bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity
Authors: Nguyen An Phu Tran , Tsika Elpida , Kelly Kaela , Levine Nathan , Chen Xi , West Andrew B. , Boularand Sylviane , Barneoud Pascal , Moore Darren J.
Published: December 2019

Abstract

Mutations in theleucine-rich repeat kinase 2(LRRK2) gene cause late-onset, autosomal dominant familial Parkinson’s disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PD-linked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegenerationin vivovia a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model ofLRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.
Climbing fiber synapses rapidly inhibit neighboring Purkinje cells via ephaptic coupling
Authors: Han Kyung-Seok , Chen Christopher H. , Khan Mehak M. , Guo Chong , Regehr Wade G.
Published: December 2019

Climbing fibers (CFs) from the inferior olive (IO) provide strong excitatory inputs onto the dendrites of cerebellar Purkinje cells (PC), and trigger distinctive responses known as complex spikes (CSs). We find that in awake, behaving mice, a CS in one PC suppresses conventional simple spikes (SSs) in neighboring PCs for several milliseconds. This involves a novel form of ephaptic coupling, in which an excitatory synapse nonsynaptically inhibits neighboring cells by generating large negative extracellular signals near their dendrites. The distance dependence of CS-SS ephaptic signaling, combined with the known divergence of CF synapses made by IO neurons, allows a single IO neuron to influence the output of the cerebellum by synchronously suppressing the firing of potentially over one hundred PCs. Optogenetic studiesin vivoand dynamic clamp studies in slice indicate that such brief PC suppression can effectively promote firing in neurons in the deep cerebellar nuclei and motor thalamus.
Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer
Authors: English Krystal , Shepherd Andrew , Nzor Ndidi-Ese , Trinh Ronnie , Kavelaars Annemieke , Heijnen Cobi J.
Published: December 2019

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunctionin vivoandin vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used anin vitrosystem in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in those neurons that had received mitochondria from astrocytes. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. The Rho-GTPase Miro-1 is known to contribute to mitochondrial motility and transfer. We show that siRNA-mediated knockdown of Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.

In conclusion, we identified transfer of mitochondria from astrocytes to neurons damaged by cisplatin as an important repair mechanism to protect cortical neurons against the toxic effects of this chemotherapeutic.

Significance statement

Chemotherapy-induced neurotoxicity is a serious health problem and little is known about the underlying mechanisms. Especially neurons are very sensitive to cisplatin treatment. We show that astrocytes can protect neurons damaged by cisplatin by improving neuronal survival, mitochondrial health, and calcium dynamicsin vitro. This beneficial effect of astrocytes is dependent on the transfer of mitochondria from astrocytes to the damaged neurons. Our findings provide evidence for an important endogenous protective neuro-glial mechanism that could contribute to prevention of neuronal death as a result of cisplatin treatment and thereby aid in sustaining brain health of patients during chemotherapy.
Honeybee colony performance affected by crop diversity and farmland structure: a modelling framework
Authors: Horn Juliane , Becher Matthias A. , Johst Karin , Kennedy Peter J. , Osborne Juliet L. , Radchuk Viktoriia , Grimm Volker
Published: December 2019

Forage availability has been suggested as one driver of the observed decline in honeybees. However, little is known about the effects of its spatiotemporal variation on colony success. We present a modelling framework for assessing honeybee colony viability in cropping systems. Based on two real farmland structures, we developed a landscape generator to design cropping systems varying in crop species identity, diversity, and relative abundance. The landscape scenarios generated were evaluated using the existing honeybee colony model BEEHAVE, which links foraging to in-hive dynamics. We thereby explored how different cropping systems determine spatiotemporal forage availability and, in turn, honeybee colony viability (e.g., time to extinction,TTE) and resilience (indicated by, e.g. brood mortality). To assess overall colony viability, we developed metrics,PHandPP,which quantified how much nectar and pollen provided by a cropping system per year was converted into a colony’s adult worker population. Both crop species identity and diversity determined the temporal continuity in nectar and pollen supply and thus colony viability. Overall farmland structure and relative crop abundance were less important, but details mattered. For monocultures and for four-crop species systems composed of cereals, oilseed rape, maize and sunflower,PHandPPwere below the viability threshold. Such cropping systems showed frequent, badly timed, and prolonged forage gaps leading to detrimental cascading effects on life stages and in-hive work force, which critically reduced colony resilience. Four-crop systems composed of rye-grass-dandelion pasture, trefoil-grass pasture, sunflower and phacelia ensured continuous nectar and pollen supply resulting inTTE> 5 years, andPH(269.5 kg) andPP(108 kg) being above viability thresholds for five years. Overall, trefoil-grass pasture, oilseed rape, buckwheat and phacelia improved the temporal continuity in forage supply and colony’s viability. Our results are hypothetical as they are obtained from simplified landscape settings, but they nevertheless match empirical observations, in particular the viability threshold. Our framework can be used to assess the effects of cropping systems on honeybee viability and to develop land-use strategies that help maintain pollination services by avoiding prolonged and badly timed forage gaps.
Dual Orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy
Authors: Hung Chi Jung , Ono Daisuke , Kilduff Thomas S. , Yamanaka Akihiro
Published: December 2019

