bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetic models of metabolism that consider alternative steady-state solutions of intracellular fluxes and concentrations
Authors: Hameri Tuure , Fengos Georgios , Ataman Meric , Miskovic Ljubisa , Hatzimanikatis Vassily
Published: October 2018

Large-scale kinetic models are used for designing, predicting, and understanding the metabolic responses of living cells. Kinetic models are particularly attractive for the biosynthesis of target molecules in cells as they are typically better than other types of models at capturing the complex cellular biochemistry. Using simpler stoichiometric models as scaffolds, kinetic models are built around a steady-state flux profile and a metabolite concentration vector that are typically determined via optimization. However, as the underlying optimization problem is underdetermined, even after incorporating available experimental omics data, one cannot uniquely determine the operational configuration in terms of metabolic fluxes and metabolite concentrations. As a result, some reactions can operate in either the forward or reverse direction while still agreeing with the observed physiology. Here, we analyze how the underlying uncertainty in intracellular fluxes and concentrations affects predictions of constructed kinetic models and their design in metabolic engineering and systems biology studies. To this end, we integrated the omics data of optimally grownEscherichia coliinto a stoichiometric model and constructed populations of non-linear large-scale kinetic models of alternative steady-state solutions consistent with the physiology of theE. coliaerobic metabolism. We performed metabolic control analysis (MCA) on these models, highlighting that MCA-based metabolic engineering decisions are strongly affected by the selected steady state and appear to be more sensitive to concentration values rather than flux values. To incorporate this into future studies, we propose a workflow for moving towards more reliable and robust predictions that are consistent with all alternative steady-state solutions. This workflow can be applied to all kinetic models to improve the consistency and accuracy of their predictions. Additionally, we show that, irrespective of the alternative steady-state solution, increased activity of phosphofructokinase and decreased ATP maintenance requirements would improve cellular growth of optimally grownE. coli.
Genome-wide transcription during early wheat meiosis is independent of synapsis, ploidy level and thePh1locus
Authors: Martín A.C. , Borrill P. , Higgins J. , Alabdullah A.K. , RamÍrez-González R.H. , Swarbreck D. , Uauy C. , Shaw P. , Moore G.
Published: October 2018

Polyploidization is a fundamental process in plant evolution. One of the biggest challenges faced by a new polyploid is meiosis, particularly discriminating between multiple related chromosomes so that only homologous chromosomes synapse and recombine to ensure regular chromosome segregation and balanced gametes. Despite its large genome size, high DNA repetitive content and similarity between homoeologous chromosomes, hexaploid wheat completes meiosis in a shorter period than diploid species with a much smaller genome. Therefore, during wheat meiosis, mechanisms additional to the classical model based on DNA sequence homology, must facilitate more efficient homologous recognition. One such mechanism could involve exploitation of differences in chromosome structure between homologues and homoeologues at the onset of meiosis. In turn, these chromatin changes, can be expected to be linked to transcriptional gene activity. In this study, we present an extensive analysis of a large RNA-Seq data derived from six different genotypes: wheat, wheat-rye hybrids and newly synthesized octoploid triticale, both in the presence and absence of thePh1locus. Plant material was collected at early prophase, at the transition leptotene-zygotene, when the telomere bouquet is forming and synapsis between homologues is beginning. The six genotypes exhibit different levels of synapsis and chromatin structure at this stage; therefore, recombination and consequently segregation, are also different. Unexpectedly, our study reveals that neither synapsis, whole genome duplication nor the absence of thePh1locus are associated with major changes in gene expression levels during early meiotic prophase. Overall wheat transcription at this meiotic stage is therefore highly resilient to such alterations, even in the presence of major chromatin structural changes. This suggests that post-transcriptional and post-translational processes are likely to be more important. Thus, further studies will be required to reveal whether these observations are specific to wheat meiosis, and whether there are significant changes in post-transcriptional and post-translational modifications in wheat and other polyploid species associated with their polyploidisation.
Highly mutated memory cells drive an inefficient secondary antibody response to a variant protein
Authors: Tennant Richard K , Holzer Barbara , Love John , Tchilian Elma , White Harry N
Published: October 2018

