bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational dissociation of dopaminergic and cholinergic effects on action selection and inhibitory control
Authors: Aponte Eduardo A. , Schöbi Dario , Stephan Klaas E. , Heinzle Jakob
Published: May 2019

Background

Patients with schizophrenia make more errors than healthy subjects on the antisaccade task. In this paradigm, participants are required to inhibit a reflexive saccade to a target and to select the correct action (a saccade in the opposite direction). While the precise origin of this deficit is not clear, it has been connected to aberrant dopaminergic and cholinergic neuromodulation.

Methods

To study the impact of dopamine and acetylcholine on inhibitory control and action selection, we administered two selective drugs (levodopa 200mg/galantamine 8mg) to healthy volunteers (N=100) performing the antisaccade task. A computational model (SERIA) was employed to separate the contribution of inhibitory control and action selection to empirical reaction times and error rates.

Results

Modeling suggested that levodopa improved action selection (at the cost of increased reaction times) but did not have a significant effect on inhibitory control. By contrast, according to our model, galantamine affected inhibitory control in a dose dependent fashion, reducing inhibition failures at low doses and increasing them at higher levels. These effects were sufficiently specific that the computational analysis allowed for identifying the drug administered to an individual with 70% accuracy.

Conclusions

Our results do not support the hypothesis that elevated tonic dopamine strongly impairs inhibitory control. Rather levodopa improved the ability to select correct actions. Instead, inhibitory control was modulated by cholinergic drugs. This approach may provide a starting point for future computational assays that differentiate neuromodulatory abnormalities in heterogeneous diseases like schizophrenia.
Whole genome sequencing of dog specific assemblages C and D of Giardia duodenalis from single and pooled cysts indicates host associated genes
Authors: Kooyman F.N.J. , Wagenaar J.A. , Zomer A.
Published: May 2019

Giardia duodenalis (Syn. G. intestinalis or G. lamblia) infects over 280 million people each year and numerous animals. G. duodenalis can be subdivided into 8 assemblages with different host specificity. Unculturable assemblages have so far resisted genome sequencing efforts. In this study we isolated single and pooled cysts of assemblage C and D from dog faeces by FACS and sequenced them using multiple displacement amplification and Illumina paired end sequencing. The genomes of assemblages C and D were compared with genomes of assemblages A and B from humans and assemblage E from ruminants and pigs. The genomes obtained from the pooled cysts and from the single cysts were considered complete (>99% marker genes observed) and the allelic sequence heterozygosity (ASH) of assemblage C and D was 0.89% and 0.74%, respectively. Higher than for assemblage B (> 0.43%) and much higher than for assemblages A and E (<0.01%). The flavohemoglobin and 4Fe-4S binding domain family gene involved in O2 and NO detoxification were only present in assemblages A, B and E. Cathepsin-B orthologs were found in all genomes. Six clades of cathepsin-B orthologs contained one gene of each genome, while in three clades not all assemblages were represented. We conclude that whole genome sequencing from a single Giardia cyst results in complete draft genomes making the genomes of unculturable Giardia assemblages accessible. Observed differences between the genomes of assemblage C and D on one hand and the assemblages A, B and E on the other hand are possibly associated with host specificity.
Taxonomic Bias and Traits of the Global Amphibian Pet-Trade
Authors: Mohanty Nitya Prakash , Measey John
Published: May 2019

The pet-trade is recognized as the major pathway for amphibian introductions worldwide, yet our understanding of the trade is limited. In this study, we systematically assess amphibian species in the pet-trade, i) characterising taxonomic bias and ii) evaluating species-traits as predictors of traded species and trade volume. We collated a global list of 443 traded amphibians and a regional dataset on trade volume. Species-traits (body size, native range size, clutch size, and breeding type) and conservation status, were considered as predictors of traded species and volume. We found a strong bias for certain Families, along with a preference for large-bodied and widely distributed species with a larval phase, in the pet-trade. However, species-traits performed poorly in predicting trade volume of pet amphibians in the USA. The identified species-traits and taxonomic bias of the trade is used to predict species likely to be traded as pets in the future.
DHTKD1 and OGDH display in vivo substrate overlap and form a hybrid ketoacid dehydrogenase complex
Authors: Leandro João , Dodatko Tetyana , Aten Jan , Hendrickson Ronald C. , Sanchez Roberto , Yu Chunli , DeVita Robert J. , Houten Sander M.
Published: May 2019

Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here we show that loss ofDHTKD1in GCDH-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine, and demonstrate that OGDH is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, DLST and DLD to form a hybrid α-ketoglutaric and α-ketoadipic acid dehydrogenase complex. In summary, α-ketoadipic acid is an in vivo substrate for DHTKD1, but also OGDH. The classic α-ketoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards α-ketoadipic acid.
Novel Strategies for Glutamate Clearance in the Glia-Deprived Synaptic Hub ofC. elegans
Authors: Chan Joyce , Lee Kirsten KyungHwa , Wong Jenny Chan Ying , Morocho Paola , Mano Itzhak
Published: May 2019

Brain function requires the ability to form neuronal circuits that mediate focused and accurate communication. Since the vast majority of brain synapses use Glutamate (Glu) as their neurotransmitter, unintended spillover of Glu between adjacent synapses is a critical challenge. To ensure accurate neurotransmission and avert synaptic mix-up, specialized Glu Transporters (GluTs) clear the synapse of released Glu. While classical views of neuronal morphology and physiology depict isolated spiny synapses enwrapped by GluT-expressing glia, in reality, a considerable portion of synapses are flat, glial coverage in some parts of the brain is rather sparse, and extracellular space is larger than previously estimated. This suggests that diffusion in interstitial fluids might have an important role in Glu clearance in these synapses. To understand basic principles of Glu clearance in flat-, glia-deprived synapses, we study the physiology of neuronal circuits in theC. elegansnerve ring, the nematode’s aspiny synaptic hub. We use behavioral assays, Ca2+imaging, and iGluSnFR to follow synaptic activity in intact animals. We find that synapses in a nociceptive avoidance circuit are dramatically affected by distal GluTs, while an adjacent chemoattraction circuit is controlled by proximal GluTs. We also find that pharyngeal pulsatility and mobility, which could agitate interstitial fluids, are critical for synaptic physiology. We therefore conclude that robust Glu clearance in the nematode is provided differentially by distal and proximal GluTs, aided by agitation of interstitial fluids. Such principles might be informative in determining additional factors that contribute to robust Glu clearance in other neuronal systems.

Significance Statement

The nervous system depends on faithful relay of information without inadvertent mixing of signals between neuronal circuits. Classical views of the nervous system depict isolated synapses, enwrapped by glia that express neurotransmitter-transporters. However, this view is incomplete, since many synapses are flat, deprived of glia, and exposed to a larger-than-expected extracellular space. We use optogenetic tools to investigate glutamate clearance strategies in the aspiny and glia-deprived synaptic hub of intact nematodes. We find a division of labor among Glutamate transporters: while some transporters display classical localization near the synapses, others are distal, and cooperate with agitation of interstitial fluids to prevent glutamate accumulation. These novel principles might contribute to synaptic clearance in higher animals, affecting normal neuronal physiology and disease.
Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence
Authors: Granzotto Alberto , Bomba Manuela , Castelli Vanessa , Navarra Riccardo , Massetti Noemi , Onofrj Marco , Cicalini Ilaria , del Boccio Piero , Cimini Annamaria , Piomelli Daniele , Sensi Stefano L.
Published: May 2019

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.

In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor ofde novoceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as anin vitromodel of cellular senescence. Our findings indicate that ‘aged’ neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca2+]ilevels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca2+]isignaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.

The results suggest that thede novoceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.
Genomic analysis of the tryptome reveals molecular mechanisms of gland cell evolution
Authors: Babonis Leslie S. , Ryan Joseph F. , Enjolras Camille , Martindale Mark Q.
Published: May 2019

Understanding the drivers of morphological diversity is a persistent challenge in evolutionary biology. Here, we investigate functional diversification of secretory cells in the sea anemone Nematostella vectensis to understand the mechanisms promoting cellular specialization across animals. We demonstrate regionalized expression of gland cell subtypes in the internal ectoderm of N. vectensis and show that adult gland cell identity is acquired very early in development. A phylogenetic survey of trypsins across animals suggests this gene family has undergone numerous expansions. We reveal unexpected diversity in trypsin protein structure and show that trypsin diversity arose through independent acquisitions of non-trypsin domains. Finally, we show that trypsin diversification in N. vectensis was effected through a combination of tandem duplication, exon shuffling, and retrotransposition. Together we reveal that numerous evolutionary mechanisms drove trypsin duplication and divergence during the morphological specialization of cell types and suggest the secretory cell phenotype is highly adaptable as a vehicle for novel secretory products.
Combinatorial design of chemical-dependent protein switches for controlling intracellular electron transfer
Authors: Wu Bingyan , Atkinson Joshua T. , Kahanda Dimithree , Bennett George. N. , Silberg Jonathan J.
Published: May 2019