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the tuberal hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons in mice decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated conditional transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. The total time in cataplexy and the mean cataplexy bout duration increased significantly in double-ablated mice compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy and that compromised MCH neurons may exacerbate symptoms in some narcoleptic patients. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range during wakefulness, a state with EEG characteristics indistinguishable from the transition from NREM into REM sleep. Together, these results indicate a functional interaction between orexin and MCH neuronsin vivothat suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.
Foster thy young: Enhanced prediction of orphan genes in assembled genomes
Authors: Li Jing , Singh Urminder , Bhandary Priyanka , Campbell Jacqueline , Arendsee Zebulun , Seetharam Arun S. , Wurtele Eve Syrkin
Published: December 2019

Proteins encoded by newly-emerged genes (“orphan genes”) share no sequence similarity with proteins in any other species. They provide organisms with a reservoir of genetic elements to quickly respond to changing selection pressures. Here, we systematically assess the ability of five gene annotation pipelines to accurately predict genes in genomes according to phylostratal origin. BRAKER and MAKER are existing, popularab initiotools that infer gene structures by machine learning. Direct Inference is an evidence-based pipeline we developed to predict gene structures from alignments of RNA-Seq data. The BIND pipeline integratesab initiopredictions of BRAKER and Direct inference; MIND combines Direct Inference and MAKER predictions. We use highly-curated Arabidopsis and yeast annotations as gold-standard benchmarks, and cross-validate in rice. Each pipeline under-predicts orphan genes (as few as 11 percent, under one prediction scenario). Increasing RNA-Seq diversity greatly improves prediction efficacy. The combined methods (BIND and MIND) yield best predictions overall, BIND identifying 68% of annotated orphan genes and 99% of ancient genes in Arabidopsis. We provide a light weight, flexible, reproducible solution to improve gene prediction.
Molecular basis of differential parasitism between non-encapsulated and encapsulatedTrichinellarevealed by a high-quality genome assembly
Authors: Liu Xiaolei , Feng Yayan , Bai Xue , Wang Xuelin , Qin Rui , Tang Bin , Yu Xinxin , Yang Yong , Liu Mingyuan , Gao Fei
Published: December 2019

Understanding roles of repetitive sequences in genomes of parasites could offer insights into their evolution, speciation, and parasitism. As a unique intracellular nematode,Trichinellaconsists of two clades, encapsulated and non-encapsulated. Genomic correlation to the distinct differences between the two clades is still unclear. Here we report an annotated draft reference genome of non-encapsulatedTrichinella,T. pseudospiralis, and performed comparative analyses with encapsulatedT. spiralis. Genome analysis revealed that, duringTrichinellaevolution, repetitive sequence insertions played an important role in gene family expansion in synergy with DNA methylation, especially for the DNase II members of the phospholipase D superfamily and Glutathione S-transferases. We further identify the genomic and epigenomic regulation of excretory/secretory products in relation to differences in parasitism, pathology and immunology between the two cladesTrichinella. The present study provided a foundation for further elucidation of mechanism of nurse cell formation and immunoevasion as well as identification of phamarcological and diagnostic targets of trichinellosis.
MACREL: antimicrobial peptide screening in genomes and metagenomes
Authors: Santos-Junior Célio Dias , Pan Shaojun , Zhao Xing-Ming , Coelho Luis Pedro
Published: December 2019

Motivation

Antimicrobial peptides (AMPs) have the potential to tackle multidrug-resistant pathogens in both clinical and non-clinical contexts. The recent growth in the availability of genomes and metagenomes provides an opportunity forin silicoprediction of novel AMP molecules. However, due to the small size of these peptides, standard gene prospection methods cannot be applied in this domain and alternative approaches are necessary. In particular, standard gene prediction methods have low precision for short peptides, and functional classification by homology results in low recall.

Results

Here, we present Macrel (for metagenomic AMP classification and retrieval), which is an end-to-end pipeline for the prospection of high-quality AMP candidates from (meta)genomes. For this, we introduce a novel set of 22 peptide features. These were used to build classifiers which perform similarly to the state-of-the-art in the prediction of both antimicrobial and hemolytic activity of peptides, but with enhanced precision (using standard benchmarks as well as a stricter testing regime). We demonstrate that Macrel recovers high-quality AMP candidates using realistic simulations and real data.

