bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Genome Size and Metabolic Rate in Extant Vertebrates
Authors: Gardner Jacob D. , Laurin Michel , Organ Chris L.
Published: July 2019

Genome size has long been hypothesized to affect metabolic rate in various groups of animals. The mechanism behind this proposed association is the nucleotypic effect, in which large nucleus and cell sizes influence cellular metabolism through surface area-to-volume ratios. Here, we provide a review of the recent literature on the relationship between genome size and metabolic rate. We also conduct an analysis using phylogenetic comparative methods and a large sample of extant vertebrates. We find no evidence that the effect of genome size improves upon models in explaining metabolic rate variation. Not surprisingly, our results show a strong positive relationship between metabolic rate and body mass, as well as a substantial difference in metabolic rate between endothermic and ectothermic vertebrates, controlling for body mass. The presence of endothermy can also explain elevated rate shifts in metabolic rate whereas genome size cannot. We further find no evidence for a punctuated model of evolution for metabolic rate. Our results do not rule out the possibility that genome size affects cellular physiology in some tissues, but they are consistent with previous research suggesting little support for a direct functional connection between genome size and basal metabolic rate in extant vertebrates.
A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs
Authors: Baumann Sebastian , Komissarov Artem , Gili Maria , Ruprecht Verena , Wieser Stefan , Maurer Sebastian P.
Published: July 2019

Through the asymmetric distribution of mRNAs cells spatially regulate gene expression to create cyto-plasmic domains with specialized functions. In mammalian neurons, mRNA localization is required for essential processes as cell polarization, migration and synaptic plasticity underlying long-term memory formation. The essential components driving cytoplasmic mRNA transport in neurons and mammalian cells are not known. Here, we report the first reconstitution of a mammalian mRNA transport system revealing that the tumour suppressor adenomatous polyposis coli (APC) forms stable complexes with the axonally localised β-actin and β2B-tubulin mRNAs which are linked to a heterotrimeric kinesin-2 via the cargo adaptor KAP3. APC activates kinesin-2 and both proteins are sufficient to drive specific transport of defined mRNA packages. Guanine-rich sequences located in 3’UTRs of axonal mRNAs increase transport efficiency and balance the access of different mRNAs to the transport system. Our findings reveal for the first time a minimal set of proteins capable of driving kinesin-based, mammalian mRNA transport.
Elucidating the Molecular Basis of pH Activation of an Engineered Mechanosensitive Channel
Authors: Immadisetty Kalyan , Polasa Adithya , Shelton Reid , Moradi Mahmoud
Published: July 2019

Mechanosensitive (MS) channels detect and respond to changes in the pressure profile of cellular membranes and transduce the mechanical energy into electrical and/or chemical signals. However, by re-engineering the MS channels, chemical signals such as pH change can trigger the activation of some MS channels. This paper elucidate the activation mechanism of an engineered MS channel of large conductance (MscL) at an atomic level through a combination of equilibrium, non-equilibrium, biased, and unbiased molecular dynamics (MD) simulations for the first time. Comparing the wild-type and engineered MscL activation processes at an atomic level suggests that the two systems are likely to be associated with different active states and different transition pathways. These findings indicate that (1) periplasmic loops play a key role in the activation process of MscL, (2) the loss of various hydrogen bonds and salt bridge interactions in the engineered MscL channel causes the spontaneous opening of the channel, and (3) the most significant interactions lost during the activation process are those between the transmembrane (TM) helices 1 and 2 (TM1 and TM2) in engineered MscL channel. In this research, the orientation-based biasing approach for producing and optimizing an open MscL model is a promising way to characterize unknown protein functional states and to research the activation processes in ion channels. String method with swarms of trajectories (SMwST) was used to identify the optimal transition pathway and elucidate the activation mechanism of the engineered MscL. Finally, the free energy profile of engineered MscL associated with the activation process using a novel along-the-path free energy calculation approach is constructed. This work paves the way for a computational framework for the studies aimed at designing pH-triggered channel-functionalized drug delivery liposomes.
Quantifying posterior effect size distribution of susceptibility loci by common summary statistics
Authors: Vsevolozhskaya Olga A. , Zaykin Dmitri V.
Published: July 2019

Testing millions of SNPs in genetic association studies has become standard routine for disease gene discovery, followed by prioritization of the strongest signals based on the set of the smallest P-values. In light of recent re-evaluation of statistical practice, it has been suggested that P-values are unfit as summaries of statistical evidence. Despite this criticism, P-values are commonly used and are unlikely to be abandoned by practitioners. Moreover, P-values contain information that can be utilized to address the concerns about their flaws and misuse. We present a new method for utilizing evidence summarized by P-values for estimating odds ratio (OR) based on its approximate posterior distribution. In our method, only P-value, sample size, and standard deviation for log(OR) are needed as summaries of data, accompanied by a suitable prior distribution for log(OR) that can assume any shape. The parameter of interest, log(OR), is the only parameter with a specified prior distribution, hence our model is a mix of classical and Bayesian approaches. We show that our “Mix Bayes” (MB) method retains the main advantages of the Bayesian approach: it yields direct probability statements about hypotheses for OR and is resistant to biases caused by selection of top-scoring SNPs. MB enjoys greater flexibility than similarly inspired methods in the assumed distribution for the summary statistic and in the form of the prior for the parameter of interest. We illustrate our method by presenting interval estimates of effect size for reported genetic associations with lung cancer. Although we focus on OR, our method is not limited to this particular measure of effect size and can be used broadly for assessing reliability of findings in studies testing multiple predictors.
Evolutionary Analyses of RNA Editing and Amino Acid Recoding in Cephalopods
Authors: Wang Mingye (Christina) , Mohlhenrich Erik
Published: July 2019

