF4a, or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA binding proteins, and poly(A)+ mRNAs, and as such represent an important compartment for storage of mRNAs and regulation of their translation. Emerging work on SGs indicates they may play important roles in cancer, neurodegenerative disease, and viral infection, often promoting survival. Yet much previous work on SGs formation and function has employed acute stress conditions, which may not accurately reflect the chronic stresses that manifest in human disease. We used prolonged nutrient starvation to investigate SG formation and function during chronic stress. Surprisingly, SGs that form under chronic nutrient starvation lack 40S ribosomes, do not actively exchange their constituent components with cytoplasmic pools, and promote cell death. These results imply that SG assembly and function in the context of prolonged nutrient starvation stress differ significantly from what has been described for acute stress conditions.

Summary Statement

This work characterizes the mechanisms of formation of a novel type of stress granule that is induced in response to long-term starvation, and unlike previously described stress granules, functions in a pro-death capacity.
Unexpected versatility in the metabolism and ecophysiology of globally relevant nitrite-oxidizingNitrotogabacteria
Authors: Boddicker Andrew M. , Mosier Annika C.
Published: May 2018

Nitrite-oxidizing bacteria (NOB) play a critical role in the mitigation of nitrogen pollution from freshwater systems by metabolizing nitrite to nitrate, which is removed via assimilation, denitrification, or anammox. Recent studies revealed that NOB are phylogenetically and metabolically diverse, yet most of our knowledge of NOB comes from only a few cultured representatives. Using enrichment methods and genomic sequencing, we identified four novelCandidatusNitrotoga NOB species from freshwater sediments and water column samples in Colorado, USA. Genome assembly revealed highly conserved 16S rRNA gene sequences, but a surprisingly broad metabolic potential including genes for nitrogen, sulfur, hydrogen, and organic carbon metabolism. Genomic predictions suggest thatNitrotogacan metabolize in low oxygen or anaerobic conditions, which may support a previously unrecognized environmental niche. An array of antibiotic and metal resistance genes likely allowsNitrotogato withstand environmental pressures in impacted systems. Phylogenetic analyses reveal a deeply divergent nitrite oxidoreductase alpha subunit (NxrA) not represented in any other NOB, suggesting a novel evolutionary trajectory forNitrotoga.Nitrotoga-like 16S rRNA gene sequences were prevalent in globally distributed environments. This work considerably expands our knowledge of theNitrotogagenus and improves our understanding of their role in the global nitrogen cycle.
Easily phylotyping E. coli via the EzClermont web app and command-line tool
Authors: Waters Nicholas R. , Abram Florence , Brennan Fiona , Holmes Ashleigh , Pritchard Leighton
Published: May 2018

The Clermont PCR method of phylotyping Escherichia coli has remained a useful classification scheme despite the proliferation of higher-resolution sequence typing schemes. We have implemented an in silico Clermont PCR method as both a web app and as a command-line tool to allow researchers to easily apply this phylotyping scheme to genome assemblies easily.

Availability and Implementation

EzClermont is available as a web app at http://www.ezclermont.org. For local use, EzClermont can be installed with pip or installed from the source code at https://github.com/nickp60/ezclermont. All analysis was done with version 0.4.0.

Contact

n.waters4@nuigalway.ie, leighton.pritchard@strath.ac.uk

Supplementary information

Table S1: test dataset; S2: validation dataset; S3: results.
A legacy role for DNA binding of Lon protects against genotoxic stress
Authors: Zeinert Rilee D. , Ogdahl Justyne L. , Liu Jing , Yang Qiyuan , Du Yunguang , Barros Benjamin B. , Freddolino Peter L. , Haynes Cole M. , Chien Peter
Published: May 2018

DNA binding proteins are essential for cellular life, but persistently bound complexes have toxic consequences. Here we show that the proteotoxic responsive bacterial protease Lon clears proteins from DNA to promote genotoxic stress resistance. Purified Lon binds DNA and degrades neighboring bound proteins, while a fully active DNA-blind Lon variant does not. This variant can degrade substrates as normal during unstressed growth, complements pleotropic phenotypes of Δlon, including proteotoxic resilience, but remains sensitive to genotoxic stresses and fails to degrade proteins efficiently during DNA damage. Transposon sequencing reveals that Δlonis vulnerable to loss of protein-DNA eviction factors and we use dynamic nucleoid occupancy profiling to show that chromosome-wide protein turnover relies on Lon DNA binding. Finally, disrupting Lon binding to mitochondria genomes also results in genotoxic stress sensitivity, consistent with the bacterial ancestry of this organelle. We propose that clearance of persistent proteins from DNA by Lon originated in free-living α-proteobacteria and maintained during the evolution of mitochondria.