One challenge with controlling electron flow in cells is the lack of biomolecules that directly couple the sensing of environmental conditions to electron transfer efficiency. To overcome this protein component limitation, we randomly inserted the ligand binding domain (LBD) from the human estrogen receptor (ER) into a thermostable 2Fe-2S ferredoxin (Fd) fromMastigocladus laminosusand used a bacterial selection to identify Fd-LBD fusion proteins that support electron transfer from a Fd-NADP reductase (FNR) to a Fd-dependent sulfite reductase (SIR). Mapping LBD insertion sites onto structure revealed that Fd tolerates domain insertion adjacent to or within the tetracysteine motif that coordinates the 2Fe-2S metallocluster. With both classes of the fusion proteins, cellular ET was enhanced by the ER antagonist 4-hydroxytamoxifen. In addition, one of Fds arising from ER-LBD insertion within the tetracysteine motif acquires an oxygen-tolerant 2Fe-2S cluster, suggesting that ET is regulated through post-translational ligand binding.
The neuropeptide Drosulfakinin regulates social isolation-induced aggression inDrosophila
Authors: Agrawal Pavan , Kao Damian , Chung Phuong , Looger Loren L.
Published: May 2019

Social isolation strongly modulates behavior across the animal kingdom. We utilized the fruit flyDrosophila melanogasterto study social isolation-driven changes in animal behavior and gene expression in the brain. RNA-seq identified several head-expressed genes strongly responding to social isolation or enrichment. Of particular interest, social isolation downregulated expression of the gene encoding the neuropeptideDrosulfakinin(Dsk), the homologue of vertebrate cholecystokinin (CCK), which is critical for many mammalian social behaviors.Dskknockdown significantly increased social isolation-induced aggression. Genetic activation or silencing ofDskneurons each similarly increased isolation-driven aggression. Our results suggest a U-shaped dependence of social isolation-induced aggressive behavior onDsksignaling, similar to the actions of many neuromodulators in other contexts.

Data availability

The raw sequence data from RNA-seq experiments has been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra) with accession number: PRJNA481582. Supplementary files and figures accompany this article.
Angiogenic activity of cytochalasin B-induced membrane vesicles of human mesenchymal stem cells
Authors: Gomzikova M.O. , Zhuravleva M.N. , Vorobev V.V. , Salafutdinov I.I. , Laikov A.V. , Kletukhina S.K. , Martynova E.V. , Tazetdinova L.G. , Ntekim A.I. , Khaiboullina S.F. , Rizvanov A.A.
Published: May 2019

Background

The cytochalasin B-induced membrane vesicles (CIMVs) are suggested to be used as a vehicle for the delivery of therapeutics. However, the angiogenic activity and therapeutic potential of human mesenchymal stem cells (MSCs) derived CIMVs (CIMVs-MSCs) remains unknown.

Objectives

The objectives of this study were to analyzed the morphology, size distribution, molecular composition and angiogenic properties of CIMVs-MSCs.

Methods

The morphology of CIMVs-MSC was analyzed by scanning electron microscopy. The proteomic analysis, multiplex analysis and immunostaining were used to characterize the molecular composition of the CIMVs-MSCs. The transfer of surface proteins from a donor to a recipient cell mediated by CIMVs-MSCs was demonstrated using immunostaining and confocal microscopy. The angiogenic potential of CIMVs-MSCs was evaluated using in vivo approach of subcutaneous implantation of CIMVs-MSCs in mixture with Matrigel matrix.

Results

Human CIMVs-MSCs retain parental MSCs content such as growth factors, cytokines, chemokines: EGF, FGF-2, Eotaxin, TGF-α, G-CSF, Flt-3L, GM-CSF, Fractalkine, IFNα2, IFN-γ, GRO, IL-10, MCP-3, IL-12p40, MDC, IL-12p70, IL-15, sCD40L, IL-17A, IL-1RA, IL-1a, IL-9, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP_1a, MIP-1b, TNF-α, TNF-β, VEGF. CIMVs-MSCs also have the expression of surface receptors similar to those in parental human MSCs (CD90+, CD29+, CD44+, CD73+). Additionally, CIMVs-MSCs could transfer membrane receptors to the surfaces of target cellsin vitro. Finally, CIMVs-MSCs can induce angiogenesisin vivoafter subcutaneous injection into adult rats.