RNA editing is a post-transcriptional modification process that alters nucleotides of mRNA and consequently the amino acids of the translated protein without changing the original DNA sequence. In human and other mammals, amino acid recoding from RNA editing is rare, and most edits are non-adaptive and provide no fitness advantage (1). However, recently it was discovered that in soft-bodied cephalopods, which are exceptionally intelligent and include squid, octopus, and cuttlefish, RNA editing is widespread and positively selected (2). To examine the effects of RNA editing on individual genes, we developed a “diversity score” system that quantitatively assesses the amount of diversity generated in each gene, incorporating combinatorial diversity and the radicalness of amino acid changes. Using this metric, we compiled a list of top 100 genes across the cephalopod species that are most diversified by RNA editing. This list of candidate genes provides directions for future research into the specific functional impact of RNA editing in terms of protein structure and cellular function on individual proteins. Additionally, considering the connection of RNA editing to the nervous system, and the exceptional intelligence of cephalopod, the candidate genes may shed light to the molecular development of behavioral complexity and intelligence. To further investigate global influences of RNA editing on the transcriptome, we investigated changes in nucleotide composition and codon usage biases in edited genes and coleoid transcriptome in general. Results show that these features indeed correlate with editing and may correspond to causes or effects of RNA editing. In addition, we characterized the unusual RNA editing in cephalopods by analyzing ratio of radical to conservative amino acid substitutions (R/C) and distribution of amino acid recoding from editing. Our results show that compared to model organisms, editing in cephalopods have significantly decreased R/C ratio and distinct distribution of amino acid substitutions that favor conservative over radical changes, indicating selection at the amino acid level and providing a potential mechanism for the evolution of widespread RNA editing in cephalopods.
Attenuation of Motion Artifacts in fMRI using Discrete Reconstruction of Irregular fMRI Trajectories (DRIFT)
Authors: Parker David , Razlighi Qolamreza
Published: July 2019

Numerous studies reported motion as the most detrimental source of noise and artifacts in functional magnetic resonance imaging (fMRI). Different approaches have been proposed and used to attenuate the effect of motion on fMRI data, including both prospective and retrospective (post-processing) techniques. However, each type of motion (e.g. translation versus rotation or in-plane versus out-of-plane) has a distinct effect on the MR signal, which is not fully understood nor appropriately modeled in the field. In addition, effects of the same motion can be substantially different depending on when it occurs during the pulse sequence (e.g. RF excitation, gradient encoding, or k-space read-out). Thus, each distinct kind of motion and the time of its occurrence may require a unique approach to be optimally corrected. Therefore, we start with an investigation of the effects of different motions on the MR signal based on the Bloch equation. We then simulate their unique effects with a comprehensive fMRI simulator. Our results indicate that current motion correction methods fail to completely address the motion problem. Retrospective techniques such as spatial realignment can correct for between-volume misalignment, but fail to address within volume contamination and spin-history artifacts. Because of the steady state nature of the fMRI acquisition, spin-history artifacts arising from over/under excitation during slice-selection causes the motion artifacts to contaminate MR signal even after cessation of motion, which makes it challenging to be corrected retrospectively. Prospective motion correction has been proposed to prevent spin-history artifacts, but fails to address motion artifacts during k-space readout. In this article, we propose a novel method to remove these artifacts: Discrete reconstruction of irregular fMRI trajectory (DRIFT). Our method calculates the exact displacement of k-space recording due to motion at each dwell time and retrospectively corrects each slice of the fMRI volume using an inverse nonuniform Fourier transform. We evaluate our proposed methods using simulated data as well as fMRI data collected from a rotating phantom inside a 3T Siemens Prisma scanner. We conclude that a hybrid approach with both prospective and retrospective components are essentially required for optimal removal of motion artifacts from the fMRI data.
Functional divergence of two duplicatedFertilization Independent Endospermgenes in rice with respect to seed development
Authors: Pan Meiyao , Cheng Xiaojun , Zhiguo E , Niu Baixiao , Chen Chen
Published: July 2019

