bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic variants disrupt human RGS14 binding to NHERF1 and regulation of NPT2A-mediated phosphate transport
Authors: Friedman Peter A. , Mamonova Tatyana , Magyar Clara E. , Squires Katherine E. , Sneddon W. Bruce , Emlet David R. , Hepler John R.
Published: February 2019

RGS14 is a multifunctional scaffolding protein that integrates G protein, MAPK, and Ca++/CaM signaling pathways. RGS14 contains an RGS domain, tandem Ras/Rap-binding domains, and a G protein regulatory motif. Human/primate RGS14 differ from rodent proteins by possessing a carboxy-terminal extension encoding a Type I PDZ ligand. RGS14 has been implicated in disordered phosphate metabolism. The human RGS14 gene is adjacent to SLC34A1 that encodes the NPT2A sodium-phosphate cotransporter. Hormone-regulated NPT2A requires the PDZ protein NHERF1 which contains two PDZ domains (PDZ1 and PDZ2). NHERF1 binds the PDZ ligand carboxy tail of NPT2A to regulate phosphate uptake, and this NPT2A:NHERF1 complex is inhibited by parathyroid hormone (PTH). Studies here define roles for RGS14 in NHERF1-dependent, PTH-sensitive phosphate transport. We found that RGS14 binds to NHERF1 via the PDZ2 domain. PTH inhibits NPT2A-mediated phosphate transport and RGS14 blocked this action. Several rare human mutations have been reported in the RGS14 PDZ ligand located at residues 563 (D563N, D563G) and 565 (A565S, A565V). D563N disrupted RGS14 binding to NHERF1 and did not interfere with PTH action, whereas D563G, A565S, and A565V bound NHERF1 and were functionally equivalent to wild-type RGS14. Computational analysis and molecular dynamics modeling of NHERF1 PDZ2 binding to the RGS14 C-terminal PDZ ligands refined the structural determinants of this interaction. Additional studies demonstrated that RGS14 is expressed in human kidney proximal and distal tubule cells. Together, our findings are consistent with the view that RGS14 contributes to PTH-sensitive phosphate transport in humans. RGS14 coding variants may cause disordered phosphate metabolism.
Effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in Sprague-Dawley and Wistar rats
Authors: Taffe Michael A. , Creehan K. M. , Vandewater Sophia A. , Kerr Tony M. , Cole Maury
Published: February 2019

A novel inhalation system based on e-cigarette technology has been recently shown to produce hypothermic and anti-nociceptive effects of Δ9-tetrahydrocannabinol (THC) in rats. Indirect comparison of some prior investigations suggested differential impact of inhaled THC between Wistar (WI) and Sprague-Dawley (SD) rats, thus this study was conducted to directly compare the strains.

Groups (N=8 per strain) of age matched male SD and WI rats were prepared with radiotelemetry devices to measure temperature and then exposed to vapor from the propylene glycol (PG) vehicle or THC (25, 100, 200 mg/mL of PG) for 30 or 40 minutes. Additional studies evaluated plasma THC levels and anti-nociceptive effects after THC inhalation as well as the thermoregulatory effect of intraperitoneal injection of THC (5-30 mg/kg).

Hypothermic effects of inhaled THC was more pronounced in SD rats however plasma levels of THC were identical across strains under either fixed inhalation conditions or injection of a mg/kg equivalent dose. Strain differences in hypothermia were even more pronounced after i.p. injection of THC with SD rats exhibiting dose-dependent temperature reduction after 5 or 10 mg/kg, i.p. and the WI rats only exhibiting significant hypothermia after 20 mg/kg, i.p. The anti-nociceptive effects of inhaled THC (100, 200 mg/mL) did not differ significantly across the strains. These studies confirm an insensitivity of WI rats, compared with SD rats, to the hypothermia induced by THC following inhalation conditions that produced identical plasma THC and anti-nociception. Thus strain differences were not due to differential THC delivery via vapor inhalation.
Quantitative prediction of enhancer-promoter interactions
Authors: Belokopytova P.S. , Mozheiko E.A. , Nuriddinov M.A. , Fishman D. , Fishman V.
Published: February 2019

Recent experimental and computational efforts provided large datasets describing 3-dimensional organization of mouse and human genomes and showed interconnection between expression profile, epigenetic status and spatial interactions of loci. These interconnections were utilized to infer spatial organization of chromatin, including enhancer-promoter contacts, from 1-dimensional epigenetic marks. Here we showed that predictive power of some of these algorithms is overestimated due to peculiar properties of biological data. We proposed an alternative approach, which gives high-quality predictions of chromatin interactions using only information about gene expression and CTCF-binding. Using multiple metrics, we confirmed that our algorithm could efficiently predict 3-dimensional architecture of normal and rearranged genomes.
Will climate change affect sugar beet establishment of the 21st century? Insights from a simulation study using a crop emergence model
Authors: Lamichhane Jay Ram , Constantin Julie , Aubertot Jean-Noël , Dürr Carolyne
Published: February 2019