Conclusions

Human CIMVs-MSCs have similar content, immunophenotype and angiogenic activity to those of the parental MSCs. Therefore, we believe that human CIMVs-MSCs could be used for cell free therapy of degenerative diseases.
Apicomplexan F-actin is required for efficient nuclear entry during host cell invasion
Authors: Del Rosario Mario , Periz Javier , Pavlou Georgios , Lyth Oliver , Latorre-Barragan Fernanda , Das Sujaan , Pall Gurman S. , Stortz Johannes Felix , Lemgruber Leandro , Baum Jake , Tardieux Isabelle , Meissner Markus
Published: May 2019

The obligate intracellular parasites Toxoplasma gondii and Plasmodium spp. invade host cells by injecting a protein complex into the membrane of the targeted cell that bridges the two cells through the assembly of a ring-like junction. This circular junction stretches while the parasites applies a traction force to pass through; a step that typically concurs with transient constriction of the parasite body. Here we show that the junction can oppose resistance to the passage of the parasite’s nucleus. Super-resolution microscopy and real time imaging highlighted an F-actin pool at the apex of pre-invading parasite, an F-actin ring at the junction area during invasion but also networks of perinuclear and posteriorly localized F-actin. Mutant parasites with dysfunctional acto-myosin showed significant decrease of junctional and perinuclear F-actin and are coincidently affected in nuclear passage through the junction. We propose that the F-actin machinery eases nuclear passage by stabilising the junction and pushing the nucleus through the constriction, providing first evidence for a dual contribution of actin-forces during host cell invasion by apicomplexan parasites.
β-Actin and Nuclear Myosin I are responsible for nucleolar reorganization during DNA Repair
Authors: Cerutti Elena , Daniel Laurianne , Donnio Lise-Marie , Neuillet Damien , Magnani Charlene , Mari Pierre-Olivier , Giglia-Mari Giuseppina
Published: May 2019

During DNA Repair, ribosomal DNA and RNA polymerase I (rDNA/RNAP1) are reorganized within the nucleolus. Until now, the proteins and the molecular mechanism governing this reorganisation remained unknown.

Here we show that Nuclear Myosin I (NMI) and Nuclear Beta Actin (ACTβ) are essential for the proper reorganisation of the nucleolus, after completion of the DNA Repair reaction.

In NMI and ACTβ depleted cells, the rDNA/RNAP1 complex can be displaced at the periphery of the nucleolus after DNA damage but cannot re-enter within the nucleolus after completion of the DNA Repair. Both proteins act concertedly in this process. NMI binds the damaged rDNA at the periphery of the nucleolus, while ACTβ brings the rDNA back within the nucleolus after DNA repair completion. Our results reveal a previously unidentified function for NMI and ACTβ and disclose how these two proteins work in coordination to re-establish the proper rDNA position after DNA repair.
Pelvic bone structures in free-ranging Eurasian lynx (Lynx lynx) from Switzerland: a radiological pelvimetry study
Authors: Morend Fanny , Lang Johann , Vidondo Beatriz , Ryser-Degiorgis Marie-Pierre
Published: May 2019

The observation of severe pelvic malformations in Eurasian lynx (Lynx lynx) from a population reintroduced to Switzerland raised the question as to whether inbreeding may contribute to the development of congenital pelvic malformations. We aimed at providing baseline data on the pelvic morphology of Eurasian lynx from the reintroduced populations in Switzerland, at assessing potential differences in pelvic conformation between the two main Swiss populations, among age classes and between sexes, and at detecting pelvic anomalies. We performed measurements of 10 pelvic parameters on the radiographs of 57 lynx of both sexes and different ages taken from 1997-2015. We calculated two ratios (vertical diameter/acetabula; sagittal diameter/transversal diameter) and two areas (pelvic outlet and inlet) to describe the shape of the pelvis. Our results showed that the Eurasian lynx is a mesatipelvic species, with a pelvis length corresponding to approximatively 20% of the body length. We found no statistically significant differences between the two examined populations but observed growth-related pelvis size differences among age groups. Sexual dimorphism was obvious in the adult age group only: two parameters reflecting pelvic width were larger in females, likely to meet the physiological requirements of parturition. By contrast, pelvis length, conjugata vera, diagonal conjugata, vertical diameter and sagittal diameter were larger in males, in agreement with their larger body size. Accordingly, the ratio between the sagittal and transversal diameters was significantly larger in males, i.e. adult males have a different pelvic shape than adult females. Furthermore, pelvimetry highlighted one adult individual with values outside the calculated reference range, suggesting a possible congenital or developmental pathological morphology of the internal pelvis. Our work generated baseline data of the pelvic morphology including growth and sexual dimorphism of the Eurasian lynx. These data could also be useful for estimating age and sex in skeletal remains.
Length-dependent disassembly maintains four different flagellar lengths in Giardia
Authors: McInally SG , Kondev J , Dawson Scott C.
Published: May 2019