A powerful vaccine against mutable viruses might induce memory antibodies that either strongly bound antigenic variants or that could rapidly undergo secondary affinity maturation to achieve this. We have recently shown after secondary immunization of mice with a widely variant protein (Burton et al. 2018) that IgM+ memory B-cells with few mutations supported an efficient secondary germinal centre (GC) and serum response, superior to a primary response to the same protein. Here, boosting with more closely related proteins produced a GC response dominated by highly mutated B-cells that failed, not efficiently improving serum avidity even in the presence of extra adjuvant, and that was worse than a primary response. This supports a hypothesis that over certain antigenic differences, a cross reactive, mutated, memory B-cell compartment can be an impediment to affinity maturation.
Disease mortality in domesticated animals is predicted by host evolutionary relationships
Authors: Farrell Maxwell J. , Davies T. J.
Published: October 2018

Infectious diseases of domesticated animals impact human well-being via food insecurity, loss of livelihoods, and human infections. While much research has focused on parasites that infect single host species, most parasites of domesticated mammals infect multiple species. The impact of multi-host parasites varies across hosts; some rarely result in death, whereas others are nearly always fatal. Despite their high ecological and societal costs, we currently lack theory for predicting the lethality of multi-host parasites. Here, using a global dataset of over 4000 case-fatality rates for 65 infectious diseases (caused by micro and macro-parasites) and 12 domesticated host species, we show that the average evolutionary distance from an infected host to other mammal host species is a strong predictor of disease-induced mortality. We find that as parasites infect species outside of their documented phy-1 logenetic host range, they are more likely to result in lethal infections, with the odds of death doubling for each additional 10 million years of evolutionary distance. Our results for domesticated animal diseases reveal patterns in the evolution of highly lethal parasites that are difficult to observe in the wild, and further suggest that the severity of infectious diseases may be predicted from evolutionary relationships among hosts.
Using the drug-protein interactome to identify anti-ageing compounds for humans
Authors: Fuentealba Valenzuela Matías , Melike Dönertaş Handan , Williams Rhianna , Labbadia Johnathan , Thornton Janet , Partridge Linda
Published: October 2018

Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.

Author Summary

Human life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.
The neonatal Fc receptor is a pan-echovirus receptor
Authors: Morosky Stefanie , Evans Azia , Lemon Kathryn , Schmus Sandra , Bakkenist Christopher J. , Coyne Carolyn B
Published: October 2018

Echoviruses are the main causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglubulin (β2M) renders human brain microvascular cells resistant to infection by a panel of echoviruses at the stage of virus attachment and that a blocking antibody to β2M inhibit echovirus infection in cell lines and in primary human fetal intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders non-permissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echoviral particles and neutralizes infection. Lastly, we show that primary cells isolated from mice that express human FcRn are highly susceptible to echovirus infection. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

Significance

Echoviruses are associated with aseptic meningitis and induce severe disease, and even death, in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life in intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood-brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, with the primary entry site of infection in the intestinal tract and subsequent infection of secondary tissues including the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of infants and neonates to echovirus-induced disease.
Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history
Authors: Vyas Deven N. , Mulligan Connie J.
Published: October 2018

Objectives

Modern humans are thought to have interbred with Neanderthals in the Near East soon after modern humans dispersed out of Africa. This introgression event likely took place in either the Levant or southern Arabian depending on which dispersal route out of Africa was followed. In this study, we compare Neanderthal introgression in contemporary Levantine and southern Arabian populations to investigate Neanderthal introgression and to study Near Eastern population history.

Materials and Methods

We analyzed genotyping data on >400,000 autosomal SNPs from seven Levantine and five southern Arabian populations and compared those data to populations from around the world including Neanderthal and Denisovan genomes. We used f4and D statistics to estimate and compare levels of Neanderthal introgression between Levantine, southern Arabian, and comparative global populations. We also identified 1,581 putative Neanderthal-introgressed SNPs within our dataset and analyzed their allele frequencies as a means to compare introgression patterns in Levantine and southern Arabian genomes.

Results

We find that Levantine and southern Arabian populations have similar levels of Neanderthal introgression to each other but lower levels than other non-Africans. Furthermore, we find that introgressed SNPs have very similar allele frequencies in the Levant and southern Arabia, which indicates that Neanderthal introgression is similarly distributed in Levantine and southern Arabian genomes.