Fertilization Independent Endosperm (FIE) is an essential member of Polycomb Repression Complex 2 (PRC2) that plays important roles in the developmental regulation of plants.OsFIE1andOsFIE2are twoFIEhomologs in the rice genome. Here, we showed thatOsFIE1probably duplicated fromOsFIE2after the origin of the tribe Oryzeae, but has a specific expression pattern and methylation landscape. During evolution,OsFIE1underwent a less intensive purifying selection than didOsFIE2. The mutantosfie1produced smaller seeds and displayed reduced dormancy, indicating thatOsFIE1predominantly functions in late seed development. Ectopic expression ofOsFIE1, but notOsFIE2, was deleterious to vegetative growth in a dosage-dependent manner. The newly evolved N-terminal tail of OsFIE1 was probably not the cause of the adverse effects on vegetative growth. The CRISPR/Cas9-derived mutantosfie2exhibited impaired cellularization of the endosperm, which suggested thatOsFIE2is indispensable for early seed development as a positive regulator of cellularization. Autonomous endosperm was observed in bothOsFIE2+−andosfie1/OsFIE2+−but at a very low frequency. Although OsFIE1-PRC2 exhibited H3K27me3 methyltransferase ability in plants, OsFIE1-PRC2 is likely to be less important for development in rice than is OsFIE2-PRC2. Our findings revealed the functional divergence ofOsFIE1andOsFIE2and shed light on their distinct evolution following duplication.
Retroconversion of estrogens into androgens by bacteriaviaa cobalamin-mediated methylation
Authors: Wang Po-Hsiang , Chen Yi-Lung , Wei Sean Ting-Shyang , Wu Kan , Lee Tzong-Huei , Wu Tien-Yu , Chiang Yin-Ru
Published: July 2019

Steroid estrogens modulate physiology and development of vertebrates. Biosynthesis of C18estrogens from C19androgens by the O2-dependent aromatase is thought to be irreversible. Here, we report a denitrifyingDenitratisomasp. strain DHT3 capable of catabolizing estrogens or androgens anaerobically. Strain DHT3 genome contains a polycistronic gene clusteremtABCDdifferentially transcribed under estrogen-fed conditions.emtABCDencodes a cobalamin-dependent methyltransferase system conserved among estrogen-utilizing anaerobes;emtA-disrupted strain DHT3 can catabolize androgens but not estrogens. These data, along with the observed androgen production in estrogen-fed strain DHT3 cultures, indicate the occurrence of a cobalamin-mediated estrogen methylation to form androgens. Consistently, the estrogen conversion into androgens in strain DHT3 cell-extracts requires methylcobalamin and is inhibited by propyl-iodide, a specific inhibitor of cobalamin-dependent enzymes. The identification of the cobalamin-mediated estrogen methylation thus represents an unprecedented metabolic link between cobalamin and steroid metabolism and suggests that retroconversion of estrogens into androgens occurs in the biosphere.
Mutational Crosstalk between Nuclear Driver Genes and Mitochondrial DNA in Gingivobuccal Oral Cancer
Authors: Palodhi Arindam , Sarkar Soumi , Maitra Arindam
Published: July 2019

Somatic alterations in nuclear and mitochondrial genomes are known to play important role in the initiation and progress of tumours. However, crosstalk between these two genomic components in tumours have not been well investigated till date. We have excavated evidence of such crosstalk in gingivobuccal oral cancer. We have identified significant correlation between somatic mutations in nuclear driver genes and mitochondrial genes in 89 gingivobuccal oral cancer patients. Strong positive correlation between nuclear driver genes CASP8, NOTCH1, USP9X, TRPM3 and mitochondrial genes has been observed. Patients having mutations in nuclear driver genes except TP53, were also shown to harbour higher mitochondrial mutation load. TP53 mutations were shown to be negatively correlated with somatic mutations in mitochondrial 12S rRNA and ATP6. Also, TP53 mutations were negatively correlated with mutations in NOTCH1, HRAS and USP9X. We have identified a number of nuclear genes coexpressed with mitochondrial genes, although their association with tumorigenesis could not be established. Our observations suggest that in the absence of mutations in TP53, mutations in mtDNA and other driver genes might aid in the progression of cancer in a complementary fashion.
Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation-induced anticipatory fear in a rat model
Authors: Tan Shawn Zheng Kai , Temel Yasin , Chan Ariel Yovela , Mok Andrea Tsz Ching , Perucho Jose Angelo Udal , Blokland Arjan , Acquili Luca , Lim Wei Ling , Lim Lee Wei
Published: July 2019

Background

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful tool for modelling anticipatory fear and agoraphobia.

Methods

In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then used tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons.

Results

Although acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, chronic administrations of both drugs were comparably effective. We found that the number of dopaminergic neurons in the ventral tegmental area (VTA) was lowered in both chronic buspirone and escitalopram groups. We showed a strong correlation between the number of dopaminergic neurons and freezing in the VTA. We further showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta in escitalopram and buspirone groups, respectively.

Limitations

Although our data strongly hint to a role of dopaminergic mechanisms in the dlPAG induced fear response, more in-depth studies with larger sample sizes are needed to understand the neuronal mechanisms underlying the interactions between serotonergic drugs and dopaminergic cell number and fear behavior.