DNA binding by the Lon protease protects against genotoxic damage in a manner preserved from bacteria to mitochondria.
How Much Information is Provided by Human Epigenomic Data? An Evolutionary View
Authors: Gulko Brad , Siepel Adam
Published: May 2018

Here, we ask the question, “How much information do available epigenomic data sets provide about human genomic function, individually or in combination?” We consider nine epigenomic and annotation features across 115 cell types and measure genomic function by using signatures of natural selection as a proxy. We measure information as the reduction in entropy under a probabilistic evolutionary model that describes genetic variation across ∼50 diverse humans and several nonhuman primates. We find that several genomic features yield more information in combination than they do individually, with DNase-seq displaying particularly strong synergy. Most of the entropy in human genetic variation, by far, reflects mutation and neutral drift; the genome-wide reduction in entropy due to selection is equivalent to only a small fraction of the storage requirements of a single human genome. Based on this framework, we produce cell-type-specific maps of the probability that a mutation at each nucleotide will have fitness consequences (FitCons scores). These scores are predictive of known functional elements and disease-associated variants, they reveal relationships among cell types, and they suggest that ∼8% of nucleotide sites are constrained by natural selection.
N-terminal degradation activates the Nlrp1b inflammasome
Authors: Chui Ashley J. , Okondo Marian C. , Rao Sahana D. , Gai Kuo , Griswold Andrew R. , Vittimberga Brooke A. , Bachovchin Daniel A.
Published: May 2018

Intracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptotic cell death. The anthrax lethal factor metalloprotease and small molecule DPP8/9 inhibitors both activate the Nlrp1b inflammasome, but the molecular mechanism of Nlrp1b activation is not known. Here, we used genome-wide CRISPR/Cas9 knockout screens to identify genes required for Nlrp1b-mediated pyroptosis, and discovered that lethal factor induces cell deathviathe N-end rule proteasomal degradation pathway. Lethal factor directly cleaves Nlrp1b, which induces the N-end rule-mediated degradation of the Nlrp1b N-terminus and thereby frees the Nlrp1b C-terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the Nlrp1b N-terminus, but, in contrast, not through the N-end rule pathway. Overall, these data reveal that N-terminal degradation is the common mechanism for activation of this innate immune sensor protein.

One Sentence Summary

Proteasome-mediated degradation of the Nlrp1b N-terminus releases the Nlrp1b C-terminus to activate caspase-1 and induce pyroptotic cell death.
Psychosocial stress and central adiposity: A Brazilian study with users of the public health system
Authors: Freitas Flávia Vitorino , Barbosa Wagner Miranda , Silva Laíz Aparecida Azevedo , Garozi Marianna Junger de Oliveira , Pinheiro Júlia de Assis , Ribeiro Borçoi Aline , Conti Catarine Lima , Arpini Juliana Krüger , de Paula Heberth , de Oliveira Mayara Mota , Archanjo Anderson Barros , de Freitas Érika Aparecida Silva , de Oliveira Daniela Rodrigues , Borloti Elizeu Batista , Louro Iuri Drumond , Alvares-da-Silva Adriana Madeira
Published: May 2018

Objective

To assess the association between indicators of psychosocial stress and central adiposity in adult users of the Unified Health System (SUS) from Southeast of Brazil.

Methods

This cross-sectional study was conducted with 384 adults (20 to 59 years old) from the city of Alegre, Southeastern Brazil. The simple random sample represented the population using the public health system of the municipality. The prevalence of obesity was based on the Body Mass Index, and central adiposity (dependent variable) was measured by waist circumference in centimeters. The independent variables were the following indicators of psychosocial stress: food and nutrition insecurity (yes/no), serum cortisol (μg/dL), symptoms suggestive of depression using the Beck Depression Inventory-II ≥ 17 (yes/no), and altered blood pressure ≥ 130/85 mmHg (yes/no). Univariate linear regression was performed between central adiposity and each stress indicator, and later the models were adjusted for socioeconomic, health, and lifestyle variables. All analyses were stratified by rural and urban location.

Results

The prevalence of weight excess was 68.3%, and 71.5% of individuals presented an increased risk for metabolic complications related to central adiposity. Mean waist circumference scores for the rural and urban population were 89.3 ± 12.7 cm and 92.9 ± 14.7 cm, respectively (p = 0.012). Indicators of stress that were associated with central adiposity were: cortisol in the rural population and altered blood pressure in the urban population. This occurred both in the raw analysis and in the models adjusted for confounding factors.