Availability

Macrel is implemented in Python 3. It is available as open source athttps://github.com/BigDataBiology/macreland through bioconda. Classification of peptides or prediction of AMPs in contigs can also be performed on the webserver:http://big-data-biology.org/software/macrel.
Different strategies to manageVarroa jacobsoniandTropilaelaps mercedesaein Papua New Guinea
Authors: Roberts John MK , Schouten Cooper N , Sengere Reuben W , Jave John , Lloyd David
Published: December 2019

Apiculture in the Pacific nation of Papua New Guinea (PNG) is under significant pressure from emerging parasitic mites,Varroa jacobsoniandTropilaelaps mercedesae. While numerous mite control products exist, beekeepers in Papua New Guinea have limited access and resources for these products and their effectiveness under local conditions is untested. Here we determined the effectiveness of two brood manipulation strategies – queen caging and queen removal – for managingV. jacobsoniandT. mercedesaein comparison to the chemical miticide Bayvarol®. Our results found Bayvarol®was the most effective control strategy forV. jacobsoni, maintaining high efficacy (>90%) over four months with significantly reduced mean numbers ofV. jacobsonicompared to untreated control hives. In contrast, mean numbers ofT. mercedesaewere significantly reduced by the brood manipulation strategies over two months, but not by Bayvarol®compared to the controls. These results highlight that a combination of different strategies is likely needed to effectively manage both mite pests in PNG. We discuss how these strategies could be optimised and adopted to achieve better mite management for PNG beekeepers.
UHRF1-SRA recognizes symmetric non-CG methylated DNA through dual-flip out of 5-methyl cytosines
Authors: Nakarakanti Naveen Kumar , Abhishek Suman , Deeksha Waghela , Rajakumara Eerappa
Published: December 2019

Non-CG DNA methylation (non-mCG) is enriched in the genome of brain neurons and germline cells. Non-mCG is differentially distributed on neuronal X-chromosome in males and females. Accumulation of non-mCG during postnatal brain development correlates with reduced gene expression and inactivation of distal regulatory elements, and allele specific gene regulation. Recently, UHRF1 has been found to contribute tode novonon-CG methylation, however, whether UHRF1 could recognize non-mCG is not known. Here, we have demonstrated through calorimetric measurements that the SRA domain of UHRF1 can recognize mCH and fully-mCHG, types of non-mCG. Furthermore, our ITC binding analyses with methylated CG DNA (mCG) revealed 6-fold decrease in binding affinity for fully-mCG compared to hemi-mCG and, despite symmetrical 5mCs, stoichiometry of 1:1 for UHRF1 SRA binding to fully-mCG indicates UHRF1 may not form stable complex with fully-mCG DNA. In contrast, UHRF1 SRA recognizes fully-mCHG with a stoichiometry of 2:1 protein to DNA duplex, and has tighter binding compared to fully-mCG. Crystal structure of UHRF1 SRA bound to 5mC containing DNA in fully-mCHG context revealed dual flip-out mechanism of 5mC recognition. Altogether, this study indicates that UHRF1 SRA also recognizes non-mCG DNA, besides known hemi-mCG DNA and exhibits contrasting mechanisms for hemi-mCG and fully-mCHG DNA recognition. These findings may open a new window to investigate the biological function of non-CG methylation recognition by the UHRF1.
A high quality reference genome for the fish pathogenStreptococcus iniae
Authors: Alsheikh-Hussain Areej S. , Ben Zakour Nouri L. , Forde Brian M. , Silayeva Oleksandra , Barnes Andrew C. , Beatson Scott A.
Published: December 2019

Fish mortality caused byStreptococcus iniaeis a major economic problem in fish aquaculture in warm and temperate regions globally. There is also risk of zoonotic infection byS. iniaethrough handling of contaminated fish. In this study, we present the complete genome sequence ofS. iniaestrain QMA0248, isolated from farmed barramundi in South Australia. The 2.12 Mb genome ofS. iniaeQMA0248 carries a 32 Kb prophage, a 12 Kb genomic island, and 92 discrete insertion sequence (IS) elements. These include 9 novel IS types that belong mostly to the IS3family. Comparative and phylogenetic analysis betweenS. iniaeQMA0248 and publicly available completeS. iniaegenomes revealed discrepancies that are likely due to misassembly in the genomes of isolates ISET0901 and ISNO. We also determined by long-range PCR that a tandem duplication of an rRNA region in the PacBio assembly of QMA0248 was an assembly error. A similar rRNA duplication in the PacBio genome ofS. iniae89353 may also be a misassembly. Our study not only highlights assembly problems in existing genomes, but provides a high quality reference genome forS. iniaeQMA0248, including manually curated mobile genetic elements, that will assist futureS. iniaecomparative genomic and evolutionary studies.
A novel virus alters gene expression and vacuolar morphology inMalasseziacells and induces a TLR3-mediated inflammatory immune response
Authors: Park Minji , Cho Yong-Joon , Kim Donggyu , Yang Chul-Su , Lee Shi Mun , Dawson Thomas L. , Nakamizo Satoshi , Kabashima Kenji , Lee Yang Won , Jung Won Hee
Published: December 2019