Discussion

We infer that the ancestors of contemporary Levantine and southern Arabian populations received Neanderthal introgression prior to separating from each other and that there has been extensive gene flow between these populations.
Altered chromatin localization of hybrid lethality proteins inDrosophila
Authors: Cooper J.C. , Lukacs A. , Reich S. , Schauer T. , Imhof A. , Phadnis N.
Published: October 2018

Understanding hybrid incompatibilities is a fundamental pursuit in evolutionary genetics. In crosses betweenDrosophila melanogasterfemales andDrosophila simulansmales, the interaction of at least three genes is necessary for hybrid male lethality:Hmrmel,Lhrsim, andgfzfsim. All three hybrid incompatibility genes are chromatin associated factors. While HMR and LHR physically bind each other and function together in a single complex, the connection between either of these proteins andgfzfremains mysterious. Here, we investigate the allele specific chromatin binding patterns ofgfzf. First, our cytological analyses show that there is little difference in protein localization of GFZF between the two species except at telomeric sequences. In particular, GFZF binds the telomeric retrotransposon repeat arrays, and the differential binding of GFZF at telomeres reflects the rapid changes in sequence composition at telomeres betweenD. melanogasterandD. simulans. Second, we investigate the patterns of GFZF and HMR co-localization and find that the two proteins do not normally co-localize inD. melanogaster. However, in inter-species hybrids, HMR shows extensive mis-localization to GFZF sites, and this altered localization requires the presence ofgfzfsim. Third, we find by ChIP-Seq that over-expression of HMR and LHR within species is sufficient to cause HMR to mis-localize to GFZF binding sites, indicating that HMR has a natural low affinity for GFZF sites. Together, these studies provide the first insights into the different properties ofgfzfbetweenD. melanogasterandD. simulansas well as a molecular interaction betweengfzfandHmrin the form of altered protein localization.
OrgaQuant: Intestinal Organoid Localization and Quantification Using Deep Convolutional Neural Networks
Authors: Kassis Timothy , Hernandez-Gordillo Victor , Langer Ronit , Griffith Linda G.
Published: October 2018

Organoid cultures are proving to be powerful in vitro models that closely mimic the cellular constituents of their native tissue. The organoids are typically expanded and cultured in a 3D environment using either naturally derived or synthetic extracellular matrices. Assessing the morphology and growth characteristics of these cultures has been difficult due to the many imaging artifacts that accompany the corresponding images. Unlike single cell cultures, there are no reliable segmentation techniques that allow for the localization and quantification of organoids in their 3D culture environment. Here we describe OrgaQuant, a deep convolutional neural network implementation that can locate and quantify the size distribution of intestinal organoids in brightfield images. OrgaQuant is an end-to-end trained neural network that requires no parameter tweaking, thus it can be fully automated to analyze thousands of images with no user intervention. To develop OrgaQuant we created a unique dataset of manually annotated intestinal organoid images and trained an object detection pipeline using TensorFlow. We have made the dataset, trained model and inference scripts publically available along with detailed usage instructions.
Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala
Authors: Kononoff Jenni , Melas Philippe A. , Qvist Johanna S. , Guglielmo Giordano de , Kallupi Marsida , Kandel Eric R. , George Olivier
Published: October 2018

Background

Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies of drug addiction strongly suggest that the nucleus accumbens (NAcc) is a viable target for deep brain stimulation (DBS).

Objective

Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated.

Methods

Rats were made cocaine-dependent by allowing them to self-administer cocaine in long-access sessions (6 h, 0.5 mg/kg/infusion). The effects of high-frequency DBS of the NAcc shell on cocaine intake was then studied. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.

Results

Contrary to our expectations, DBS of the NAcc shell induced a slight increase in both cocaine self-administration and cocaine-induced locomotor activity. In addition, 18 h into cocaine withdrawal, we found that DBS decreased irritability-like behavior. We also found that DBS-induced a robust increase in both cytosolic and synaptosomal levels of GluR1, but not GluR2, specifically in the central nucleus of the amygdala but not in other brain regions.

Conclusions

These preclinical results with cocaine-dependent animals do not support high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of cocaine addiction in active cocaine users. However, the decrease in irritability-like behavior during cocaine abstinence, together with previous findings showing that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, warrants future investigations of DBS as a treatment for negative emotional states and craving during abstinence.