Conclusion

Chronic treatment with an SSRI and a 5-HT1A agonist decrease the number of dopaminergic neurons in the VTA. These effects seem to be associated with reduced dlPAG-induced anticipatory freezing behaviour.

Key Points

Chronic treatment of escitalopram and buspirone was effective in reducing dlPAG induced anticipatory freezing behaviour.

The number of dopaminergic neurons in the ventral tegmental area (VTA) was lowered in both chronic buspirone and escitalopram groups and was correlated to freezing.

We found positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta in escitalopram and buspirone groups, respectively.
Mathematical modeling of the role of α-synuclein and dopamine in cell death in Parkinson’s disease provides the molecular basis to the toxicity of different point mutations
Authors: Saxena Gourvendu , Khandelwal Utkarsh , Doble Mukesh
Published: July 2019

Different types of α-synuclein and non-β-amyloid component (NAC) peptides have been shown to induce cell death, with varying degree of toxicity, in various in vitro experiments. Oxidative stress has also been associated and proved to be involved in the pathogenesis of neuronal cell death in Parkinson’s disease. Oxidative stress has been shown to accelerate the aggregation of α-synuclein in vitro and in resent studies α-synuclein has been shown to increase oxidative stress. Thus it seems like a vicious cycle, one promoting the other.

In this present work we have modeled the α-synuclein pathway to increase cytoplasmic Dopamine concentration, and thereby increasing the Reactive Oxygen Species (ROS) level of the cell, which consequently results in cell death. This model relates the α-synuclein concentration with the fractional cell survival and provides insight of crucial reaction(s) of α-synuclein which promote cell death. It predicts the toxicity of the type of α-synuclein and also explains the pattern of cell death with increasing concentration of α-synuclein. First we modeled a part of the pathway i.e. from dopamine to cell death. The results were compared with experimental data available for PC12 neuronal cell line. Then modeling of full pathway was done and the results were compared with experimental data available for Human neuroblastoma SH-SY5Y cells. It is predicted from this model that higher the auto catalysis of dopamine, higher is the cell death. Interestingly, the model predicts that NAC (1-18) not only hinders the vesicles coming from Endoplasmic Reticulum, to fuse with Golgi bodies, but also reduces the synthesis of Dopamine and the formation of vesicles from Endoplasmic Reticulum. The model is generalized and can predict the toxicity of any protein which impedes the early secretary pathway in dopaminergic cells and also the cell survival pattern with increasing concentration of the protein.
MicroRNA clusters integrate evolutionary constraints on expression and target affinities: the miR-6/5/4/286/3/309 cluster in Drosophila leg development
Authors: Qu Zhe , Yiu Wing Chung , Yip Ho Yin , Nong Wenyan , Yu Clare W.C. , Lee Ivy H.T. , Wong Annette Y.P. , Wong Nicola W.Y. , Cheung Fiona K.M. , Chan Ting Fung , Lau Kwok Fai , Zhong Silin , Chu Ka Hou , Tobe Stephen S. , Ferrier David E.K. , Bendena William G. , Hui Jerome H.L.
Published: July 2019

A striking feature of microRNAs is that they are often clustered in the genomes of animals. The functional and evolutionary consequences of this clustering remain obscure. Here, we investigated a microRNA cluster miR-6/5/4/286/3/309 that is conserved across drosophilid lineages. Small RNA sequencing revealed expression of this microRNA cluster in Drosophila melanogaster leg discs, and conditional overexpression of the whole cluster resulted in leg appendage shortening. Transgenic overexpression lines expressing different combinations of microRNA cluster members were also constructed. Expression of individual microRNAs from the cluster resulted in a normal wild-type phenotype, but either the expression of several ancient microRNAs together (miR-5/4/286/3/309) or more recently evolved clustered microRNAs (miR-6-1/2/3) can recapitulate the phenotypes generated by the whole-cluster overexpression. Screening of transgenic fly lines revealed down-regulation of leg patterning gene cassettes in generation of the leg-shortening phenotype. Furthermore, cell transfection with different combinations of microRNA cluster members revealed a suite of downstream genes targeted by all cluster members, as well as complements of targets that are unique for distinct microRNAs. Considering together the microRNA targets and the evolutionary ages of each microRNA in the cluster demonstrates the importance of microRNA clustering, where new members can reinforce and modify the selection forces on both the cluster regulation and the gene regulatory network of existing microRNAs.
The impact of genistein supplementation on tendon functional properties and gene expression in estrogen deficient rats
Authors: Carroll Chad C. , Patel Shivam H. , Simmons Jessica , Gordon Ben DH. , Olson Jay F. , Chemelewski Kali , Saw Shannon , Hale Taben M. , Howden Reuben , Sabbaghi Arman
Published: July 2019

Purpose

Tendinopathy risk increases with menopause. The phytoestrogen genistein prevents collagen loss during estrogen deficiency [ovariectomy (OVX)]. The influence of genistein on tendon function and extracellular matrix (ECM) regulation are not well known. We determined the impact of genistein on tendon function and examined potential mechanisms by which genistein alters tendon ECM.