Ongoing climate change has been reported to have far-reaching impact on crop development and yield in many regions of the globe including Europe. However, little is known about the potential impact of climate change on specific stages of the crop cycle including crop establishment, although it is a crucial stage of the annual crop cycles. For the first time, we performed a simulation study to pinpoint how sugar beet sowing conditions of the next eight decades will be altered under future climate change and if these variations will affect sowing dates, germination and emergence as well as bolting rates of this crop. We chose Northern France as an important study site, representative of sugar beet growing basin in Northern Europe. Sugar beet emergence simulations were performed for a period between 2020 and 2100, taking into account five sowing dates (mid-February, 1st March, mid-March, 1st April and mid-April). Soil water contents and temperatures in the 0-10 cm soil horizon were first simulated with the STICS soil-crop model using the most pessimistic IPCC scenario (RCP 8.5) to feed the SIMPLE crop emergence model. We also evaluated the probability of field access for the earlier sowings, based on the amount of cumulated rainfall during February and March. When analyzed by sowing date and for successive 20-year period from 2020 to 2100, there was a significant increase in seedbed temperatures by 2°C after 2060 while no change in cumulative rainfall was found before and after sowings, compared with the past. Emergence rate was generally higher for 2081-2100, while time to reach the maximum emergence rate decreased by about one week, compared with other periods, due to higher average seedbed temperatures. The rate of non-germinated seeds decreased, especially for the earlier sowing dates, but the frequency of non-emergence due to water stress increased after 2060 for all sowing dates, including the mid-February sowing. Bolting remains a risk for sowings before mid-March although this risk will be markedly decreased after 2060. The changes in seedbed conditions will be significant after 2060 in terms of temperatures. However, the possibility of field access will be a main limiting factor for earlier sowings, as no significant changes in cumulative rainfall, compared with the past, will occur under future climate change. When field access is not a constraint, an anticipation of the sowing date, compared to the currently practiced sowing (i.e. mid-March), will lead to decreased risks for the sugar beet crop establishment and bolting. The use of future climate scenarios coupled with a crop model allows a precise insight into the future sowing conditions, and provide helpful information to better project future farming systems.
Characterization of Pch2 localization determinants reveals a nucleolar-independent role in the meiotic recombination checkpoint
Authors: Herruzo Esther , Santos Beatriz , Freire Raimundo , Carballo Jesús A. , San-Segundo Pedro A.
Published: February 2019

The meiotic recombination checkpoint blocks meiotic cell cycle progression in response to synapsis and/or recombination defects to prevent aberrant chromosome segregation. The evolutionarily-conserved budding yeast Pch2TRIP13AAA+ ATPase participates in this pathway by supporting phosphorylation of the Hop1HORMADadaptor at T318. In the wild type, Pch2 localizes to synapsed chromosomes and to the unsynapsed rDNA region (nucleolus), excluding Hop1. In contrast, in synaptonemal complex (SC)-defectivezip1Δmutants, which undergo checkpoint activation, Pch2 is detected only on the nucleolus. Alterations in some epigenetic marks that lead to Pch2 dispersion from the nucleolus suppresszip1Δ-induced checkpoint arrest. These observations have led to the notion that Pch2 nucleolar localization could be important for the meiotic recombination checkpoint. Here we investigate how Pch2 chromosomal distribution impacts on checkpoint function. We have generated and characterized several mutations that alter Pch2 localization pattern resulting in aberrant Hop1 distribution and compromised meiotic checkpoint response. Besides the AAA+ signature, we have identified a basic motif in the extended N-terminal domain critical for Pch2’s checkpoint function and localization. We have also examined the functional relevance of the described Orc1-Pch2 interaction. Both proteins colocalize in the rDNA, and Orc1 depletion during meiotic prophase prevents Pch2 targeting to the rDNA allowing unwanted Hop1 accumulation on this region. However, Pch2 association with SC components remains intact in the absence of Orc1. We finally show that checkpoint activation is not affected by the lack of Orc1 demonstrating that, in contrast to previous hypotheses, nucleolar localization of Pch2 is actually dispensable for the meiotic checkpoint.
An ex vivo tissue model of cartilage degradation suggests that cartilage state can be determined from secreted key protein patterns
Authors: Neidlin Michael , Chantzi Efthymia , Macheras George , Gustafsson Mats G , Alexopoulos Leonidas G
Published: February 2019

The pathophysiology of osteoarthritis (OA) involves dysregulation of anabolic and catabolic processes associated with a broad panel of cytokines and other secreted proteins and ultimately lead to cartilage degradation. An increased understanding about the interactions of these proteins by means of systematic in vitro analyses may give new ideas regarding pharmaceutical candidates for treatment of OA and related cartilage degradation.

Therefore, first an ex vivo tissue model of cartilage degradation was established by culturing full thickness tissue explants with bacterial collagenase II. Then responses of healthy and degrading cartilage were analyzed by measuring protein abundance in tissue supernatant with a 26-multiplex protein profiling assay, after exposing them to a panel of 55 protein stimulations present in synovial joints of OA patients. Multivariate data analysis including exhaustive pairwise variable subset selection was used to identify the most outstanding changes in the measured protein secretions. This revealed that the MMP9 response is outstandingly low in degraded compared to healthy cartilage and that there are several protein pairs like IFNG and MMP9 that can be used for successful discrimination between degraded and healthy samples.