Conclusion

The associations between stress and adiposity were different between rural (cortisol - inverse association) and urban (altered blood pressure) lifestyles, confirming the influence of local and psychosocial subsistence on the modulation of stress and on how individuals react or restrain stressors. Stress reduction strategies can be useful in public health programs designed to prevent or treat obesity.
Binding specificities of human RNA binding proteins towards structured and linear RNA sequences
Authors: Jolma Arttu , Zhang Jilin , Mondragón Estefania , Morgunova Ekaterina , Kivioja Teemu , Laverty Kaitlin U. , Yin Yimeng , Zhu Fangjie , Bourenkov Gleb , Morris Quaid , Hughes Timothy R. , Maher Louis James , Taipale Jussi
Published: May 2018

Sequence specific RNA-binding proteins (RBPs) control many important processes affecting gene expression. They regulate RNA metabolism at multiple levels, by affecting splicing of nascent transcripts, RNA folding, base modification, transport, localization, translation and stability. Despite their central role in most aspects of RNA metabolism and function, most RBP binding specificities remain unknown or incompletely defined. To address this, we have assembled a genome-scale collection of RBPs and their RNA binding domains (RBDs), and assessed their specificities using high throughput RNA-SELEX (HTR-SELEX). Approximately 70% of RBPs for which we obtained a motif bound to short linear sequences, whereas ~30% preferred structured motifs folding into stem-loops. We also found that many RBPs can bind to multiple distinctly different motifs. Analysis of the matches of the motifs in human genomic sequences suggested novel roles for many RBPs. We found that three cytoplasmic proteins, ZC3H12A, ZC3H12B and ZC3H12C bound to motifs resembling the splice donor sequence, suggesting that these proteins are involved in degradation of cytoplasmic viral and/or unspliced transcripts. Surprisingly, structural analysis revealed that the RNA motif was not bound by the conventional C3H1 RNA-binding domain of ZC3H12B. Instead, the RNA motif was bound by the ZC3H12B’s PilT N-terminus (PIN) RNase domain, revealing a potential mechanism by which unconventional RNA binding domains containing active sites or molecule-binding pockets could interact with short, structured RNA molecules. Our collection containing 145 high resolution binding specificity models for 86 RBPs is the largest systematic resource for the analysis of human RBPs, and will greatly facilitate future analysis of the various biological roles of this important class of proteins.
Changing Times: Fluorescence-lifetime Analysis of Amyloidogenic SF-IAPP Fusion Protein
Authors: Antimonova Olga I , Lebedev Dmitry V , Zabrodskaya Yana A , Grudinina Natalia A , Shavlovsky Michael M , Egorov Vladimir V
Published: May 2018

The fluorescence lifetime of the superfolder green fluorescent protein (SF) and the SF protein fused with islet amyloid polypeptide (SF-IAPP) were studied in polyacrylamide gel. It was shown that the SF average fluorescence lifetime under these conditions slightly differs from that of the SF-IAPP monomer. SF-IAPP does not lose the ability to form amyloid-like fibrils; meanwhile, the average fluorescence lifetime of the fusion protein in fibrils is reduced. We propose the application of Fluorescent-lifetime Imaging Microscopy (FLIM) to the measurement of average fluorescence lifetimes of fusion proteins (amyloidogenic protein–SF) in the context of studies using cellular models of conformational diseases.
Combined use of procalcitonin and C-reactive protein levels can help clinically diagnose bacterial co-infections in children infected with H1N1 influenza
Authors: Li Zhihao , He Liya , Li Shuhua , He Waner , Zha Caihui , Hou Qiaozhen , Wang Weiying , Sun Xin , Liang Huiying , Ou Wanxing
Published: May 2018

Objective

This study evaluated the diagnostic value of measuring the levels of procalcitonin (PCT) and C-reactive protein (CRP) to differentiate children co-infected with H1N1 influenza and bacteria from children infected with H1N1 influenza alone and to provide a reliable clinical diagnostic support system with improved accuracy and precision control.

Methods

Consecutive patients (children aged <5 years) with laboratory-confirmed H1N1 influenza who were hospitalized or received outpatient care from a tertiary-care hospital in Canton, China between 1 January 2012 and 1 September 2017 were included in the present study. Laboratory results, including serum PCT and CRP levels, white blood cell (WBC) counts, and blood and sputum cultures, were analyzed. The predictive value of the combination of biomarkers versus either biomarker alone for diagnosing bacterial co-infections was evaluated using logistic regression analyses.

Results

Of 3180 children infected with H1N1 influenza, 226 (7.1%) met the bacterial co-infection criteria, with Staphylococcus pneumoniae being the most commonly identified bacteria (36.28%). Significantly higher PCT (1.46 vs 0.21 ng/ml, p<0.001) and CRP (19.20 vs 5.10 mg/dl, p<0.001) levels were detected in the bacterial co-infection group than in the H1N1 infection only group. Multivariate logistic regression analysis showed independent associations between PCT (odds ratio [OR]: 1.73, 95% confidence interval [CI],1.34-2.42, p<0.001) and CRP levels (OR:1.09, 95% CI, 1.06-1.13, p<0.001) with bacterial co-infections. Using PCT or CRP levels alone, the areas under the curves (AUCs) for predicting bacterial co-infections were 0.801 (95%CI, 0.772-0.855) and 0.762 (95%CI, 0.722-0.803), respectively. Using a combination of PCT and CRP, the logistic regression-based model, Logit(P)=-1.912+0.546 PCT+0.087 CRP, showed significantly greater accuracy (AUC: 0.893, 95%CI: 0.842-0.934) than did the other three biomarkers.