Materials and Methods

Eight-week-old rats (n=42) were divided into three groups: intact, OVX, or OVX-genistein (6mg/kg/day) for 6-weeks. Tail fascicles were assessed with a Deben tensile stage. Achilles tendon mRNA expression was determined with digital droplet PCR. Tendon-derived fibroblasts were also treated with genistein in the presence of estrogen receptor (ER) antagonists.

Results

Compared to intact, stress tended to be lower in untreated OVX rats (p=0.022). Further, modulus and energy density were greater in genistein-treated rats (p<0.05) compared to intact. Neither OVX nor genistein altered expression of Col1a1, Col3a1, Casp3, Casp8, Mmp1a, Mmp2, or Mmp9 (p>0.05). Compared to intact, Tnmd and Esr1 expression was greater and Pcna and Timp1 expression lower in OVX rats (p<0.05). Genistein treatment returned Tnmd, Pcna, and Timp1 to levels of Intact-Vehicle (p<0.05), but did not alter Scx or Esr1 (p>0.05). Several β-catenin/Wnt signaling related molecules were not altered by OVX or genistein (p>0.05).In vitro, genistein blunted cell proliferation but not via ERs.

Conclusions

Our findings demonstrate that genistein improves tendon function. Genistein inhibits cell proliferationin vitrobut not via ER. The effect of genisteinin vivowas predominately on genes related to cell proliferation rather than collagen remodeling.
Multifaceted adaptation of the neural decision process with prior knowledge of time constraints and stimulus probability
Authors: Kelly Simon P. , Corbett Elaine A. , O’Connell Redmond G.
Published: July 2019

When selecting actions in response to noisy sensory stimuli, the brain can exploit prior knowledge of time constraints, stimulus discriminability and stimulus probability to hone the decision process. Although behavioral models typically explain such effects through adjustments to decision criteria only, the full range of underlying neural process adjustments remains to be established. Here, we draw on human neurophysiological signals reflecting decision formation to construct and constrain a multi-tiered model of prior-informed motion discrimination, in which a motor-independent representation of cumulative evidence feeds build-to-threshold motor signals that receive additional dynamic urgency and bias signal components. The neurally-informed model not only provides a superior quantitative fit to prior-biased behavior across three distinct task regimes (easy, time-pressured and weak evidence), but also reveals adjustments to evidence accumulation rate, urgency rate, and the timing of accumulation onset and motor execution which go undetected or are discrepant in more standard diffusion-model analysis of behavior.
Alignment of LC-MS Profiles by Neighbor-wise Compound-specific Graphical Time Warping with Misalignment Detection
Authors: Wu Chiung-Ting , Herrington David M. , Wang Yizhi , Ebbels Timothy , Karaman Ibrahim , Wang Yue , Yu Guoqiang
Published: July 2019

Motivation

Liquid chromatography - mass spectrometry (LC-MS) is a standard method for proteomics and metabolomics analysis of biological samples. Unfortunately, it suffers from various changes in the retention times (RT) of the same compound in different samples, and these must be subsequently corrected (aligned) during data processing. Classic alignment methods such as in the popular XCMS package often assume a single time-warping function for each sample. Thus, the potentially varying RT drift for compounds with different masses in a sample is neglected in these methods. Moreover, the systematic change in RT drift across run order is often not considered by alignment algorithms. Therefore, these methods cannot completely correct misalignments. For a large-scale experiment involving many samples, the existence of misalignment becomes inevitable and concerning.

Results

Here we describe an integrated reference-free profile alignment method, neighbor-wise compound-specific Graphical Time Warping (ncGTW), that can detect misaligned features and align profiles by leveraging expected RT drift structures and compound-specific warping functions. Specifically, ncGTW uses individualized warping functions for different compounds and assigns constraint edges on warping functions of neighboring samples. Validated with both realistic synthetic data and internal quality control samples, ncGTW applied to two large-scale metabolomics LC-MS datasets identifies many misaligned features and successfully realigns them. These features would otherwise be discarded or uncorrected using existing methods. The ncGTW software tool is developed currently as a plug-in to the XCMS package.

Availability and Implementation

An R package of ncGTW is freely available at https://github.com/ChiungTingWu/ncGTW. A detailed user’s manual and a vignette are provided within the package.