Most fungal viruses have been identified in plant pathogens, whereas the presence of viral particles in human pathogenic fungi is less well studied. In the present study, we observed extrachromosomal double-stranded RNA (dsRNA) segments in various clinical isolates ofMalasseziaspecies.Malasseziais the most dominant fungal genus on the human skin surface, and species in this group are considered etiological factors of various skin diseases including dandruff, seborrheic dermatitis, and atopic dermatitis. We identified novel dsRNA segments, and our sequencing results revealed that the virus, named MrV40, belongs to the Totiviridae family and contains an additional satellite dsRNA segment encoding a novel protein. The transcriptome of virus-infectedMalassezia restrictacells was compared to that of virus-cured cells, and the results showed that transcripts involved in ribosomal biosynthesis were downregulated and those involved in energy production and programmed cell death were upregulated. Moreover, transmission electron microscopy revealed significantly larger vacuoles in virus-infectedM. restrictacells, indicating that MrV40 infection dramatically alteredM. restrictaphysiology. Our analysis also revealed that viral nucleic acid from MrV40 induced a TLR3-mediated inflammatory immune response in bone marrow-derived dendritic cells, suggesting that a viral element contributes to the pathogenicity ofMalassezia.

Importance

Malasseziais the most dominant fungal genus on the human skin surface and is associated with various skin diseases including dandruff and seborrheic dermatitis. AmongMalasseziaspecies,Malassezia restrictais the most widely observed species on the human skin. In the current study, we identified a novel dsRNA virus, named MrV40, inM. restrictaand characterized the sequence and structure of the viral genome along with an independent satellite dsRNA viral segment. Moreover, expression of genes involved in ribosomal synthesis and programmed cell death was altered, indicating that virus infection affected the physiology of the fungal host cells. Our data also showed that the viral nucleic acid from MrV40 induces a TLR3-mediated inflammatory immune response in bone marrow-derived dendritic cells, indicating that a viral element likely contributes to the pathogenicity ofMalassezia. This is the first study to identify and characterize a novel mycovirus inMalassezia.
Using force data to self-pace an instrumented treadmill and measure self-selected walking speed
Authors: Song Seungmoon , Choi HoJung , Collins Steven H.
Published: December 2019

Background

Self-selected speed is an important functional index of walking. A self-pacing controller that reliably matches walking speed without additional hardware can be useful for measuring self-selected speed in a treadmill-based laboratory.

Methods

We adapted a previously proposed self-pacing controller for force-instrumented treadmills and validated its use for measuring self-selected speeds. We first evaluated the controller’s estimation of subject speed and position from the force-plates by comparing it to those from motion capture data. We then compared five tests of self-selected speed. Ten healthy adults completed a standard 10-meter walk test, a 150-meter walk test, a commonly used manual treadmill speed selection test, a two-minute self-paced treadmill test, and a 150-meter self-paced treadmill test. In each case, subjects were instructed to walk at or select their comfortable speed. We also assessed the time taken for a trial and a survey on comfort and ease of choosing a speed in all the tests.

Results

The self-pacing algorithm estimated subject speed and position accurately, with root mean square differences compared to motion capture of 0.023 m s−1and 0.014 m, respectively. Self-selected speeds from both self-paced treadmill tests correlated well with those from the 10-meter walk test (R> 0.93,p< 1 × 10−13). Subjects walked slower on average in the self-paced treadmill tests (1.23 ± 0.27 m s−1) than in the 10-meter walk test (1.32 ± 0.18 m s−1) but the speed differences within subjects were consistent. These correlations and walking speeds are comparable to those from the manual treadmill speed selection test (R= 0.89,p= 3 × 10−11; 1.18 ± 0.24 m s−1). Comfort and ease of speed selection were similar in the self-paced tests and the manual speed selection test, but the self-paced tests required only about a third of the time to complete. Our results demonstrate that these self-paced treadmill tests can be a strong alternative to the commonly used manual treadmill speed selection test.