Taken together, the results show that the characteristic changes in protein responses discovered seem promising for accurate detection/diagnosis of degrading cartilage in general and OA in particular. More generally the employed ex vivo tissue model seems promising for drug discovery and development projects related to cartilage degradation, for example when trying to uncover the unknown interactions between secreted proteins in healthy and degraded tissues.
Efficient Electric Field Simulations for Transcranial Brain Stimulation
Authors: Saturnino Guilherme B , Madsen Kristoffer H , Thielscher Axel
Published: February 2019

Objective

Transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) modulate brain activity non-invasively by generating electric fields either by electromagnetic induction or by injecting currents via skin electrodes. Numerical simulations based on anatomically detailed head models of the TMS and TES electric fields can help us to understand and optimize the spatial stimulation pattern in the brain. However, most realistic simulations are still slow, and their numerical accuracy and the factors that influence it have not been evaluated in detail so far.

Approach

We present and validate a new implementation of the Finite Element Method (FEM) for TMS and TES that is based on modern algorithms and libraries. We also evaluate the convergence of the simulations and give estimates for the discretization errors.

Main results

Comparisons with analytical solutions for spherical head models validate our new FEM implementation. It is five to ten times faster than previous implementations. The convergence results suggest that accurately capturing the tissue geometry in addition to choosing a sufficiently high mesh density is of fundamental importance for accurate simulations.

Significance

The new implementation allows for a substantial increase in computational efficiency of TMS and TES simulations. This is especially relevant for applications such as the systematic assessment of model uncertainty and the optimization of multi-electrode TES montages. The results of our systematic error analysis allow the user to select the best tradeoff between model resolution and simulation speed for a specific application. The new FEM code will be made openly available as a part of our open-source software SimNIBS 3.0.
Rectal swabs in critically-ill patients provide discordant representations of the gut microbiome compared to stool samples: a brief methodologic report
Authors: Fair Katherine , Dunlap Daniel G. , Fitch Adam , Morris Alison , McVerry Bryan J. , Kitsios Georgios D.
Published: February 2019

The role of the gut microbiome in critical illness is being actively investigated, but the optimal sampling methods for sequencing studies of gut microbiota remain unknown. Stool samples are generally considered gold-standard but are not practical to obtain in the intensive care unit (ICU), and thus, rectal swabs are often used. However, the reliability of rectal swabs for gut microbiome profiling has not been established in this clinical setting. In this study, we compared 16S rRNA gene sequencing results between rectal swab and stool samples collected at three timepoints in mechanically-ventilated critically-ill adults. Rectal swabs comprised 89% of samples collected at the baseline timepoint, but stool samples became more available at later time-points. Significant differences in alpha and beta-diversity between rectal swabs and stool samples were observed (p<0.003), but these differences were primarily due to baseline samples. Higher relative abundance of Actinobacteria phyla (typically skin microbes) was present in rectal swabs compared to stool samples (p<0.02), a difference that was attenuated overtime. The progressive similarity of rectal swabs and stool samples likely results from increasing stool coating of the rectal vault and direct soiling of the rectal swabs taken at later time points. Therefore, inferences about the role of the gut microbiome in critical illness should be drawn cautiously and take into account the actual type and timing of samples analyzed.

Statement of Importance

Rectal swabs are considered reliable alternatives to stool samples for gut microbiome profiling in outpatients or healthy adults, but their reliability in critically-ill patients has not been defined. Because stool sampling is not practical or often feasible in the intensive care unit, we performed a detailed comparison of gut microbial sequencing profiles between rectal swabs vs. stool samples in a longitudinal cohort of critically-ill patients. We identified systematic differences in gut microbial profiles between rectal swabs and stool samples, and highlighted that timing of rectal swabbing had a significant impact on sequencing results. Our methodological findings should inform future investigations of the role of the gut microbiome in critical illness.
Conservation and flexibility in the gene regulatory landscape of Heliconiine butterfly wings
Authors: Hanly Joseph J , Wallbank Richard WR , McMillan W Owen , Jiggins Chris D
Published: February 2019

Background

Many traits evolve bycis-regulatory modification, by which changes to non-coding sequences affect the binding affinity for available transcription factors and thus modify the expression profile of genes. Multiple examples ofcis-regulatory evolution have been described at pattern switch genes responsible for butterfly wing pattern polymorphism, including in the diverse neotropical genusHeliconius, but the identities of the factors that can regulate these switch genes have not been identified.

Results

We investigated the spatial transcriptomic landscape across the wings of three closely related butterfly species, two of which have a convergently-evolved, co-mimetic pattern, the other having a divergent pattern. We identified candidate factors for regulating the expression of wing patterning genes, including transcription factors with a conserved expression profile in all three species, and others, including both transcription factors and Wnt pathway genes, with markedly different profiles in each of the three species. We verified the conserved expression profile of the transcription factor homothorax by immunofluorescence, and showed that its expression profile strongly correlates with that of the selector gene optix in butterflies with the Amazonian forewing pattern element ‘dennis’.