Contact

yuewang@vt.edu, yug@vt.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
An actin nucleation complex catalyzes filament formation at sites of exocytosis
Authors: Glomb Oliver , Wu Yehui , Rieger Lucia , Rüthnick Diana , Mulaw Medhanie , Johnsson Nils
Published: July 2019

Due to the local enrichment of factors that influence its formation, dynamics, and organization, the actin cytoskeleton displays different shapes and functions within the same cell. In yeast cells post-Golgi vesicles ride on long actin cables to the bud tip. The scaffold proteins Boi1 and Boi2 participate in tethering and docking these vesicles to the plasma membrane. Here we show that Boi1/2 also recruit nucleation and elongation factors to form actin filaments at sites of exocytosis. Disrupting the physical connection between Boi1/2 and the nucleation factor Bud6 impairs filament formation in the bud, reduces the directed movement of the vesicles to the tip, and shortens their tethering time at the cortex. Artificially transplanting Boi1 from the bud tip to the peroxisomal membrane partially redirects the actin cytoskeleton and the vesicular flow towards the peroxisome, and creates an alternative, rudimentary vesicle-docking zone. We conclude that Boi1/2 is sufficient to induce the formation of a cortical actin structure that receives and aligns incoming vesicles before fusing with the membrane.
Gene discoveries in autism are biased towards comorbidity with intellectual disability
Authors: Jensen Matthew , Smolen Corrine , Girirajan Santhosh
Published: July 2019

Autism typically presents with a highly heterogeneous set of features, including frequent comorbidity with intellectual disability (ID). The overlap between these two phenotypes has confounded the accurate diagnosis and discovery of genetic factors associated with autism. We analyzed genetic variants in 2,290 individuals with autism from the Simons Simplex Collection (SSC) who have either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity. We found that individuals who carried variants in a set of 173 reported autism-associated genes showed decreased IQ (p=5.49×10−6) and increased autism severity (p=0.013) compared with individuals without such variants. A subset of autism-associated genes also showed strong evidence for ID comorbidity in published case reports. We also found that individuals with high-functioning autism (IQ>100) had lower frequencies of CNVs (p=0.065) and LGD variants (p=0.021) compared with individuals who manifested both autism and ID (IQ<70). These data indicated thatde novoLGD variants conferred a 1.53-fold higher risk (p=0.035) towards comorbid ID, while LGD mutations specifically disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID. Furthermore,de novoLGD variants in individuals with high-functioning autism were more likely to disrupt genes with little functional relevance towards neurodevelopment, as demonstrated by evidence from pathogenicity metrics, expression patterns in the developing brain, and mouse model phenotypes. Overall, our data suggest thatde novopathogenic variants disrupting genes associated with autism contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.
MRI Powered and Triggered Current Stimulator for Concurrent Stimulation and MRI
Authors: Mandal Ranajay , Babaria Nishant , Cao Jiayue , Lu Kun-Han , Liu Zhongming
Published: July 2019

Bioelectric stimulation during concurrent magnetic resonance imaging (MRI) is of interest to basic and translational studies. However, existing stimulation systems often interfere with MRI, are difficult to use or scale up, have limited efficacy, or cause safety concerns. To address these issues, we present a novel device capable of supplying current stimulation synchronized with MRI while being wirelessly powered by the MRI gradient fields. Results from testing it with phantoms and live animals in a 7 Tesla small-animal MRI system suggest that the device is able to harvest up to 72 (or 18) mW power during typical echo-planar imaging (or fast low angle shot imaging) and usable for stimulating peripheral muscle or nerve to modulate the brain or the gut, with minimal effects on MRI image quality. As a compact and standalone system, the plug-and-play device is suitable for animal research and merits further development for human applications.
Absolute measurement of the tissue origins of cell-free DNA in the healthy state and following paracetamol overdose
Authors: Laurent Danny , Semple Fiona , Starkey Lewis Philip J. , Rose Elaine , Black Holly A. , Forbes Stuart J. , Arends Mark J. , Dear James W. , Aitman Timothy J.
Published: July 2019

Background

Despite the emergence of cell-free DNA (cfDNA) as a clinical biomarker in cancer, the tissue origins of cfDNA in healthy individuals have to date been inferred only by indirect and relative measurement methods, such as tissue-specific methylation and nucleosomal profiling.

Methods

We performed the first direct, absolute measurement of the tissue origins of cfDNA, using tissue-specific knockout mouse strains, in both healthy mice and following paracetamol (APAP) overdose. We then investigated the utility of total cfDNA and the percentage of liver-specific cfDNA as clinical biomarkers in patients presenting with APAP overdose.

Results

Analysis of cfDNA from healthy tissue-specific knockout mice showed that cfDNA originates predominantly from white and red blood cell lineages, with minor contribution from hepatocytes, and no detectable contribution from skeletal and cardiac muscle. Following APAP overdose in mice, total plasma cfDNA and the percentage fraction originating from hepatocytes increased by ~100 and ~19-fold respectively. Total cfDNA increased by an average of more than 236-fold in clinical samples from APAP overdose patients with biochemical evidence of liver injury, and 18-fold in patients without biochemically apparent liver injury. Measurement of liver-specific cfDNA, using droplet digital PCR and methylation analysis, revealed that the contribution of liver to cfDNA was increased by an average of 175-fold in APAP overdose patients with biochemically apparent liver injury compared to healthy subjects, but was not increased in overdose patients with normal liver function tests.