Conclusions

The combination of PCT and CRP levels could provide a useful method of distinguishing bacterial co-infections from an H1N1 influenza infection alone in children during the early disease phase. After further validation, the flexible model derived here could assist clinicians in decision-making processes.
Stabilized Independent Component Analysis outperforms other methods in finding reproducible signals in tumoral transcriptomes
Authors: Cantini Laura , Kairov Ulykbek , de Reyniès Aurélien , Barillot Emmanuel , Radvanyi François , Zinovyev Andrei
Published: May 2018

Motivation

Matrix factorization methods are widely exploited in order to reduce dimensionality of transcriptomic datasets to the action of few hidden factors (metagenes). Applying such methods to similar independent datasets should yield reproducible inter-series outputs, though it was never demonstrated yet.

Results

We systematically test state-of-art methods of matrix factorization on several transcriptomic datasets of the same cancer type. Inspired by concepts of evolutionary bioinformatics, we design a new framework based on Reciprocally Best Hit (RBH) graphs in order to benchmark the method’s reproducibility. We show that a particular protocol of application of Independent Component Analysis (ICA), accompanied by a stabilisation procedure, leads to a significant increase in the inter-series output reproducibility. Moreover, we show that the signals detected through this method are systematically more interpretable than those of other state-of-art methods. We developed a user-friendly tool BIODICA for performing the Stabilized ICA-based RBH meta-analysis. We apply this methodology to the study of colorectal cancer (CRC) for which 14 independent publicly available transcriptomic datasets can be collected. The resulting RBH graph maps the landscape of interconnected factors that can be associated to biological processes or to technological artefacts. These factors can be used as clinical biomarkers or robust and tumor-type specific transcriptomic signatures of tumoral cells or tumoral microenvironment. Their intensities in different samples shed light on the mechanistic basis of CRC molecular subtyping.

Availability

The BIODICA tool is available from https://github.com/LabBandSB/BIODICA.

Contact

laura.cantini@curie.fr and andrei.zinovyev@curie.fr

Supplementary information

Supplementary data are available at Bioinformatics online.
Variants ofDNMT3Acause transcript-specific DNA methylation patterns and affect hematopoietic differentiation
Authors: Božić Tanja , Frobel Joana , Raic Annamarija , Ticconi Fabio , Kuo Chao-Chung , Heilmann-Heimbach Stefanie , Goecke Tamme W. , Zenke Martin , Jost Edgar , Costa Ivan G. , Wagner Wolfgang
Published: May 2018

Thede novoDNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing ofDNMT3Ahas characteristic epigenetic and functional sequels. SpecificDNMT3Atranscripts were either downregulated or overexpressed in human hematopoietic stem and progenitor cells and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that particularly transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia (AML) expression of transcript 2 correlates with itsin vitroDNA methylation and gene expression signatures and is associated with overall survival, indicating thatDNMT3Avariants impact also on malignancies. Our results demonstrate that specificDNMT3Avariants have distinct epigenetic and functional impact. Particularly DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in AML.
S phase R-loop formation is restricted by PrimPol-mediated repriming
Authors: Šviković Saša , Crisp Alastair , Tan-Wong Sue Mei , Guilliam Thomas A. , Doherty Aidan J. , Proudfoot Nicholas J. , Guilbaud Guillaume , Sale Julian E.
Published: May 2018

During DNA replication, conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here we showin vivohow R-loop formation drives a short purine-rich repeat, (GAA)10, to become a replication impediment that requires the repriming activity of the primase-polymerase PrimPol for its processive replication. Further, we show that loss of PrimPol results in a significant increase in R-loop formation around the repeat during S phase. We extend this observation by showing that PrimPol suppresses R-loop formation in genes harbouring secondary structure-forming sequences, exemplified by G quadruplex and H-DNA motifs, across the genome in both avian and human cells. Thus, R-loops promote the creation of replication blocks at susceptible sequences, while PrimPol-dependent repriming limits the extent of unscheduled R-loop formation at these sequences, mitigating their impact on replication.
Type IV collagen is essential for proper function of integrin-mediated adhesion in Drosophila muscle fibers
Authors: Kiss András A. , Popovics Nikoletta , Márton Kiss , Boldogkői Zsolt , Csiszár Katalin , Mink Mátyás
Published: May 2018

Congenital muscular dystrophy (CMD), a subgroup of myopathies and a genetically and clinically heterogeneous group of inherited muscle disorders is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen (COL4A1) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker–Warburg Syndrome or Muscle–Eye–Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, and aberrant integrin expression within the M-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in Drosophila by RNA-inhibition. Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres.
An EST-SSR based genetic linkage map and identification of QTLs for anthracnose disease resistance in water yam (Dioscorea alata L.)
Authors: Bhattacharjee Ranjana , Nwadili Christian O , Saski Christopher A , Paterne Agre , Scheffler Brian E. , Augusto Joao , Lopez-Montes Antonio , Onyeka T. J. , Kumar P. Lava , Bandyopadhyay Ranajit
Published: May 2018