Conclusions

Here we show that, in addition to factors with conserved expression profiles like homothorax, there are also a variety of transcription factors and signaling pathway components that appear to vary in their expression profiles between closely related butterfly species, highlighting the importance of genome-wide regulatory evolution between species.
‘Simultaneous tracking of cell motility in liquid and at the solid-liquid interface’
Authors: Hook Andrew L. , Flewellen James L. , Zaid Irwin M. , Berry Richard M. , Dubern Jean-Frédéric , Carabelli Alessandro , Wildman Ricky , Russell Noah , Williams Paul , Alexander Morgan R.
Published: February 2019

1.

To better understand key behaviors of living cells, such as bacterial biofilm formation, they must be observed above surfaces and at the interface between the surface and liquid medium. We have established a methodology for label-free imaging and tracking of individual cells simultaneously at both the solid-liquid interface and within the bulk, utilizing imaging modes of digital holographic microscopy (DHM) in 3D, differential interference contrast (DIC) and total internal reflectance microscopy (TIRM) in 2D as well as analysis protocols using a bespoke software package. We illustrate the power of this method by making detailed single cell measurements ofPseudomonas aeruginosain the first minutes of their interaction with a glass surface, focusing on the role of the flagella stators,motABandmotCD. Using this new method we have determined their relative contributions to bulk and near surface motion for populations of cells at the single cell level.
Cell entry-independent role for the reovirus μ1 protein in regulating necroptosis and the accumulation of viral gene products
Authors: Roebke Katherine E , Danthi Pranav
Published: February 2019

The reovirus outer capsid protein μ1 regulates cell death in infected cells. To distinguish between the role of incoming, capsid-associated and newly synthesized μ1, we used siRNA-mediated knockdown. Loss of newly synthesized μ1 protein does not impact apoptotic cell death in HeLa cells but enhances necroptosis in L929 cells. Knockdown of μ1 also impacts aspects of viral replication. We found that while μ1 knockdown results in diminished release of infectious viral progeny from infected cells, viral minus strand RNA, plus strand RNA, and proteins that are not targeted by the μ1 siRNA accumulate to a greater extent when compared to control siRNA-treated cells. Furthermore, we observe a decrease in sensitivity of these viral products to inhibition by GuHCl (which targets minus strand synthesis to produce dsRNA) when μ1 is knocked down. Following μ1 knockdown, cell death is also less sensitive to treatment with GuHCl. Our studies suggest that the absence of μ1 allows enhanced transcriptional activity of newly synthesized cores and the consequent accumulation of viral gene products. We speculate that enhanced accumulation and detection of these gene products due to a μ1 knockdown potentiates RIP3 dependent cell death.

IMPORTANCE

We use mammalian reovirus as a model to study how virus infections result in cell death. Here, we sought to determine how viral factors regulate cell death. Our work highlights a previously unknown role for reovirus outer capsid protein μ1 in limiting the induction of a necrotic form of cell death called necroptosis. Induction of cell death by necroptosis requires the detection of viral gene products late in infection. μ1 limits cell death by this mechanism because it prevents excessive accumulation of viral gene products that trigger cell death.
Diet induces reproducible alterations in the mouse and human gut microbiome
Authors: Bisanz Jordan E. , Upadhyay Vaibhav , Turnbaugh Jessie A. , Ly Kimberly , Turnbaugh Peter J.
Published: February 2019

The degree to which diet reproducibly alters the human and mouse gut microbiota remains unclear. Here, we focus on the consumption of a high-fat diet (HFD), one of the most frequently studied dietary interventions in mice. We employed a subject-level meta-analysis framework for unbiased collection and analysis of publicly available 16S rRNA gene and metagenomic sequencing data from studies examining HFD in rodent models. In total, we re-analyzed 27 studies, 1101 samples, and 106 million reads mapping to 16S rRNA gene sequences. We report reproducible changes in gut microbial community structure both within and between studies, including a significant increase in the Firmicutes phylum and decrease in the Bacteroidetes phylum; however, reduced alpha diversity is not a consistent feature of HFD. Finer taxonomic analysis revealed that the strongest signal of HFD on microbiota species composition is Lactococcus spp., which we demonstrate is a common dietary contaminant through the molecular testing of dietary ingredients, culturing, microscopy, and germ-free mouse experiments. After in silico removal of Lactococcus spp., we employed machine learning to define a unique operational taxonomic unit (OTU)-based signature capable of predicting the dietary intake of mice and demonstrate that phylogenetic and gene-family transformations of this model are capable of accurately predicting human samples in controlled feeding settings (area under the receiver operator curve = 0.75 and 0.88 respectively). Together, these results demonstrate the utility of microbiome meta-analyses in identifying robust bacterial signals for mechanistic studies and creates a framework for the routine meta-analysis of microbiome studies in preclinical models.
Epistasis Detection using Model Based Multifactor Dimensionality Reduction in Structured Populations
Authors: Abegaz Fentaw , Van Lishout François , Mahachie John Jestinah M , Chiachoompu Kridsadakorn , Bhardwaj Archana , Gusareva Elena S. , Wei Zhi , Hakonarson Hakon , Van Steen Kristel
Published: February 2019