How flagellar length regulation is achieved in multiciliated eukaryotic cells with flagella of different equilibrium lengths is unknown. The protist Giardia lamblia is an ideal model to evaluate length regulation as it has flagella of four different lengths. Giardia axonemes have both non-membrane-bound and membrane-bound regions, but lack transition zones. Here we quantified the contributions of intraflagellar transport (IFT)-mediated assembly and kinesin-13-mediated disassembly to length control. IFT particles assemble and inject at Giardia’s flagellar pore complexes, which act as diffusion barriers functionally analogous to the transition zone to compartmentalize the membrane-bound regions of flagella. IFT-mediated assembly is length-independent as train size, speed, and injection frequencies are similar between flagella of different lengths. In Giardia, kinesin-13 mediates a length-dependent disassembly mechanism of length regulation to balance length-independent IFT-mediated assembly, resulting in different lengths. We anticipate that similar control mechanisms are widespread in multiciliated cells where cytoplasmic precursor pools are not limiting.
Individual Prediction of Psychotherapy Outcome in Posttraumatic Stress Disorder using Neuroimaging Data
Authors: Zhutovsky Paul , Thomas Rajat M. , Olff Miranda , van Rooij Sanne J.H. , Kennis Mitzy , van Wingen Guido A. , Geuze Elbert
Published: May 2019

Objective

Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30-50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level.

Methods

Forty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation.

Results

A RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE < 0.05) while a RSN centered on the pre-supplementary motor area distinguished between responders and non-responders on an individual-level with 81.4% accuracy (P < 0.001, 84.8% sensitivity, 78% specificity and AUC of 0.93). No significant single-subject classification or group differences were observed for gray matter volume.

Conclusions

This proof-of-concept study demonstrates the feasibility of using rs-fMRI to develop neuroimaging biomarkers for treatment response, which could enable personalized treatment of patients with PTSD.
Perception of rhythmic speech is modulated by focal bilateral tACS
Authors: Zoefel Benedikt , Allard Isobella , Anil Megha , Davis Matthew H
Published: May 2019

Several recent studies have used transcranial alternating stimulation (tACS) to demonstrate a causal role of neural oscillatory activity in speech processing. In particular, it has been shown that the ability to understand speech in a multi-speaker scenario or background noise depends on the timing of speech presentation relative to simultaneously applied tACS. However, it is possible that tACS did not change actual speech perception but rather auditory stream segregation. In this study, we tested whether the phase relation between tACS and the rhythm of degraded words, presented in silence, modulates word report accuracy. We found strong evidence for a tACS-induced modulation of speech perception, but only if the stimulation was applied bilaterally using ring electrodes (not for unilateral left hemisphere stimulation with square electrodes). These results were only obtained when data was analyzed using a statistical approach that was identified as optimal in a previous simulation study. The effect was driven by a phasic disruption of word report scores. Our results suggest a causal role of neural entrainment for speech perception and emphasize the importance of optimizing stimulation protocols and statistical approaches for brain stimulation research.
The complete mitochondrial genome ofCalyptogena marissinica(Heterodonta: Veneroida: Vesicomyidae): insight into the deep-sea adaptive evolution of vesicomyids
Authors: Yang Mei , Gong Lin , Sui Jixing , Li Xinzheng
Published: May 2019

The deep sea is one of the most extreme environments on earth, with low oxygen, high hydrostatic pressure and high levels of toxins. Species of the family Vesicomyidae are among the dominant chemosymbiotic bivalves found in this harsh habitat. Mitochondria play a vital role in oxygen usage and energy metabolism; thus, they may be under selection during the adaptive evolution of deep-sea vesicomyids. In this study, the mitochondrial genome (mitogenome) of the vesicomyid bivalveCalyptogena marissinicawas sequenced with Illumina sequencing. The mitogenome ofC. marissinicais 17,374 bp in length and contains 13 protein-coding genes, 2 ribosomal RNA genes (rrnSandrrnL) and 22 transfer RNA genes. All of these genes are encoded on the heavy strand. Some special elements, such as tandem repeat sequences, “G(A)nT” motifs and AT-rich sequences, were observed in the control region of theC. marissinicamitogenome, which is involved in the regulation of replication and transcription of the mitogenome and may be helpful in adjusting the mitochondrial energy metabolism of organisms to adapt to the deep-sea environment. The gene arrangement of protein-coding genes was identical to that of other sequenced vesicomyids. Phylogenetic analyses clusteredC. marissinicawith previously reported vesicomyid bivalves with high support values. Positive selection analysis revealed evidence of adaptive change in the mitogenome of Vesicomyidae. Ten potentially important adaptive residues were identified, which were located incox1, cox3, cob, nad2, nad4andnad5. Overall, this study sheds light on the mitogenomic adaptation of vesicomyid bivalves that inhabit the deep-sea environment.
Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies
Authors: Yee Sook Wah , Stecula Adrian , Chien Huan-Chieh , Zou Ling , Feofanova Elena V. , van Borselen Marjolein , Cheung Kit Wun Kathy , Yousri Noha A. , Suhre Karsten , Kinchen Jason M. , Boerwinkle Eric , Irannejad Roshanak , Yu Bing , Giacomini Kathleen M.
Published: May 2019

Variation in sex hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1×10−30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels.