Water yam (Dioscorea alata L.) is one of the most important food yams with wide geographical distribution in tropics. One of the major constraints to water yam production is anthracnose disease caused by a fungus, Colletotrichum gloesporioides (Penz.). There are no economically feasible solutions as chemical sprays or cultural practices, such as crop rotation are seldom convenient for smallholder farmers for sustainable control of the disease. Breeding for development of durable genetic resistant varieties is known to offer lasting solution to control endemic disease threats to crop production. However, breeding for resistance to anthracnose has been slow considering the biological constraints related to the heterozygous and vegetative propagation of the crop. The development of saturated linkage maps with high marker density, such as SSRs, followed by identification of QTLs can accelerate the speed and precision of resistance breeding in water yam. A total of 380 EST-SSRs were used to generate a saturated linkage map. About 60.19% of SSRs showed Mendelian segregation pattern, however, it had no effect on the construction of linkage map. All 380 EST-SSRs were mapped into 20 linkage groups covering a total length of 2559.66 cM, which agrees with the diploid nature (2n = 2x = 20) of the parents used in the cross. Majority of the markers were mapped on linkage group 1 comprising of 97 EST-SSRs. This is the first genetic linkage map of water yam constructed using EST-SSRs. QTL localization was based on phenotypic data collected over a 3-year period of inoculating the mapping population with the most virulent strain of C. gloeosporoides from West Africa. Using the mean permutation value of LOD scores as threshold value for declaring a putative QTL on all linkage groups, one QTL was consistently observed on linkage group (LG) 14 in all the three years and average score data. This QTL was found at position interval of 71.12 – 84.76 cM explaining 68.94% of the total phenotypic variation in the average score data. The high marker density allowed identification of QTLs and association for anthracnose disease, which could be validated in other mapping populations and used in marker-assisted breeding in D. alata improvement programmes.
Evolution of shell flattening and the loss of coiling in top shells (Gastropoda: Trochidae: Fossarininae) on wave-swept rock reefs
Authors: Yamamori Luna , Kato Makoto
Published: May 2018

Flattening of coiled shells has occurred in numerous gastropod lineages, probably as an adaptation to life in narrow protected spaces, such as crevices or the undersides of rocks. While several genera in the top snail family (Trochidae) have flattened shells, two Fossarininae genera,BroderipiaandRoya, are unique in having shells that are limpet-like and zygomorphic, lacking any trace of coiling. The sister genera of these two genera areFossarinaandSynaptocochlea, both of which have coiled shells and live in rock crevices or the vacant shells of sessile organisms. AlthoughBroderipiahas recently been identified as living symbiotically in the pits of sea urchins, the habitat and biology ofRoyaare poorly known. After an extensive search for rareRoyasnails on rocky shores of the Japanese Archipelago, we found liveRoya eximiasnails on intertidal/subtidal rock surfaces exposed to strong waves. TheRoyasnails crawled swiftly over wave-swept rock surfaces at low tide, while they retreated into the vacant shells of barnacles at high tide, where they adhered firmly to the inner wall. A survey of the macrobenthic communities around the snail habitat showed thatRoyasnails inhabited only wave-swept rocks of exposed reefs, where the substrata was covered by encrusting red algae and barnacles. Despite the abnormal shell morphology, the radula was similar to other species in the subfamily, and the diet ofRoyasnails was mainly pennate diatoms. The limpet-like shell ofRoyacaused loss of coiling and contraction of the soft body, acquisition of a zygomorphic flat body, expansion of the foot sole and loss of the operculum. All of these changes improved tolerance of strong waves and the ability to cling to rock surfaces, and thus enabled a lifestyle split between wave-swept rock surfaces and refugia of vacant barnacle shells.
Selective sweeps under dominance and inbreeding
Authors: Hartfield Matthew , Bataillon Thomas
Published: May 2018

A major research goal in evolutionary genetics is to uncover loci experiencing positive selection. One approach involves finding ‘selective sweeps’ patterns, which can either be ‘hard sweeps’ formed byde novomutation, or ‘soft sweeps’ arising from recurrent mutation or existing standing variation. Existing theory generally assumes outcrossing populations, and it is unclear how dominance affects soft sweeps. We consider how arbitrary dominance and inbreeding via self-fertilisation affect hard and soft sweep signatures. With increased self-fertilisation, they are maintained over longer map distances due to reduced effective recombination and faster beneficial allele fixation times. Dominance can affect sweep patterns in outcrossers if the derived variant originates from either a single novel allele, or from recurrent mutation. These models highlight the challenges in distinguishing hard and soft sweeps, and propose methods to differentiate between scenarios.
Establishment and equilibrium levels of deleterious mutations in large populations
Authors: Viljoen Johan W. , de Villiers J. Pieter , Van Zyl Augustus J. , Mezzavilla Massimo , Pepper Michael S.
Published: May 2018