Conclusions

The self-paced force-instrumented treadmill well adapts to subject walking speed and reliably measures self-selected walking speeds. We provide the self-pacing software to facilitate use by gait researchers and clinicians.
The Ty1 integrase nuclear localization signal is necessary and sufficient for retrotransposon targeting to tRNA genes
Authors: Asif-Laidin Amna , Conesa Christine , Bonnet Amandine , Grison Camille , Adhya Indranil , Menouni Rachid , Fayol Hélène , Palmic Noé , Acker Joël , Lesage Pascale
Published: December 2019

Integration of transposable elements into the genome is mutagenic. Mechanisms that target integration into relatively safe locations and minimize deleterious consequences for cell fitness have emerged during evolution. In budding yeast, the integration of the Ty1 LTR retrotransposon upstream of RNA polymerase III (Pol III)-transcribed genes requires the interaction between the AC40 subunit of Pol III and Ty1 integrase (IN1). Here we show that the IN1-AC40 interaction involves a short linker sequence in the bipartite nuclear localization signal (bNLS) of IN1. Mutations in this sequence do not impact the frequency of Ty1 retromobility, instead they decrease the recruitment of IN1 to Pol III-transcribed genes and the subsequent integration of Ty1 at these loci. The replacement of Ty5 retrotransposon targeting sequence by the IN1 bNLS induces Ty5 integration into Pol III-transcribed genes. Therefore, the IN1 bNLS is both necessary and sufficient to confer integration site specificity on Ty1 and Ty5 retrotransposons.
Imputed Genomic Data Reveals a Moderate Effect of Low Frequency Variants to the Heritability of Complex Human Traits
Authors: Hartman Kevin A , Rashkin Sara R , Witte John S , Hernandez Ryan D
Published: December 2019

The genetic architecture of complex human traits remains largely unknown. The distribution of heritability across the minor allele frequency (MAF) spectrum for a trait will be a function of the MAF of its causal variants and their effect sizes. Assumptions about these relationships underpin the tools used to estimate heritability. We examine the performance of two widely used tools, Haseman-Elston (HE) Regression and genomic-relatedness-based restricted maximum-likelihood (GREML). Our simulations show that HE is less biased than GREML under a wide variety of models and that the estimated standard error for HE tends to be substantially overestimated. We then applied HE Regression to infer the heritability of 72 quantitative biomedical traits from up to 50,000 individuals with genotype and imputation data from the UK Biobank. We found that adding each individuals’ geolocation as covariates corrected for population stratification that could not be accounted for by principal components alone (particularly for rare variants). The biomedical traits we analyzed had an average heritability of 0.27, with low frequency variants (MAF≤0.05) explaining an average of 47.7% of the total heritability (and lower frequency variants with MAF≤0.02 explaining a majority of our increased heritability over previous estimates). Variants in regions of low linkage disequilibrium (LD) accounted for 3.3-fold more heritability than the variants in regions of high LD, an effect primarily driven by low frequency variants. These findings suggest a moderate action of negative selection on the causal variants of these traits.
A MUC5B polymorphism associated with Idiopathic Pulmonary Fibrosis mediates overexpression through decreased CpG methylation and C/EBPβ transcriptional activation
Authors: Armesto-Jimenez Amaranta U. , Arason Ari J. , Stefansson Olafur A. , Gudmundsson Gunnar , Gudjonsson Thorarinn , Magnusson Magnus K.
Published: December 2019

Idiopathic pulmonary fibrosis is a progressive and fatal lung disease of unknown aetiology. The strongest genetic risk factor associated with IPF development is aMUC5Bpromoter polymorphism (rs35705950). However, the mechanism underlying its effects remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression. We have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. Our results demonstrate that the minor allele (T) associated withrs35705950disturbs a DNA methylation site, directly increasing MUC5B expression. Furthermore, this same variant also creates a novel binding site for the transcription factor C/EBPβ leading to transcriptional activation ofMUC5B. Our findings provide a novel insight into the regulatory effects of the IPF risk allele,rs35705950and identifies C/EBPβ as an important regulatory factor in the development of IPF.
Multi-genomic analysis of the Cation Diffusion Facilitator transporters from algae
Authors: Ibuot Aniefon , Dean Andrew P. , Pittman Jon K.
Published: December 2019

Metal transport processes are relatively poorly understood in algae in comparison to higher plants and other eukaryotes. A screen of genomes from 33 taxonomically diverse algal species was conducted to identify members of the Cation Diffusion Facilitator (CDF) family of metal ion transporter. All algal genomes contained at least one CDF gene with four species having >10 CDF genes (median of 5 genes per genome), further confirming that this is a ubiquitous gene family. Phylogenetic analysis suggested a CDF gene organisation of five groups, which includes Zn-CDF, Fe/Zn-CDF and Mn-CDF groups, consistent with previous phylogenetic analyses, and two functionally undefined groups. One of these undefined groups was algal specific although excluded chlorophyte and rhodophyte sequences. The majority of sequences (22 out of 26 sequences) from this group had a putative ion binding site motif within transmembrane domain 2 and 5 that was distinct from other CDF proteins, such that alanine or serine replaced the conserved histidine residue. The phylogenetic grouping was supported by sequence cluster analysis. Yeast heterologous expression of CDF proteins from Chlamydomonas reinhardtii indicated Zn2+ and Co2+ transport function by CrMTP1, and Mn2+ transport function by CrMTP2, CrMTP3 and CrMTP4, which validated the phylogenetic prediction. However, the Mn-CDF protein CrMTP3 was also able to provide zinc and cobalt tolerance to the Zn- and Co-sensitive zrc1cot1 yeast strain. There is wide diversity of CDF transporters within the algae lineage, and some of these genes may be attractive targets for future applications of metal content engineering in plants or microorganisms.
Ubiquitin Links Smoothened to Intraflagellar Transport to Regulate Hedgehog Signaling
Authors: Desai Paurav B. , Stuck Michael W. , Lv Bo , Pazour Gregory J.
Published: December 2019