Author Summary

Steroid hormones, ranging from sex steroids such as testosterone to glucocorticoids play key roles in human health and disease. Accordingly, the identification of the genes and proteins involved in their synthesis, disposition and elimination has been the subject of numerous genetic studies. We have been intrigued by recent studies demonstrating that genetic variants in or near a gene encoding SLC22A24 are strongly associated with steroid levels. SLC22A24 is an orphan transporter with no known ligands and no known biological functions. In this study, we use cellular and computational methods to show that SLC22A24 transports steroid conjugates, bile acids and other dicarboxylic acids. Based on the direction of association of a common stop codon in SLC22A24 with lower levels of steroids, our studies suggest that the transporter functions to reabsorb steroid conjugates in the kidney, a surprising finding, given that conjugation pathways generally function to polar molecules that are readily eliminated by the kidney. The absence of the transporter gene in many species and its presence in higher order primates suggest that SLC22A24 plays a specialized role in steroid homeostasis. Overall, our studies indicate that SLC22A24 functions in the reabsorption of conjugated steroids in the kidney.
Epigenetics and transcription regulation during eukaryotic diversification: the saga of TFIID
Authors: Antonova Simona V. , Boeren Jeffrey , Timmers H.T. Marc , Snel Berend
Published: May 2019

The basal transcription factor TFIID is central for RNA polymerase II-dependent transcription. Human TFIID is endowed with chromatin reader and DNA-binding domains and protein interaction surfaces. Fourteen TFIID TATA-binding protein (TBP)-associated factor (TAF) subunits assemble into the holocomplex, which shares subunits with the Spt–Ada–Gcn5–acetyltransferase (SAGA) coactivator. Here, we discuss the structural and functional evolution of TFIID and its divergence from SAGA. Our orthologous tree and domain analyses reveal dynamic gains and losses of epigenetic readers, plant-specific functions of TAF1 and TAF4, the HEAT2-like repeat in TAF2, and, importantly, the pre-LECA origin of TFIID and SAGA. TFIID evolution exemplifies the dynamic plasticity in transcription complexes in the eukaryotic lineage.
Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism
Authors: Pearson Stephanie , Loft Anne , Rajbhandari Prashant , Simcox Judith , Lee Sanghoon , Tontonoz Peter , Mandrup Susanne , Villanueva Claudio J.
Published: May 2019

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.
MITF—the first 25 years
Authors: Goding Colin R. , Arnheiter Heinz
Published: May 2019

All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.
Daedalus and Gasz recruit Armitage to mitochondria, bringing piRNA precursors to the biogenesis machinery
Authors: Munafò Marzia , Manelli Vera , Falconio Federica A. , Sawle Ashley , Kneuss Emma , Eastwood Evelyn L. , Seah Jun Wen Eugene , Czech Benjamin , Hannon Gregory J.
Published: May 2019

The Piwi-interacting RNA (piRNA) pathway is a small RNA-based immune system that silences mobile genetic elements in animal germlines. piRNA biogenesis requires a specialized machinery that converts long single-stranded precursors into small RNAs of ∼25-nucleotides in length. This process involves factors that operate in two different subcellular compartments: the nuage/Yb body and mitochondria. How these two sites communicate to achieve accurate substrate selection and efficient processing remains unclear. Here, we investigate a previously uncharacterized piRNA biogenesis factor, Daedalus (Daed), that is located on the outer mitochondrial membrane. Daed is essential for Zucchini-mediated piRNA production and the correct localization of the indispensable piRNA biogenesis factor Armitage (Armi). We found that Gasz and Daed interact with each other and likely provide a mitochondrial “anchoring platform” to ensure that Armi is held in place, proximal to Zucchini, during piRNA processing. Our data suggest that Armi initially identifies piRNA precursors in nuage/Yb bodies in a manner that depends on Piwi and then moves to mitochondria to present precursors to the mitochondrial biogenesis machinery. These results represent a significant step in understanding a critical aspect of transposon silencing; namely, how RNAs are chosen to instruct the piRNA machinery in the nature of its silencing targets.
Recompleting the Caenorhabditis elegans genome
Authors: Yoshimura Jun , Ichikawa Kazuki , Shoura Massa J. , Artiles Karen L. , Gabdank Idan , Wahba Lamia , Smith Cheryl L. , Edgley Mark L. , Rougvie Ann E. , Fire Andrew Z. , Morishita Shinichi , Schwarz Erich M.
Published: May 2019