Analytical and statistical stochastic approaches are used to model and predict the dispersion of mutations through a large population. These approaches are used to quantify the magnitude of a heterozygous selective advantage of a mutation in the presence of a homozygous disadvantage. Random effects such as genetic drift are accounted for, which are likely to extinguish even highly advantageous mutations while the prevalence is still low. Dunbar’s results regarding the cognitive upper limit of the number of stable social relationships that humans can maintain are used to determine a realistic community size - a reduced local subset of the total population - from which an individual can select mates. This reduction in effective population size has a dramatic effect on the probability of establishing mutations, as well as the eventual equilibrium values that are reached in the case of mutations conferring a heterozygous selective advantage, but a homozygous disadvantage, as in the case of cystic fibrosis and sickle cell disease. The magnitude of this selective advantage can then be estimated based on observed occurrence levels of a specific mutation in a population, without requiring prior information regarding its phenotypic manifestation.

Author summary

Deleterious mutations such as cystic fibrosis and sickle cell anemia can disperse through human populations due to the selective advantage that it bestows on heterozygous carriers, depending on environmental conditions. As its prevalence increases, the probability of generating homozygous offspring, with its concomitant selective disadvantage, also grows until an eventual equilibrium is reached between the number of carriers and wild-type individuals. In this work computer modelling is used to combine Dunbar’s anthropological observations predicting upper bounds to the number of stable human social relationships with observed prevalence levels, to estimate the absolute magnitude of the heterozygous selective advantage bestowed by such a deleterious genetic variation, without requiring knowledge regarding the specific mechanism whereby such an advantage is manifested.
Salmonella-vectored vaccine delivering three Clostridium perfringens antigens protects poultry against necrotic enteritis.
Authors: Wilde Shyra , Jiang Yanlong , Tafoya Amanda M. , Horsman Jamie , Yousif Miranda , Vazquez Luis Armando , Roland Kenneth L.
Published: May 2018

Necrotic enteritis is an economically important poultry disease caused by the bacterium Clostridium perfringens. There are currently no necrotic enteritis vaccines available for use in broiler birds, the most important target population. Salmonella-vectored vaccines represent a convenient and effective option for controlling this disease. We used a single attenuated Salmonella vaccine strain, engineered to lyse within the host, to deliver up to three C. perfringens antigens. Two of the antigens were toxoids, based on C. perfringens ?-toxin and NetB toxin. The third antigen was fructose-1,6-bisphosphate aldolase (Fba), an metabolic enzyme with an unknown role in virulence. Oral immunization with a single Salmonella vaccine strain producing either Fba, ?-toxoid and NetB toxoid, or all three antigens, was immunogenic, inducing serum, cellular and mucosal responses against Salmonella and the vectored C. perfringens antigens. All three vaccine strains were protective against virulent C. perfringens challenge. The strains delivering Fba only or all three antigens provided the best protection. We also demonstrate that both toxins and Fba are present on the C. perfringens cell surface. The presence of Fba on the cell surface suggests that Fba may function as an adhesin.
Kinase activity simultaneously determines the constitutive and the orthosteric gating in α4β1/3δ GABAA receptors in hippocampal granule cells
Authors: Dalby Nils Ole , Leurs Ulrike , Falk-Petersen Christina Birkedahl , Scholze Petra , Krall Jacob , Frølund Bente , Wellendorph Petrine
Published: May 2018

A subset of the GABAA receptors expressed in recombinant systems and neurons is known to exhibit both constitutive- and agonist-induced gating. Two such receptors are the δ-subunit containing GABAA receptors α4β1δ and α4β3δ, which are expressed in adult rodent hippocampal dentate gyrus granule cells (DGGCs). Here we show that the GABAA receptor mediated tonic current recorded in the presence of tetrodotoxin in adult rodent DGGCs is almost exclusively mediated by constitutively active δ-subunit containing GABAA receptors and that the constitutive current is absent in recordings at 24 °C or in recordings at 34 °C including an intracellular inhibitor of protein kinase C. These factors simultaneously govern the efficacy of an orthosteric agonist at α4β1/3δ receptors, Thio-THIP, in a reciprocal manner. In the absence of constitutive receptor activity, the efficacy of Thio-THIP was increased approximately four-fold relative to recording conditions that favors constitutive activity. Further, only under conditions of an absent constitutive current, the classified neutral antagonist gabazine (GBZ) alone, induced a tonic current in DGGCs (EC50 2.1 μM). This effect of GBZ was not seen in recording conditions of high constitutive activity, was inhibited by picrotoxin (PTX), potentiated by DS2, completely absent in δ-/- mice and reduced in β1-/- mice, but could not be replicated in human α4β1/3δ receptors expressed recombinantly in HEK cells. We hypothesize that specific intracellular components in neurons interact with receptors to determine constitutive gating and receptor responsiveness to orthosteric ligands.