Conclusions

We present a novel method for measurement of the tissue origins of cfDNA in healthy and disease states and demonstrate the potential of cfDNA as a clinical biomarker in APAP overdose.
The Anadromous Hickory Shad (Clupeiformes: Clupeidae, Alosa mediocris [Mitchill 1814]): Morphometric and Meristic Variation
Authors: Smith Jordan P. , Brewer Michael S. , Rulifson Roger A.
Published: July 2019

The anadromous Hickory Shad Alosa mediocris (Mitchill, 1814) (Clupeiformes: Clupeidae) is reviewed, specifically regarding morphometric and meristic variation. Despite its long history as recognized species, few descriptions of Hickory Shad morphometric and meristic characters exist in the literature. Most authors of the historic literature have failed to provide capture location for specimens, analyze large numbers of Hickory Shad, or document how morphometric and meristic characters of the species vary spatially. To address this information gap, a total of 717 mature Hickory Shad were collected from 23 different locations in Maryland, Delaware, Virginia, North Carolina, South Carolina, Georgia, and Florida using electroshocking, gill net, or rod and reel. All specimens were frozen, thawed, and 17 morphometric characters and four meristic characters were examined; a random subset (n = 463) were analyzed for an additional four meristic counts of gill rakers. Overall specimens ranged from 206-389 mm SL with a mean + SD of 278.41 + 27.69 mm, 232-435 mm FL with a mean of 310.98 + 30.35 mm, and 272-508 mm TL with a mean of 365.62 + 35.52 mm. The linear relationships between FL and TL, and FL and SL, were investigated and found to be: TL = 1.169*FL + 1.660 (n=705, r2=0.995) and SL = 0.909*FL - 4.274 (n=717, r2=0.992). Substantial differences in character means for many morphometric measurements were found between male and female specimens, suggesting strong sexual dimorphisms relating to shape. However, meristic characters did not show differences in character means by sex. No one morphometric measurement could distinguish Hickory Shad from other morphologically similar clupeids, but the meristic count of gill rakers on the lower limb of the first arch were important to separate Hickory Shad (19-22) from American Shad A. sapidissima (Wilson, 1811), Alewife A. pseudoharengus (Wilson, 1811), and Blueback Herring A. aestivalis (Mitchill, 1814).
BraggNet: integrating Bragg peaks using neural networks
Authors: Sullivan Brendan , Archibald Rick , Azadmanesh Jahaun , Vandavasi Venu Gopal , Langan Patricia S. , Coates Leighton , Lynch Vickie , Langan Paul
Published: July 2019

Neutron crystallography offers enormous potential to complement structures from X-ray crystallography by clarifying the positions of low-Z elements, namely hydrogen. Macromolecular neutron crystallography, however, remains limited, in part owing to the challenge of integrating peak shapes from pulsed-source experiments. To advance existing software, this article demonstrates the use of machine learning to refine peak locations, predict peak shapes and yield more accurate integrated intensities when applied to whole data sets from a protein crystal. The artificial neural network, based on the U-Net architecture commonly used for image segmentation, is trained using about 100 000 simulated training peaks derived from strong peaks. After 100 training epochs (a round of training over the whole data set broken into smaller batches), training converges and achieves a Dice coefficient of around 65%, in contrast to just 15% for negative control data sets. Integrating whole peak sets using the neural network yields improved intensity statistics compared with other integration methods, including k-nearest neighbours. These results demonstrate, for the first time, that neural networks can learn peak shapes and be used to integrate Bragg peaks. It is expected that integration using neural networks can be further developed to increase the quality of neutron, electron and X-ray crystallography data.
Improving the hot corrosion resistance of boiler tube steels by detonation gun sprayed coatings in actual boiler of thermal power plant
Authors: Singh Vikramjit , Goyal Khushdeep , Goyal Rakesh
Published: July 2019

Purpose

This paper aims to investigate the hot corrosion behavior of Ni-Cr and Cr3C2-NiCr coatings, deposited on T11, P91 boiler steels by detonation gun spray coating (D-Gun) process to enhance high temperature corrosion resistance.

Design/methodology/approach

Hot corrosion studies were conducted in secondary super heater zone of boiler at 900 °C for 10 cycles on bare and D-Gun coated steel specimens. The microhardness and porosity values of as-sprayed coatings were measured before exposing the specimens in the boiler environment. Each cycle consisted 100 h of heating in the boiler environment followed by 20 min of cooling in air. The weight change measurements were performed after each cycle to establish the kinetics of corrosion using thermogravimetric technique. X-ray diffraction, SEM techniques were used to analyze the corroded specimens.

Findings

Uncoated boiler steel experienced higher weight loss. The Cr3C2-NiCr coating was found to be more protective than Ni-Cr coating. The phases revealed the formation of oxide scale on coated specimens, mainly consist of nickel and chromium, which are reported to be protective against the hot corrosion.