In genome-wide association studies, the extent and impact of confounding due population structure have been well recognized. Inadequate handling of such confounding is likely to lead to spurious associations, hampering replication and the identification of causal variants. Several strategies have been developed for protecting associations against confounding, the most popular one is based on Principal Component Analysis. In contrast, the extent and impact of confounding due to population structure in gene-gene interaction association epistasis studies are much less investigated and understood. In particular, the role of non-linear genetic population substructure in epistasis detection is largely under-investigated, especially outside a regression framework. In order to identify causal variants in synergy, to improve interpretability and replicability of epistasis results, we introduce three strategies based on model-based multifactor dimensionality reduction (MB-MDR) approach for structured populations. We demonstrate through extensive simulation studies the effect of various degrees of genetic population structure and relatedness on epistasis detection and propose appropriate remedial measures based on linear and non-linear sample genetic similarity.

Authors Summary

One of the biggest challenges in human genetics is to understand the genetic basis of complex diseases such as cancer, diabetes, heart disease, depression, asthma, inflammatory bowel disease and hypertension, for instance via identifying genes, gene-gene and gene-environment interactions in association studies. Over the years, a more prominent role has been given to gene-gene interaction (epistasis) detection, in view of precision medicine and the hunt for novel drug targets and biomarkers. However, the increasing number of consortium-based epistasis studies that are marked by heterogeneous sample collections due to population structure or shared genetic ancestry are likely to be prone to spurious association and low power detection of associated or causal genes. In this work we introduced various strategies in epistasis studies with correction for confounding due to population structure. Based on extensive simulation studies we demonstrated the effect of genetic population structure on epistasis detection and investigated remedial measures to confounding by linear and nonlinear sample genetic similarity.
RAB1B interacts with TRAF3 to promote antiviral innate immunity
Authors: Beachboard Dia C. , Park Moonhee , Vijayan Madhuvanthi , Fernando Dillon J. , Williams Graham D. , Horner Stacy M.
Published: February 2019

Nucleic acid-based antiviral innate immunity activates a signaling cascade that induces type I and type III interferons (IFNs), and other cytokines. This signaling, which is highly regulated, is initiated by pattern recognition receptors, such as RIG-I, that sense viral RNA and then signal to the adaptor protein, MAVS. This adaptor protein then recruits additional signaling proteins, including TRAF3 and TBK1, to form a signaling complex that results in IRF3 activation for transcriptional induction of IFN. Here, we show that the GTPase trafficking protein RAB1B positively regulates RIG-I signaling to promote IFN-β induction and the antiviral response. Over-expression of RAB1B increases RIG-I-mediated signaling to IFN-β, while deletion results in reduced signaling of this pathway. Additionally, this loss of RAB1B results in a dampened antiviral response, as Zika virus infection is enhanced in the absence of RAB1B. Importantly, we identified the mechanism of RAB1B action by determining that it interacts with TRAF3 to facilitate the interaction of TRAF3 with MAVS. Thus, we identified RAB1B as a regulator of TRAF3 to promote the formation of innate immune signaling complexes in response to nucleic acid sensing.
A primer genetic toolkit for exploring mitochondrial biology and disease using zebrafish
Authors: Sabharwal Ankit , Campbell Jarryd M. , WareJoncas Zachary , Wishman Mark , Ata Hirotaka , Liu Wiebin , Ichino Noriko , Bergren Jake D. , Urban Mark D. , Urban Rhianna , Poshusta Tanya L. , Ding Yonghe , Xu Xiaolei , Clark Karl J. , Ekker Stephen C.
Published: February 2019

Mitochondria are a dynamic eukaryotic innovation that play diverse roles in biology and disease. The mitochondrial genome is remarkably conserved in all vertebrates, encoding the same 37 gene set and overall genomic structure ranging from 16,596 base pairs (bp) in the teleost zebrafish (Danio rerio) to 16,569 bp in humans. Mitochondrial disorders are amongst the most prevalent inherited diseases affecting roughly 1 in every 5000 individuals. Currently, few effective treatments exist for those with mitochondrial ailments, representing a major unmet patient need. Mitochondrial dysfunction is also implicated to be a common component of a wide variety of other human illnesses ranging from neurodegenerative disorders like Huntington’s disease and Parkinson’s disease to autoimmune illnesses such as multiple sclerosis and rheumatoid arthritis. The electron transport chain (ETC) component of mitochondria is critical for mitochondrial biology and defects can lead to many mitochondrial disease symptoms. Here we present a publicly available collection of genetic mutants created in highly conserved, nuclear-encoded mitochondrial genes inDanio rerio. The zebrafish system represents a potentially powerful new opportunity for the study of mitochondrial biology and disease due to the large number of orthologous genes shared with humans and the many advanced features of this model system from genetics to imaging. This collection includes 22 mutant lines in 18 different genes created by locus-specific gene editing to induce frameshift or splice acceptor mutations leading to predicted protein truncation during translation. Also included are 6 lines created by the random insertion of the gene-breaking transposon (GBT) protein trap cassette. All of these targeted mutant alleles truncate conserved domains of genes critical to the proper function of the ETC or genes that have been implicated in human mitochondrial disease. This collection is designed to accelerate the use of zebrafish to study of many different aspects of mitochondrial function with the goal of widening our understanding of their role in biology and human disease.
The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.
Authors: Shallcross John , Hamor Peter , Bechard Allison , Romano Madison , Knackstedt Lori , Schwendt Marek
Published: February 2019