Significance statement

The presented data highlight how recording conditions for whole cell patch clamp analysis of α4β1/3δ GABAA receptors can mask important pharmacological effects. Specifically, orthosteric agonists appear with reduced efficacy, and other ligands, here exemplified with the well-known antagonist GBZ, are misinterpreted as being inactive/neutral, although they could have effect in constitutively silent receptors. Unmasking of potential hidden effects are easily done using recording conditions of reduced kinase activity in a relevant neuronal context. It follows that in pathologies with changes in phosphorylation level of δ-subunit containing GABAA receptors, the efficacy of an agonist of these receptors, measured by whole-cell recordings in vitro, will not match the efficacy of the same agonist in an unperturbed neuron in vivo.
Analyzing Dwell Times with the Generalized Method of Moments
Authors: Piatt Sadie , Price Allen C.
Published: May 2018

The Generalized Method of Moments (GMM) is a statistical method for the analysis of samples from random processes. First developed for the analysis of econometric data, the method is here formulated to extract hidden kinetic parameters from measurements of single molecule dwell times. Our method is based on the analysis of cumulants of the measured dwell times. We develop a general form of an objective function whose minimization can return estimates of decay parameters for any number of intermediates directly from the data. We test the performance of our technique using both simulated and experimental data. We also compare the performance of our method to nonlinear least-squares minimization (NL-LSQM), a commonly-used technique for analysis of single molecule dwell times. Our findings indicate that the GMM performs comparably to NL-LSQM over most of the parameter range we explore. It offers some benefits compared with NL-LSQM in that it does not require binning, exhibits slightly lower bias and variance with small sample sizes (N<20), and is somewhat superior in identifying fast decay times with these same low count data sets. Our results show that the GMM can be a useful tool and complements standard approaches to analysis of single molecule dwell times.
Expression and purification of a functional heteromeric GABAAreceptor for structural studies
Authors: Claxton Derek P , Gouaux Eric
Published: May 2018

The multi-subunit GABA-gated chloride channels of the Cys-loop receptor family, known as GABAAreceptors, function as the primary gatekeepers of fast inhibitory neurotransmission in the central nervous system. In addition to their role in controlling synaptic tone, these receptors are the targets of a vast array of therapeutic compounds that potentiate channel gating. Importantly, functional activity and pharmacological efficacy of GABAAreceptors is coupled directly to the subunit composition. However, the absence of high resolution structural information precludes an explicit determination of the molecular mechanism of ligand binding to ion channel gating and modulation. Efforts to obtain this data are hindered largely by the lack of heterologous expression and purification protocols for high expressing receptor constructs. To address this issue, we describe a unique approach to identify bona fide functional GABAAreceptor subunit combinations by using theXenopusoocyte as an expression host in combination with fluorescence detection size exclusion chromatography. The results demonstrate that formation of a defined pentameric species is dependent on subunit composition. Furthermore, receptor subunits can tolerate large truncations in non-conserved M3/M4 cytoplasmic loop, although removal of N-linked glycosylation sites is negatively correlated with expression level. Additionally, we report methods to improve GABAAreceptor expression in mammalian cell culture that employ recombinant baculovirus transduction. From these methods we have identified a well-behaving minimal functional construct for the α1/β1 GABAAreceptor subtype that can be purified in milligram quantities while retaining high affinity agonist binding activity.
Developing competencies to lead innovation in Indian manufacturing: an education model
Authors: Datta Partha Priya
Published: May 2018

Purpose

This paper aims to explore the implementation of an innovation in an executive education programme in the context of the Indian manufacturing industry. This paper presents an understanding of a conceptual framework for delivering a unique manufacturing leadership programme, explaining the different linkages between government, industry and academia for changing the mindset of participants and growth of a nation by developing highly skilful employees to lead India’s manufacturing industry.

Design/methodology/approach

The paper reports a single case study of an innovative manufacturing leadership development programme. Primary data were obtained from focus group studies and interviews. Documentary evidence in the form of reports, student work, course curriculum and meeting minutes was studied. The individual participants in the programme are used as units of analysis to explore systems of innovation, at individual levels. The analysis was carried out by applying theoretical models to explain the design, delivery and development of the programme over the years.

Findings

The findings from this research are an exploration of factors for sustaining the value of a system of innovation with special focus on a subsystem of knowledge creation and competence building. Institutional change is found to be a key input to the innovation process in terms of a collaborative mindset between three different academic institutes well known in different areas of expertise. Building an innovative coordination mechanism and curriculum combining academics with practical learning helped in changing the mindset of the students and faculty of the programme. This is linked to the development of country through leadership development by mindset change in mentors and students. The findings show that the studied programme has grown in terms of creating demand (in the form of increased applicants), guaranteeing 100 per cent placement with an average 50 per cent increase in salary and accelerated career in terms of role in the organisation. This was possible through continuous improvement practices for making local changes to the programme from time to time and building a community of practice in collaboration with industry.