Originality/value

There is very limited reported literature on hot corrosion behavior of Ni-Cr and Cr3C2-NiCr coatings deposited on the T11 and P91 substrates by detonation gun (D-gun) spray technique. T11 and P91 alloy steels have been chosen for this study because these two alloys are used to manufacture boiler tubes used in Indian thermal power plants.
Dynamics of stakeholder engagement in mega transport infrastructure projects
Authors: Erkul Mehmet , Yitmen Ibrahim , Celik Tahir
Published: July 2019

Purpose

The purpose of this paper is to investigate the practice of stakeholder engagement as a social network dynamics for stakeholder satisfaction and project success in the lifecycle of mega transport infrastructure projects (MTIPs).

Design/methodology/approach

Hypotheses indicating the positive relationships between stakeholders’ effective attributes, stakeholder engagement as social network dynamics and project success through stakeholders’ satisfaction have been developed. Based on a questionnaire survey and semi-structured interviews, responses have been gathered from the representative groups and organizations on their social network dynamics for their satisfaction and project success. A hypothesized structural equation model has been tested using AMOS statistical software package.

Findings

The analysis highlighted the engagement of the stakeholders within the strategic intents of the project with the public needs and expectations. The model depicts the processes of building social network models based on the capturing of the project’s data in relation to the stakeholders’ communication and satisfaction across the key issues for success in the lifecycle of MTIP.

Practical implications

The model is applicable on most MTIP with a diverse stakeholder base and the underlying complexity associated with the community participation and consultation processes. The model will also support wider stakeholder engagement in the planning of MTIP with optimal operationalization and service delivery from a community perspective.

Originality/value

The research involves an approach for rationalizing the stakeholder engagement policies of the MTIPs by providing an empirically grounded model simultaneously linking various aspects of stakeholder effective attributes, stakeholder engagement and their relationships to stakeholder satisfaction and project success in MTIPs.
Overcoming the monetization challenge in freemium online games
Authors: Beltagui Ahmad , Schmidt Thomas , Candi Marina , Roberts Deborah Lynn
Published: July 2019

Purpose

Online games based on a freemium business model face the monetization challenge. The purpose of this paper is to examine how players’ achievement orientation, social orientation and sense of community contribute to willingness to pay (WtP).

Design/methodology/approach

A multi-method study of an online game community is used. Interviews and participant observation are used to develop an understanding of social and achievement orientations followed by the development of hypotheses that are tested using survey data.

Findings

The findings indicate that a sense of community is positively related to WtP, whereas satisfaction or dissatisfaction with the service provider is not. The authors examine the moderating role of players’ achievement orientation and social orientation and find that while a stronger connection to the community may encourage achievement-oriented players to pay, the opposite is indicated for socially oriented players.

Practical implications

Decision makers need to understand that not all players are potential payers; while socially oriented users can help to maintain and grow the community, achievement-oriented players are more likely to pay for the value they extract from the community.

Originality/value

While communities are held together by people with common interests, which intuitively suggests that WtP increases with the strength of connection to the community, the authors find this only applies in the case of players with an achievement orientation. For those with a social orientation, WtP may actually decrease as their connection to the community increases. These perhaps counter-intuitive findings constitute a novel contribution of value for both theory and practice.
The impact of implicit vs explicit grammar teaching through scaffolding on Iranian learners’ speaking achievement; focusing on fluency, accuracy, and complexity
Authors: Moeen Ali Akbar , Nejadansari Daryoush , Dabaghi Azizolla
Published: July 2019

Purpose

The purpose of this paper is to investigate the impact of teaching grammar through implicit and explicit approach by applying scaffolding technique on learners’ speaking abilities including: accuracy, fluency and complexity.

Design/methodology/approach

To this end, 90 BA students of architecture in Yazd Azad University were selected and homogenized through Oxford Placement Test. They were assigned to three groups each including 30 participants, and took an IELTS speaking as pre-test to ensure that they had the same speaking ability prior to the begging of the experiment. In the course of the study, the first experimental group (EG1) received implicit instruction through scaffolding, and the second experimental group (EG2) was taught through explicit instruction. In contrast, control group did not receive any kind of grammar teaching. After the completion of the treatment, all groups took speaking post-test.

Findings

The results of the study showed that while both explicit and implicit teaching of grammar through scaffolding had a significant impact on learners’ speaking fluency, implicit teaching in comparison with explicit teaching was more significantly effective on learners’ speaking fluency. Similarly, both implicit and explicit teaching of grammar through scaffolding had significant impact on learners’ speaking accuracy and complexity, but explicit teaching compared to implicit teaching was more significantly effective.

Practical implications

The results of the study are mainly beneficial to teachers in the way that they can teach grammar in a more efficient way, and consequently improve learners’ speaking. In addition, curriculum developers and second language learners will benefit from the results of this research.

Originality/value

There has always been a controversy over an effective way to teach speaking skill in EFL classes over the last decades. In this regard, one of the most controversial approaches to teaching speaking arose from the dichotomy of teaching grammar through implicit or explicit teaching of rules. This paper has originality in that it delves into this controversial issue at length and in details.