Highlights

High-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposed

DBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent rats

DBS increases the level of GluR1 specifically in the central nucleus of the amygdala
TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer
Authors: Lio Chan-Wang J. , Shukla Vipul , Samaniego-Castruita Daniela , González-Avalos Edahi , Chakraborty Abhijit , Yue Xiaojing , Schatz David G. , Ay Ferhat , Rao Anjana
Published: October 2018

TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Here we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of Aicda, encoding the cytidine deaminase AID essential for CSR. TET enzymes deposit 5hmC, demethylate and maintain chromatin accessibility at two TET-responsive elements, TetE1 and TetE2, located within a superenhancer in the Aicda locus. Transcriptional profiling identified BATF as the bZIP transcription factor involved in TET-dependent Aicda expression. 5hmC is not deposited at TetE1 in activated Batf-deficient B cells, indicating that BATF recruits TET proteins to the Aicda enhancer. Our data emphasize the importance of TET enzymes for bolstering AID expression, and highlight 5hmC as an epigenetic mark that captures enhancer dynamics during cell activation.
Suppressor of Fused controls the proliferation of postnatal neural stem and precursor cells via a Gli3-dependent mechanism
Authors: Gomez Hector G. , Castillo Jesse Garcia , Noguchi Hirofumi , Aguilar David , Pleasure Samuel J. , Yabut Odessa R.
Published: October 2018

The ventricular-subventricular zone (V-SVZ) of the forebrain is the source of neurogenic stem/precursor cells for adaptive and homeostatic needs throughout the life of most mammals. Here, we report that Suppressor of Fused (SUFU) plays a critical role in the establishment of the V-SVZ at early neonatal stages by controlling the proliferation of distinct subpopulations of stem/precursor cells. Conditional deletion of Sufu in radial glial progenitor cells (RGCs) at E13.5 resulted in a dramatic increase in the proliferation of Sox2+ Type B cells, as well as Gsx2+ ventral forebrain derived transit amplifying precursor cells (TACs). In contrast, we found a significant decrease in Tbr2+ dorsal forebrain derived TACs indicating that innate differences between dorsal and ventral forebrain derived Type B cells influence Sufu function. However, most precursors failed to survive and accumulated in the dorsal V-SVZ, demonstrating that precursors are unable to transition into functional differentiated progenies. These defects were accompanied by reduced Gli3 expression, yet despite reduced Gli3 levels, activation of Sonic hedgehog (Shh) signaling did not occur implying that the Sufu-Gli3 regulatory axis may influence other signaling pathways in the neonatal dorsal V-SVZ. These data suggest that Sufu plays a critical role in controlling Gli3 function in the establishment and survival of functional stem/precursor cells in the postnatal dorsal V-SVZ.

SUMMARY STATEMENT

Conditional deletion of Sufu cause dramatic expansion of neural stem/precursor cells in the neonatal ventricular-subventricular (SVZ) zone. This defect occurs through a Gli3-dependent mechanism that results in the downregulation of Shh signaling.
ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo
Authors: Sleigh James N. , Tosolini Andrew P. , Gordon David , Devoy Anny , Fratta Pietro , Fisher Elizabeth M. C. , Talbot Kevin , Schiavo Giampietro
Published: October 2018

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, in vivo evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the in vivo dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (Tardbp and Fus). TDP-43M337V mice, which show neuromuscular pathology but no overt motor neuron loss, displayed in vivo perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant FusΔ14/+ mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.
Effect of Dietary Fat on the Metabolism of Energy and Nitrogen, Serum Parameters, Rumen Fermentation, and Microbiota in twin Hu Male Lambs
Authors: Li Wenjuan , Tao Hui , Zhang Naifeng , Ma Tao , Deng Kaidong , Xie Biao , Jia Peng , Diao Qiyu
Published: October 2018

Background

Fat is the main substance that provides energy to animals. However, the use of fat in twin Hu lambs has not been investigated. Thirty pairs of male twin lambs were examined to investigate the effects of dietary fat on the metabolism of energy and nitrogen, ruminal fermentation, and microbial communities. The twins are randomly allotted to two groups (high fat: HF, normal fat: NF). Two diets of equal protein and different fat levels. The metabolism test was made at 50-60 days of age. Nine pairs of twin lambs are slaughtered randomly, and the rumen fluid is collected at 60 days of age.