Originality/value

The value of this research lies in highlighting the importance of international cooperation in speeding up the process of transferring management and technological knowledge from academia to industry. The framework developed for implementing a system of learning for creating a national system of innovation in manufacturing can be generalised to develop more such programmes in emerging nations for addressing skill challenges to lead future innovative projects.
Academy–industry linking capabilities as a determinant of innovation
Authors: Garcia-Montijo Leslie , Perez-Soltero Alonso
Published: May 2018

Purpose

The purpose of this paper is to analyze the importance of the linkage between academia and industry from a business perspective. The analysis focuses on the impact generated from these collaboration programs to promote innovation. Data for the analysis was obtained through a measurement instrument, which allows evaluating multiple dimensions of capacity of absorption as determinants of the innovation.

Design/methodology/approach

The methodology consisted of the implementation of the measurement instrument for the managers in the companies who were involved in the collaborative projects. From the answers obtained, an analysis of strengths and weaknesses was performed, categorized by absorptive capacity dimensions, satisfaction with linkage relationship and innovative impact. In addition, a comparative exercise is presented with the purpose of learning the position of the Postgraduate Program in Industrial Engineering in México, and finally, an analysis of Spearman’s coefficient was performed to verify whether the linkage influenced innovation for this case study.

Findings

There is a positive correlation between linkage and innovation. An unexpected finding was the level of satisfaction of the companies that collaborated with the academy and the real situation of each dimension to determine the improvements in the policies and mechanisms of linkage.

Research limitations/implications

One of the main challenges of this paper was to identify and contact the managers of the projects. These projects have been performed and completed in several companies from 2011 to date. Over this time, some managers have changed their employment status and even their places of residence. Therefore, establishing contact and performing interviews with the managers directly linked to each project was a complex process.

Originality/value

This is the first paper that demonstrates and measures the relationship between linkage and innovation through an instrument of absorptive capacity, which determines the behavior of each dimension where strengths and weaknesses of collaboration relationships are detected and determines the punctual impact on innovation from the perspective of the businessmen involved.
Supply chain management scholar’s research impact: moderated mediation analysis
Authors: Zhang Yucheng , Wu Yenchun Jim , Goh Mark , Liu Xinhong
Published: May 2018

Purpose

The purpose of this paper is to draw on social capital theory to develop a model to explain the determinants of a supply chain management scholar’s academic research impact.

Design/methodology/approach

Drawing from a database of 450 supply chain management scholars in different countries collected from ResearchGate and the World Bank, the bootstrapping method was applied on the moderated mediation analysis.

Findings

Analysis of the mediating role of a scholar’s social capital suggests that social capital theory has a strong explanatory power on the relationship between a scholar’s research skill and academic impact. To account for the boundary effect at the country-level, the authors further examine if this mechanism differs by country in the supply chain management research context.

Research limitations/implications

The findings from this study are from a single research area, which limits the generalizability of the study. Although the data are collected from different sources, including ResearchGate and the World Bank, it is cross-sectional in nature. The variables in this model do not have strong causal relationships.

Practical implications

The results suggest that supply chain management scholars can reap the benefits of their social capital. Specifically, scholars can enhance their academic impact by increasing their social capital.

Originality/value

The results provide a reference for supply chain management scholars keen on enhancing their academic research impact. It also provides a reference to explain why country-level differences can influence these scholars.
Personal digital archiving for journalists: a “private” solution to a public problem
Authors: King Rachel
Published: May 2018

Purpose

The purpose of this paper is to encourage librarians to teach digital archiving practices to journalists as a way of giving journalists the skills they need to save their work for future use and to facilitate the preservation of journalism for posterity.

Design/methodology/approach

The author has reviewed the personal digital archiving literature and analyzed how it might be specifically tailored to the unique needs of journalists.

Findings

Daily journalism has traditionally been preserved by libraries in the form of newspapers and magazines housed in library periodicals departments. Now that nearly all journalism is published online and libraries generally only have access via temporary subscriptions, libraries are prevented from doing any kind of traditional preservation work (e.g. storing copies locally). In the future, this lack of local preservation may lead to a shortage of early twenty-first century primary source material for historians.

Research limitations/implications

The needs of journalists do vary greatly based on the nature and format of their work and its publication venue, making it difficult to offer a single set of standards or recommendations.

Originality/value

While personal digital archiving advocates have generally interpreted the word “personal” to be synonymous with “private,” this paper points to the need to expand the concept to include professional activities, particularly in light of the prevalence of telecommuting and freelance work arrangements, and the lack of support and training received by remote workers and independent contractors.