Caenorhabditis elegans was the first multicellular eukaryotic genome sequenced to apparent completion. Although this assembly employed a standard C. elegans strain (N2), it used sequence data from several laboratories, with DNA propagated in bacteria and yeast. Thus, the N2 assembly has many differences from any C. elegans available today. To provide a more accurate C. elegans genome, we performed long-read assembly of VC2010, a modern strain derived from N2. Our VC2010 assembly has 99.98% identity to N2 but with an additional 1.8 Mb including tandem repeat expansions and genome duplications. For 116 structural discrepancies between N2 and VC2010, 97 structures matching VC2010 (84%) were also found in two outgroup strains, implying deficiencies in N2. Over 98% of N2 genes encoded unchanged products in VC2010; moreover, we predicted ≥53 new genes in VC2010. The recompleted genome of C. elegans should be a valuable resource for genetics, genomics, and systems biology.
FORTE – a multipurpose high-vacuum diffractometer for tender X-ray diffraction and spectroscopy at the SIRIUS beamline of Synchrotron SOLEIL
Authors: Ciatto G. , Aubert N. , Lecroard M. , Engblom C. , Fontaine P. , Dubuisson J.-M. , Abiven Y.-M. , Janolin P.-E. , Kiat J.-M. , Dumont Y. , Berini B. , Fouchet A. , Keller N.
Published: May 2019

A new high-vacuum multipurpose diffractometer (called FORTE from the French acronyms of the project) has recently been installed at the tender/hard X-ray SIRIUS beamline of Synchrotron SOLEIL, France. The geometry chosen allows one to work either in the classical Eulerian four-circle geometry for bulk X-ray diffraction (XRD) or in the z-axis geometry for surface XRD. The diffractometer nicely fits the characteristics of the SIRIUS beamline, optimized to work in the 1.1–4.5 keV range, and allows one to perform unprecedented diffraction anomalous fine structure (DAFS) experiments in the tender X-ray region, also around non-specular reflections, covering a large reciprocal-space volume. Installation of an X-ray fluorescence detector on a dedicated flange allows simultaneous DAFS and X-ray absorption (XAS) measurements. The access to the tender X-ray region paves the way to resonant investigations around the L-edges of second-row transition elements which are constituents of functional oxide materials. It also enables access to several edges of interest for semiconductors. Finally, the control architecture based on synchronized Delta Tau units opens up exciting perspectives for improvement of the mechanical sphere of confusion.
Determinants of innovation performance
Authors: Lafuente Esteban , Solano Angela , Leiva Juan Carlos , Mora-Esquivel Ronald
Published: May 2019

Purpose

The purpose of this paper is to analyse the relationship between organisational learning capabilities (OLCs) and innovation performance (IP) in organisational contexts where knowledge creation and exploitation are the business’ main source of competitive advantage.

Design/methodology/approach

The study hypotheses are tested on a unique sample of 74 high-performance businesses operating in knowledge-intensive business services (KIBS) industries and non-knowledge intensive sectors in 2016. The study employs a sequential deductive triangulation analysis (QUAN → qual) based on linear regression models and qualitative interviews.

Findings

The results indicate that OLCs positively impact IP. Additionally, the findings reveal that this relationship is stronger in organisations where knowledge creation and exploitation constitute the main source of competitive advantage, namely, KIBS firms.

Research limitations/implications

This paper offers insights into how the innovation outcomes of OLCs are heterogeneous across industries. This study contributes to a better understanding of the conditions under which the effects of developing learning-enhancing strategies occur in businesses operating in different industries.

Practical implications

Both knowledge generation and exploitation processes are critical for business success, and OLCs play a decisive role in this process. In this sense, the results suggest that managers need to turn their attention to the characteristics of business operations when considering the development of strategies aimed at enhancing OLCs.

Originality/value

The paper further explores the influence of OLCs on IP by analysing how organisational learning strategies interact with relevant organisational characteristics – that are linked here to the exploitation of knowledge-based resources – to yield superior IP.
Effects of corporate social responsibility activities for refugees
Authors: Einwiller Sabine , Ruppel Christopher , Strasser Cornelia
Published: May 2019

Purpose

When in the Summer of 2015 unprecedented numbers of refugees traveled through Austria, not only public and governmental authorities were challenged to provide support, but also the business sector. Various companies responded to the challenge by organizing relief actions, among them Austrian Federal Railways (OEBB). The purpose of this paper is to analyze the effects of this initiative on stakeholder perceptions and behavior.

Design/methodology/approach

The case of OEBB served as the research context. Data were collected by means of an online survey in May of 2016, about eight months after the initiative.