Results

The initial body weight (BW) in the HF group did not differ from that of NF group (P > 0.05), but the final BW was tended to higher than that of NF group (0.05 < P < 0.1). The digestive energy (DE), metabolism energy (ME), DE/ME in the HF group tend to be higher than those in the NF group (0.05 < P < 0.1). Ruminal ammonia nitrogen (NH3-N) and the proportion of total volatile fatty acids (TVFA) are higher than that in the NF group (P < 0.05). A high throughput sequencing analysis reveals that there were no differences between the two groups in terms of the richness estimates and diversity indices (P > 0.05). The Proteobacteria and Fibrobacteres phyla were higher than that in NF group (P<0.05).

Conclusions

This study demonstrated that high fat diet before weaning can affect the abundance of several groups of rumen bacteria in rumen, such as significantly increasing phyla Proteobacteria and Fibrobacteres, and genera of Succinivibrio, Alloprevotella, and Saccharofermentans, but significantly decreasing genera of Clostridium IV, Dialister, Roseburia, and Butyrivibrio. And high fat diet improved the performance of lambs at weight gain, energy utilization, and had effect on VFA composition but no effects on serum enzymes and serum hormone.
Building gene regulatory networks from scATAC-seq and scRNA-seq using Linked Self-Organizing Maps
Authors: Jansen Camden , Ramirez Ricardo N. , El-Ali Nicole C. , Gomez-Cabrero David , Tegner Jesper , Merkenschlager Matthias , Conesa Ana , Mortazavi Ali
Published: October 2018

Rapid advances in single-cell assays have outpaced methods for analysis of those data types. Different single-cell assays show extensive variation in sensitivity and signal to noise levels. In particular, scATAC-seq generates extremely sparse and noisy datasets. Existing methods developed to analyze this data require cells amenable to pseudo-time analysis or require datasets with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) to link scATAC-seq and scRNA-seq data that overcomes these challenges and can generate draft regulatory networks. Our SOMatic package generates chromatin and gene expression SOMs separately and combines them using a linking function. We applied SOMatic on a mouse pre-B cell differentiation time-course using controlled Ikaros over-expression to recover gene ontology enrichments, identify motifs in genomic regions showing similar single-cell profiles, and generate a gene regulatory network that both recovers known interactions and predicts new Ikaros targets during the differentiation process. The ability of linked SOMs to detect emergent properties from multiple types of highly-dimensional genomic data with very different signal properties opens new avenues for integrative analysis of single-cells.
Accurate characterization of expanded tandem repeat length and sequence through whole genome long-read sequencing on PromethION
Authors: De Roeck Arne , De Coster Wouter , Bossaerts Liene , Cacace Rita , De Pooter Tim , Van Dongen Jasper , D’Hert Svenn , De Rijk Peter , Strazisar Mojca , Van Broeckhoven Christine , Sleegers Kristel
Published: October 2018

Tandem repeats (TRs) can cause disease through their length, sequence motif interruptions, and nucleotide modifications. For many TRs, however, these features are very difficult - if not impossible - to assess, requiring low-throughput and labor-intensive assays. One example is a VNTR in ABCA7 for which we recently discovered that expanded alleles strongly increase risk of Alzheimer’s disease. Here, we investigated the potential of long-read whole genome sequencing to surmount these challenges, using the high-throughput PromethION platform from Oxford Nanopore Technologies. To overcome the limitations of conventional base calling and alignment, we developed an algorithm to study the TR size and sequence directly on raw PromethION current data.

We report the long-read sequencing of multiple human genomes (n = 11) using only a single sequencing run and flow cell per individual. With the use of fresh DNA extractions, DNA shearing to approximately 20kb and size selection, we obtained an average output of 70 gigabases (Gb) per flow cell, corresponding to a 21x genome coverage, and a maximum yield of 98 Gb (30x genome coverage). All ABCA7 VNTR alleles, including expansions up to 10,000 bases, were spanned by long sequencing reads, validated by Southern blotting. Classical approaches of TR length estimation suffered from low accuracy, low precision, DNA strand effects and/or inability to call pathogenic repeat expansions. In contrast, our novel NanoSatellite algorithm, which circumvents base calling by using dynamic time warping on raw PromethION current data, achieved more than 90% accuracy and high precision (5.6% relative standard deviation) of TR length estimation, and detected all clinically relevant repeat expansions. In addition, we identified alternative TR sequence motifs with high consistency, allowing determination of TR sequence and distinction of VNTR alleles with homozygous length.