Post-traumatic stress disorder (PTSD) is a disorder with no clear FDA-approved treatments that reduce symptoms in the majority of patients. PTSD individuals possess an impaired capacity for extinguishing fear memory associations. As such, considerable focus has been given to the development of extinction-enhancing pharmacological agents to be used in combination with PTSD treatments. Here we use a predator-threat animal model of PTSD to test the ability of two compounds to enhance contextual fear extinction and reduce anxiety. Mirroring the heterogeneity observed in human response to trauma, an exposure to predator threat, including the fox odor TMT, have been shown to induce long-term changes in anxiety behavior in only subsets of susceptible rats. Here, two weeks following a ten-minute exposure to a predator odor, rats were classified into stress-Susceptible (Sus) and stress-Resilient (Res) phenotypes using cut-off behavioral criteria for elevated plus maze and acoustic startle response performance. One week following classification, Sus rats underwent three days of context fear extinction. We found that Sus rats increased freezing from day one to day two. Treatment with the mGlu5 positive allosteric modulator CDPPB, but not the phytocannabinoid cannabidiol (CBD), prior to sessions resulted in reduced freezing. CDPPB administration resulted in an increase of Fos immunoreactive cells in the medial prefrontal cortex, indicative of increased neuronal activity. Finally, we used the light-dark box test to measure phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety two weeks after classification. We found that Res rats showed less anxiety compared to Sus rats, and that CBD, but not CDPPB, administered prior to testing was anxiolytic in Sus rats. Taken together, the present data indicate that mGlu5 PAMs such as CDPPB hold promise for treating human PTSD patients as they enhance extinction of fear without increasing general anxiety. Polytherapy with medications such as CBD may be necessary in order to attenuate general anxiety and future directions will explore this hypothesis.
Electrical coupling controls dimensionality and chaotic firing of inferior olive neurons
Authors: Hoang Huu , Lang Eric J. , Hirata Yoshito , Tokuda Isao T. , Aihara Kazuyuki , Toyama Keisuke , Kawato Mitsuo , Schweighofer Nicolas
Published: February 2019

One of the main challenges facing online neural learning systems with numerous modifiable parameters (or “degrees-of-freedom”) such as the cerebellum, is how to avoid “overfitting”. We previously proposed that the cerebellum controls the degree-of-freedoms during learning by gradually modulating the electric coupling strength between inferior olive neurons. Here, we develop a modeling technique to estimate effective coupling strengths between inferior olive neurons from in vivo recordings of Purkinje cell complex spike activity in three different coupling conditions. We show that high coupling strengths induce synchronous firing and decrease the dimensionality of inferior olive firing dynamics. In contrast, intermediate coupling strengths induce chaotic firing and increase the dimensionality of firing dynamics. Our results thus support the hypothesis that effective coupling controls the dimensionality of inferior olive firing, which may allow the olivocerebellar system to learn effectively from a small training sample set despite the low firing frequency of inferior olive neurons.
Structures of the Otopetrin Proton Channels Otop1 and Otop3
Authors: Saotome Kei , Teng Bochuan , Tsui Che Chun (Alex) , Lee Wen-Hsin , Tu Yu-Hsiang , Sansom Mark S. P. , Liman Emily R. , Ward Andrew B.
Published: February 2019

Otopetrins (Otop1-Otop3) comprise one of only two known eukaryotic proton-selective channel families. Otop1 is required for formation of otoconia and is a candidate mammalian sour taste receptor. Here, we report cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture of Otopetrins with each subunit consisting of twelve transmembrane helices divided into structurally related N and C domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a cavernous central tunnel. Two hydrophilic vestibules, as well as the intrasubunit interface between N and C domains, form conduits for water entry into the membrane plane in molecular dynamics simulations, suggesting they each could provide pathways for proton conduction. We also demonstrate the functional relevance of a salt bridge in the C domain vestibule by mutagenesis. Our results provide a structural basis for understanding the function of the Otopetrin proton channel family.
Proximity labeling reveals novel interactomes in live Drosophila tissue
Authors: Mannix Katelynn M , Starble Rebecca M. , Kaufman Ronit S. , Cooley Lynn
Published: February 2019