In the absence of hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating these dynamic movements are not well understood but defects in intraflagellar transport components including Ift27 and the BBSome cause Smo to accumulate in cilia without pathway activation. We find that in the absence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this process is dependent on Ift27 and BBSome components. Activation of hedgehog signaling decreases Smo ubiquitination, and ciliary removal, resulting in its accumulation. Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine residues in intracellular loop three cause Smo to aberrantly accumulate in cilia without pathway activation. These data provide a mechanism to control Smo’s ciliary level during hedgehog signaling by regulating the ubiquitination state of the receptor.

Hedgehog signaling involves the dynamic movement of receptors and effectors in and out of cilia. We find that the dynamics of Smo is regulated by ubiquitination, which regulates its interaction with the intraflagellar transport system to control ciliary levels of this receptor.
Identification of Six novel missense single nucleotide polymorphisms in the MAOA gene predisposing to aggressive behavior. Bioinformatics study
Authors: Abdelmoenim Abdelrahman H. , Mustafa Mujahed I. , Murshed Naseem S. , Omer Nosiba S. , Mohammed Alaa I. , Abdulmajed Rania A. , Dawoud Enas dk. , Makhawi Abdelrafie M.
Published: December 2019

Background

An astonishing observation is that aggressive behavior is actually a highly heritable. Recent experimental work and behavior research has linked individual variation in a functional polymorphism of the monoamine oxidase-A gene (MAOA) to the occurrence of anger-driven aggression. Aggressive antisocial and violent behavior has become a regularly debated topic in the scientific community; the impending question is what is the source of aggressive behavior, is it genetic or environmental or is it just an individual choice. This study aims to analyses the SNPs found in MAOA gene and it is possible association to aggressive behavior.

Method

Various bioinformatics software (SIFT, PolyPhen-2, PROVEAN, SNAP22, SNP&GO and PMut)is used to analyses the SNPs within the MAOA gene to study the structural and functional implication on the associated protein, which is further clarified using chimera software. Then gene-gene interaction is studied with geneMANIA software. Furthermore, conservation and annotation studies were done through the ConSurf server and Variant Effect Predictor (VEP) respectively.

Result

Six missense SNPs were found to affect the structural and functional prospect of MAOA protein.

Conclusion

Genetic mutation within MAOA is likely to be associated with aggressive behavior; this will enrich future management and screening possibilities for this behavior.
Phenylephrine induces relaxation of longitudinal strips from small arteries of goat legs
Authors: Marconi Kawin Padmaja , Megan Bhavithra , Venis Alen Major , Raj Renu , Subramani Sathya
Published: December 2019

Alpha adrenergic stimulation is known to produce vasoconstriction. We have earlier shown that, in spiral strips of small arteries Phenylephrine (PE) caused vasorelaxation under high nitric oxide (NO) environment. However on further experimentation it was realized that the PE-induced vasorelaxant response occurred only with longitudinal strips of small arteries even under normal NO environment while circular strips showed contraction with PE even under high NO environment. Such PE-induced vasorelaxation of longitudinal strips was blocked by Phentolamine, an alpha-adrenergic receptor blocker. On delineation of specific receptor subtype, PE-induced relaxation was found to be mediated through alpha 1D receptor. However, this phenomenon is specific to small artery, as longitudinal smooth muscle of aorta showed only contractile response to adrenergic stimulation. There is no prior report of longitudinal smooth muscle in small artery up to our knowledge. The results of this study and histological examination of vessel sections suggest the presence of longitudinal smooth muscle in small artery and their relaxant response to alpha adrenergic stimulation is a novel phenomenon.
Machine learning goes wild: Using data from captive individuals to infer wildlife behaviour
Authors: Rast W. , Kimmig S. E. , Giese L. , Berger A.
Published: December 2019

Remotely tracking distinct behaviours of animals using acceleration data and machine learning has been carried out successfully in several species in captive settings. In order to study the ecology of animals in natural habitats, such behaviour classification models need to be transferred to wild individuals. However, at present the development of those models usually requires direct observation of the target animals.

The goal of this study was to infer behaviour of wild, free roaming animals from acceleration data by training behaviour classification models on captive individuals, without the necessity to observe their wild conspecifics. We further sought to develop methods to validate the credibility of the resulting behaviour extrapolations.