Findings

Almost half of the participants mentioned OEBB’s activities for refugees in an unaided recall task. Unaided corporate social responsibility (CSR) awareness is related to people’s issue involvement and reminiscence of specific activities and communication measures. People unaidedly recalling the initiative expressed a significantly better CSR image and identification with the company; they also expressed a stronger intention to speak positively (positive word of mouth) about the company’s CSR activities. CSR image and attitude toward the initiative mediates this effect.

Research limitations/implications

The study stresses the importance of CSR awareness and communication. The non-representative sample does not allow general inferences.

Originality/value

This research uses an actual case to test the effectiveness of CSR activities and communication in the context of a highly critical situation, and sheds light on the mediating processes that drive the effects. The study extends existing knowledge from experimental studies.
GMF Aero Asia: aiming for the Middle-East base
Authors: Saragih Harriman , Sinaga Fransisca
Published: May 2019

Learning outcomes

This case study focuses on four main areas. By the end of the study, the students are expected to meet the following objectives by answering several assignment questions: understand the general business of a maintenance, repair and overhaul (MRO) company and why this business is a central player in the air transportation industry; understand and integrate certain strategy analysis tools, particularly Porter’s Generic Strategies, Ansoff Matrix, GE/McKinsey Matrix and International Market Entry Modes, to use later as justification for any recommendations about strategy; and prepare a systematic elaboration to use to recommend the company’s strategic plan.

Case overview/synopsis

This case study discusses PT GMF Aero Asia, Tbk. (GMF), a company that is based in Tangerang, Indonesia, and involved in the MRO for airlines. At the time of writing this case, the CEO was Iwan Joeniarto. The case elaborates on GMF’s competitive business operations in Indonesia and Southeast Asia, with the main focus being a discussion of Iwan’s visions for GMF’s expansion into the Middle East. This case study challenges students to think critically on the strategy level about the expansion plans of a local company into the international market. The main research questions the study attempts to answer are: What is an MRO in the aviation business? How does it relate to airport megahubs? Is the option for business expansion into the Middle East feasible for GMF? If not, are there any alternatives for that international expansion? Moreover, what recommendations can this study provide Iwan for entering that international market successfully? The students are expected to gain exposure to the international market entry in an MRO business. The students are also expected to understand and integrate the different strategy analysis concepts and tools, such as Porter’s Generic Strategies, Ansoff Matrix, GE/McKinsey Matrix and International Market Entry Modes.

Complexity academic level

This case study can be used as teaching material in several programs, including – but not limited to – the followings: Bachelor’s Degree program in Management, Business and Marketing (usually final year students), Master’s Degree in Business Management or Business Administration and Executive Education Program/Workshop/Seminar/Training for Business Development/Marketing Managers, VPs, Directors and Aviation Management Professionals. This case study can be used in the following classes/subjects: strategic management, strategic marketing management, international marketing, international business, global marketing, operations management and aviation management.

Supplementary materials

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

Subject code

CSS 11: Strategy.
Linking corporate entrepreneurship, expatriation and reverse knowledge transfers
Authors: Raziq Muhammad Mustafa , Rodrigues Cristina Doritta , Borini Felipe Mendes , Malik Omer Farooq , Saeed Abubakr
Published: May 2019

Purpose

Multinational enterprises (MNEs) encourage their subsidiaries to develop and transfer their unique knowledge and expertise back to the MNE as it is critical for the development of the MNE as a whole. However, what underlies the subsidiary ability to create such specialized knowledge that can be transferred to the MNE is less clear. The purpose of this paper is to examine the influence of MNE entrepreneurial strategy, subsidiary initiatives and expatriation on reverse knowledge transfers in a cross-country comparative context.

Design/methodology/approach

Data are gathered through surveys from 429 foreign subsidiaries operating in New Zealand and 164 subsidiaries in Brazil, and these are analyzed using variance-based structural equation modeling.

Findings

Subsidiary initiatives partially mediate the relationship between MNE entrepreneurial strategy and reverse knowledge transfers in case of subsidiaries operating in Brazil, but they fully mediate in case of New Zealand. Furthermore, expatriation, in case of the latter, has a negative interaction in the relationship between subsidiary initiative and reverse knowledge transfers, but, in case of the former, it has no moderating role. Overall, the results suggest that the influence of MNE entrepreneurial strategy and expatriation on reverse knowledge transfers can be explained by contingencies such as the subsidiary host economy and the heterogenous HQ–subsidiary relationships.

Originality/value

The paper contributes to literature by identifying some contingencies with regard to the occurrence of reverse knowledge transfers. It addresses some research calls with regard to examining reverse knowledge transfers and the role of expatriation across different empirical contexts.