Gametogenesis is dependent on intercellular communication facilitated by stable intercellular bridges connecting developing germ cells. During Drosophila oogenesis, intercellular bridges (referred to as ring canals) have a dynamic actin cytoskeleton that drives their expansion to a diameter of 10μm. While multiple proteins have been identified as components of ring canals (RCs), we lack a basic understanding of how RC proteins interact together to form and regulate the RC cytoskeleton. We optimized a procedure for proximity-dependent biotinylation in live tissue using the APEX enzyme to interrogate the RC interactome. APEX was fused to four different RC components (RC-APEX baits) and 55 unique high-confidence preys were identified. The RC-APEX baits produced almost entirely distinct interactomes that included both known RC proteins as well as uncharacterized proteins. The proximity ligation assay was used to validate close-proximity interactions between the RC-APEX baits and their respective preys. Further, an RNAi screen revealed functional roles for several high-confidence prey genes in RC biology. These findings highlight the utility of enzyme-catalyzed proximity labeling for protein interactome analysis in live tissue and expand our understanding of RC biology.
Generation of ultrashort coherent radiation based on a laser plasma accelerator
Authors: Liu Tao , Feng Chao , Xiang Dao , Liu Jiansheng , Wang Dong
Published: February 2019

A laser plasma accelerator (LPA) has the potential to realize compact free-electron laser (FEL) radiation at the regular laboratory scale. However, large initial angular divergence and energy spread dramatically hinder ways to transport the beam and realize FEL radiation. Although methods have been proposed to solve these problems, the relatively large jitter, including transverse position jitter and energy jitter, still limits the advance of these experiments. In this paper a simple method to realize coherent harmonic generation based on a LPA beam is proposed. The scheme is very compact, adopting a high-power laser split from the driver laser, a short modulator and a short radiator which has a great tolerance to these typical types of jitter. Numerical simulations indicate that coherent third-harmonic radiation with gigawatt-level power and single spike spectra can be obtained, verifying the feasibility of the scheme and indicating the capability to generate ultrashort fully coherent radiation.
The school-to-work transition, overeducation and wages of youth in Kyrgyzstan
Authors: Karymshakov Kamalbek , Sulaimanova Burulcha
Published: February 2019

Purpose

The purpose of this paper is twofold: first, it analyses the relationship between educational level, the school-to-work transition period for youth and positions which suffer from an education-job mismatch in Kyrgyzstan; and second, it investigates the effect of the education-job mismatch on the wages of youth in Kyrgyzstan.

Design/methodology/approach

The study uses the International Labor Organization 2013 data from the school-to-work transition survey for Kyrgyzstan. The Kaplan–Meier failure analysis is employed to demonstrate the relationship between school-to-work transition and mismatch status. To investigate the effect of an education-job mismatch on wages, a Mincer-type equation with OLS estimations is used. Along with this, taking into consideration potential unobserved heterogeneity issue, a propensity score matching method is applied.

Findings

The results indicate a large difference between those with tertiary education and those with non-tertiary education in terms of the probability of being employed with a wrong match. Young individuals without tertiary education are more likely to be employed with a right match. Analysis of the impact of overeducation on wages shows that the impact of overeducation depends on how it is measured. According to the objective approach, overeducated male individuals receive low wages compared to well matched, but estimation results based on the total sample of subjective approach indicate the positive effects of overeducation on wage.

Originality/value

This paper contributes to the existing literature on the school-to-work transition and overeducation by focusing on one of the transition economies, which has been largely neglected by the literature.
Organizational justice, conflict management and employee relations
Authors: Sahoo Rojalin , Sahoo Chandan Kumar
Published: February 2019

Purpose

The purpose of this paper is to examine the impact of organizational justice and conflict management on employee relations (ER) through the mediating role of climate of trust.

Design/methodology/approach

This study was conducted with a sample of 331 employees working in a power transmission unit of Odisha. Data were collected by administering a structured questionnaire and analyzed using structural equation modeling (AMOS 20).

Findings

The results reveal that climate of trust plays the role of a partial mediator between organizational justice and ER and conflict management and ER. Also, it was found that organizational justice, conflict management and climate of trust are the positive and significant predictors of ER.

Research limitations/implications

The study was confined to a single state-owned power transmission unit of an Indian state, which restricts its generalizability. The research would benefit from exploration in alternative units.

Practical implications

This scholarly work may encourage managers and decision makers to develop trust building climate by focusing on organizational justice and conflict management to flourish an environment of harmonious ER, furthermore to formulate effective strategies for cultivating facilitative work environment to enhance positive attitude among the employees to challenge future goals.

Originality/value

The research is exclusive in determining the influence of organizational justice and conflict management on ER through the mediator of climate of trust in the new perspective of the power sector that provides empirical evidence to the extant literature.
Co-movement dynamics between global sukuk and bond markets
Authors: Bhuiyan Rubaiyat Ahsan , Rahman Maya Puspa , Saiti Buerhan , Mat Ghani Gairuzazmi
Published: February 2019

Purpose

Market links (and price discovery) between financial assets and lead–lag relationships are topics of interest for financial economists, financial managers and analysts. The lead–lag relationship analysis should consider both short and long-term investors. From a portfolio diversification perspective, the first type of investor is generally more interested in determining the co-movement of financial assets at higher frequencies, which are short-run fluctuations, while the latter concentrates on the relationship at lower frequencies, or long-run fluctuations. The paper aims to discuss these issues.