We trained two machine learning algorithms proposed by the literature, Random Forest (RF) and Support Vector Machine (SVM), on data from captive red foxes (Vulpes vulpes) and later applied them to data from wild foxes. We also tested a new advance for behaviour classification, by applying a moving window to an Artificial Neural Network (ANN). Finally, we investigated four strategies to validate our classification output.

While all three machine learning algorithms performed well under training conditions, the established methods, RF and SVM, failed in classifying distinct behaviours when transferred from captive to wild foxes. Behaviour classification with the ANN and a moving window, in contrast, inferred distinct behaviours and showed consistent results for most individuals.

Our approach is a substantial improvement over the methods previously proposed in the literature as it generated plausible results for wild fox behaviour. We were able to infer the behaviour of wild animals that have never been observed in the wild and to further illustrate the outputs credibility. This framework is not restricted to foxes but can be applied to infer the behaviour of many other species and thus empowers new advances in behavioural ecology.
Characterization of the soft X-ray spectrometer PEAXIS at BESSY II
Authors: Schulz Christian , Lieutenant Klaus , Xiao Jie , Hofmann Tommy , Wong Deniz , Habicht Klaus
Published: December 2019

The performance of the recently commissioned spectrometer PEAXIS for resonant inelastic soft X-ray scattering (RIXS) and X-ray photoelectron spectroscopy and its hosting beamline U41-PEAXIS at the BESSY II synchrotron are characterized. The beamline provides linearly polarized light from 180 eV to 1600 eV allowing for RIXS measurements in the range 200–1200 eV. The monochromator optics can be operated in different configurations to provide either high flux with up to 1012 photons s−1 within the focal spot at the sample or high energy resolution with a full width at half maximum of <40 meV at an incident photon energy of ∼400 eV. The measured total energy resolution of the RIXS spectrometer is in very good agreement with theoretically predicted values obtained by ray-tracing simulations. PEAXIS features a 5 m-long RIXS spectrometer arm that can be continuously rotated about the sample position by 106° within the horizontal photon scattering plane, thus enabling the study of momentum-transfer-dependent excitations. Selected scientific examples are presented to demonstrate the instrument capabilities, including measurements of excitations in single-crystalline NiO and in liquid acetone employing a fluid cell sample manipulator. Planned upgrades of the beamline and the RIXS spectrometer to further increase the energy resolution to ∼100 meV at 1000 eV incident photon energy are discussed.
Improving hospital patient flow: a systematic review
Authors: Gualandi Raffaella , Masella Cristina , Tartaglini Daniela
Published: December 2019

Purpose

Improving hospital patient flow has become a policy priority, to effectively balance the increasing demands of an unknown and variable volume of patients with limited available hospital resources. A systematic literature review was conducted in order to identify actions, actors involved and enablers in improving hospital patient flow. The paper aims to discuss this issue.

Design/methodology/approach

Searches were conducted in Scopus, Web of Science, MEDLINE and The Cochrane Library for quantitative and qualitative empirical primary studies with patients (adults) receiving inpatient acute hospital care. The study protocol was based on PRISMA-P guidance. A critical appraisal of included studies was performed by using the Quality Improvement Minimum Quality Criteria Set.

Findings

In total, 38 key papers were identified. A wide range of actions are reported, but most studies focus on one or a few departments instead of a whole hospital. Process efficiency is most often used as a performance indicator, clinical outcomes are poorly analyzed, and patients’ expectations and experience are rarely considered. Top-management commitment and front-line staff involvement are considered key factors for the success of implementations. Patient involvement in the process improvement is rarely mentioned.

Originality/value

Achieving improvements in hospital patient flow requires the design and implementation of complex, multifaceted and coordinated interventions. This study may be of value to healthcare managers, helping them to act effectively in their context, and to researchers of future studies including the different variables and the patient’s perspective.
PSO-tuned support vector machine metamodels for assessment of turbulent flows in pipe bends
Authors: Narayanan Ganesh , Joshi Milan , Dutta Prasun , Kalita Kanak
Published: December 2019

Purpose

Computational fluid dynamics (CFD) technique is the most commonly used numerical approach to simulate fluid flow behaviour. Owing to its computationally, cost-intensive nature CFD models may not be easily and quickly deployable. In this regard, this study aims to present a support vector machine (SVM)-based metamodelling approach that can be easily trained and quickly deployed for carrying out large-scale studies.

Design/methodology/approach

Radial basis function and ε^*-insensitive loss function are used as kernel function and loss function, respectively. To prevent overfitting of the model, five-fold cross-validation root mean squared error is used while training the SVM metamodel. Rather than blindly using any SVM tuning parameters, a particle swarm optimisation (PSO) is used to fine-tune them. The developed SVM metamodel is tested using various error metrics on disjoint test data.

Findings

Using the SVM metamodel, a parametric study is conducted to understand the effect of various factors influencing the behaviour of the turbulent fluid flow in the pipe bend with CFD simulation data set. Based on the parametric study carried out, it is seen that the diametric position has the most effect on dimensionless axial velocity, whereas Reynolds number has the least effect.

Originality/value

This paper provides an effective PSO-tuned SVM metamodelling approach, which may be used as a significant cost-saving approach to quickly and accurately estimate fluid flow characteristics that, in general, require the use of expensive CFD models.
A smile – the key to everybody’s heart?
Authors: Pham Chi , Septianto Felix
Published: December 2019

Purpose

This paper aims to investigate how to improve the effectiveness of charitable advertising by matching emotional appeal (happy-faced vs sad-faced beneficiary) and message framing (recognition vs request) within advertising messages.

Design/methodology/approach

Two experiments examining real donation allocations were conducted. Study 1 established the “match-up” effect between advertising image and message. Study 2 replicated the findings of Study 1 as well as testing the mediating role of hope and sympathy.

Findings

The authors provide empirical evidence that consumers allocate a greater donation amount to a charity when they see an image of a sad-faced child combined with a request message (e.g. “please donate”), or an image of a happy-faced child combined with a recognition message (e.g. “thank you”). Notably, these effects are mediated by the emotions of hope and sympathy, respectively.

Research limitations/implications

This research highlights the importance of matching images of beneficiaries with the appropriate advertising copy. Depending on whether a charity seeks to position itself in a positive perspective to evoke hope, or alternatively, portray itself in relation to a sadder landscape that elicits sympathy, the respective choice of recognition or request messages can help boost donation outcomes.

Practical implications

Charities and non-profit organizations can develop more effective charitable advertising by purposively matching specific emotional appeals and message framings when designing advertisements.

Originality/value

The research illustrates a novel mechanism that shows when and how combining image and message can influence the effectiveness of charitable advertising.
“One country, two systems”: consumer acculturation of Hong Kong locals
Authors: Wang Jeff Jianfeng , Joy Annamma , Belk Russell , Sherry, Jr John F.
Published: December 2019

Purpose

The purpose of this paper is to examine local consumers’ acculturation process as they observe, encounter and shop with an influx of outsiders.

Design/methodology/approach

The multi-year qualitative study (involving in-depth interviews and netnography) investigates Hongkongers’ adaptation to encounters with Mainland Chinese shoppers in Hong Kong.

Findings

The authors focus on the world of luxury brand consumption, which plays a key role in signaling a newfound status for Mainlanders, and a change in identity construction for Hongkongers. Hongkongers’ acculturation process in response to large numbers of Mainland luxury shoppers includes emotional responses, behavioral adaptation and identity negotiation.

Research limitations/implications

This research has theoretical implications for consumer acculturation theory.

Practical implications

This research has managerial implications for consumers’ luxury consumption experiences.

Originality/value

First, the authors extend the consumer acculturation literature by focusing on the adaptation of locals to visitors. Unlike other acculturation studies that focus on poorer immigrants from less industrial countries to a wealthy nation, the study focuses on local perspectives of elite Hong Kong consumers about Mainland Chinese visitors who are economically well-off but lack cultural capital. Second, emotions are found to be an important component of acculturation and their causes and consequences are analyzed.
Psychosocial hazards and work engagement in the Ghanaian banking sector
Authors: Tagoe Theophilus , Amponsah-Tawiah Kwesi
Published: December 2019

Purpose

The current happenings in the Ghana banking space and anecdotal evidence suggest that employees face psychosocial issues which impact their levels of work engagement. An intervention to manage these psychosocial hazards and promote work engagement among the employees is necessary. In effect, the study has proposed the promotion of a positive psychosocial safety climate (PSC) therein. Therefore, the purpose of this paper is to examine the moderating effect of PSC on the relationship between psychosocial hazards (i.e. work stress, workplace violence and workplace bullying) and work engagement.

Design/methodology/approach

The study gathered quantitative data from six commercial banks. Miller and Brewer’s (2003) sample determination formula was used to calculate the sample. The stratified random sampling technique was used to select the respondents. Questionnaires were used for the data collection, and Structural Equation Modelling was used to analyze the data from 543 usable responses.

Findings

Workplace bullying negatively predicted work engagement, whereas work stress and workplace violence had no significant effect on work engagement. PSC had a significant positive effect on work engagement. Furthermore, PSC only moderated the workplace bullying–work engagement relationship.

Originality/value

Based on the findings, PSC can be a national and organizational intervention promoted to create a positive psychological work environment devoid of such psychosocial hazards in the Ghanaian banking sector. Also, this will foster work engagement among the employees which will culminate into increased productivity.