Design/methodology/approach

For this study, a technique was employed known as the wavelet approach, which has recently been imported to finance from engineering sciences to study the co-movement dynamics between global sukuk and bond markets. Data cover the period from January 2010 to December 2015.

Findings

The results indicate that: there is no unidirectional causality from developed market bond indices to Malaysia and Dow Jones indices, which is promising for fixed-income investors of a developed market; and in relation to emerging markets, the Malaysian sukuk market has a bidirectional causality with Indonesia, Malaysia, India and South Korea bond indices but not China bond indices, while in terms of the Dow Jones sukuk index, there is no unidirectional causality between the listed emerging markets and the sukuk index except Indonesia’s market during the sample period.

Research limitations/implications

This analysis provides evidence regarding the timely and appropriate measure of correlation changes and the behaviour of sukuk and bond indices globally, which is beneficial to the management of sukuk and bond portfolios.

Originality/value

The evidence hitherto unexplored, which was produced by the application of a wavelet cross-correlation amongst the selected sukuk and bond indices, provides robust and useful information for international financial analysts as well as long and short-term investors.
Quality management vision of future early career operations managers
Authors: Shokri Alireza , Nabhani Farhad
Published: February 2019

Purpose

The purpose of this paper is to investigate the gap between the current vision and knowledge of future early career operations managers (OM) and a common strategic total quality management (TQM) framework.

Design/methodology/approach

A survey questionnaire and a non-parametric test for different groups of participants were adopted to identify the gap and analyse the significance of these groups on the factors in the TQM framework.

Findings

A new set of TQM factors with the necessity of more knowledge and understanding of future generation were identified, followed by the identification of clear differences amongst different groups of this generation.

Practical implications

A sustainable OM practice needs managers and leaders with a sustainable knowledge development of quality management (QM); and as the result of this study, the current vision of future young OM would not echo this.

Originality/value

This study has a systematic, non-parametric approach towards currently fragmented QM analysis, and is integrated with human resource and visionary elements of future young OM and universal QM models and theories.
Stochastic modelling and availability analysis of a critical engineering system
Authors: Gupta Sorabh
Published: February 2019

Purpose

The purpose of this paper is to present the technique for evaluating the performance of a condensate system of a coal-based thermal power plant situated in the northern part of India. The data which used for system availability evaluation are not precise and are uncertain and, further, collected from concerned power plant history sheets and from discussion through plant personnel.

Design/methodology/approach

In the proposed model, traditional Markov birth-death process using a probabilistic approach is used to analyze the performance of a complex repairable condensate system of power plant up to a desired degree of accuracy. This approach has been demonstrated by breaking the condensate system into six subsystems arranged in series with two feasible states, namely, working and failed, labeled in a transition diagram and modeled as a Markov process, using Chapman–Kolmogorov equations, which are used for development of a probabilistic stochastic model for availability analysis in a more effecting manner, considering some suitable assumptions.

Findings

This study of analysis of reliability and availability can help in increasing the plant production and performance. The analysis is done with the help of availability matrices, which are developed using different combinations of failures and repair rates of all subsystems. To achieve the goal of maximum power generation, it is required to run the various subsystem of the concerned system of plant, failure free for a long duration. Therefore, the present approach may be a more powerful analysis tool to access the performance of all subsystems of a condensate system in terms of availability level achieved in availability matrices. The results of present study are found to be highly beneficial to the plant management for making maintenance decisions.

Originality/value

The present paper suggests a suitable technique for stochastic modeling and availability evaluation of an industrial system using Markovian approach and drawing a transition diagram to represent the operational behavior of the system. The present methodology includes the advantage of the ability to model and develop a more complex industrial system and helps in improving the performance and handling the uncertainties and possibilities of an industrial system.
Signature reliability of binary state node in complex bridge networks using universal generating function
Authors: Bisht Soni , Singh S.B.
Published: February 2019

Purpose

The purpose of this paper is to evaluate various reliability measures like reliability, expected lifetime (mean time to failure), signature reliability and compare networks based on the different flows.

Design/methodology/approach

The reliability characteristics of complex bridge networks have been evaluated using different algorithms with the help of universal generating function (UGF). Further, the signature reliability of the considered networks has been determined using Owen’s method.

Findings

The present paper proposes an efficient algorithm to compute the reliability indices of complex bridge networks having i.i.d. lifetime components (nodes, edges) with the help of UGF and Owen’s method. This study reveals that a slight change in the complex bridge network affects the reliability significantly. Finally, by the reliability structure function, proposed algorithms are used to find the signature and MTTF. From signature, we have determined the different failure probabilities corresponding to edges of the network.

Originality/value

In this work, we have evaluated reliability characteristics and signature reliability of the complex bridge networks using UGF method and Owen’s method respectively unlike done in the past.