In conclusion, we validated the robustness of single-experiment whole genome long-read sequencing on PromethION, a prerequisite for application of long-read sequencing in the clinic. In addition, we outperformed Southern blotting, enabling improved characterization of the role of expanded ABCA7 VNTR alleles in Alzheimer’s disease, and opening new opportunities for TR research.
Rocking curve and spatial coherence properties of a long X-ray compound refractive lens
Authors: Kohn V. G.
Published: October 2018

Semi-analytical theory of a long set of X-ray compound refractive lenses (CRLs) based on recurrence relations is developed further. The geometrical aperture, angular divergence of incident radiation and source size were accurately taken into account. Using this theory it is possible to calculate the width of the rocking curve of a long (40.7 cm) Be CRL which coincides with experimental data obtained earlier. By this approach the transverse coherence length for the X-ray beam after passing a set of CRLs of arbitrary complexity has been estimated. It is shown that at the focus this coherence length is equal to a diffraction-limited beam size (beam size in the case of a point source) and has minimal difference with the real beam size.
Three-beam convergent-beam electron diffraction for measuring crystallographic phases
Authors: Guo Yueming , Nakashima Philip N. H. , Etheridge Joanne
Published: October 2018

Under almost all circumstances, electron diffraction patterns contain information about the phases of structure factors, a consequence of the short wavelength of an electron and its strong Coulombic interaction with matter. However, extracting this information remains a challenge and no generic method exists. In this work, a set of simple analytical expressions is derived for the intensity distribution in convergent-beam electron diffraction (CBED) patterns recorded under three-beam conditions. It is shown that these expressions can be used to identify features in three-beam CBED patterns from which three-phase invariants can be extracted directly, without any iterative refinement processes. The octant, in which the three-phase invariant lies, can be determined simply by inspection of the indexed CBED patterns (i.e. the uncertainty of the phase measurement is ±22.5°). This approach is demonstrated with the experimental measurement of three-phase invariants in two simple test cases: centrosymmetric Si and non-centrosymmetric GaAs. This method may complement existing structure determination methods by providing direct measurements of three-phase invariants to replace `guessed' invariants in ab initio phasing methods and hence provide more stringent constraints to the structure solution.
5-[(4-Bromophenyl)diazenyl]-2-{2-[1-(1H-indol-3-yl)ethylidene]hydrazinyl}-4-methylthiazole dimethylformamide hemisolvate
Authors: El-Hiti Gamal A. , Abdel-Wahab Bakr F. , Alotaibi Mohammad Hayal , Yousif Emad , Hegazy Amany S. , Kariuki Benson M.
Published: October 2018

The asymmetric unit of the title compound, 2C20H17BrN6S·C3H7NO, comprises two molecules of the thiazole derivative and one molecule of dimethylformamide (DMF) solvent. The twist angles between the planes through the bromophenyl, methylthiazolyl and indolyl groups are 10.1 (1) and 44.2 (1)°, respectively, for one molecule and 11.3 (1) and 1.6 (1)° for the other. In the crystal, N—H...N hydrogen bonds link four of the main molecules into tetramers. N—H...O bonds involving the DMF solvent molecule also occur.
Are emojis fascinating brand value more than textual language? Mediating role of brand communication to SNS and brand attachment
Authors: Arya Vikas , Sethi Deepa , Verma Hemraj
Published: October 2018

Purpose

The purpose of this paper is to understand the relationship of consumers’ engagement on social networking sites (SNSs) and their brand attachment behavior in the presence of a mediator, brand communication. Further, this mediation has been studied with presence of emojis as one of the significant moderator.

Design/methodology/approach

Following a descriptive research design, an empirical investigation was carried out by approaching 252 respondents from India to collect data through online survey forms as well as physical questionnaires. The research instrument was developed using a five-point Likert-type scale and items for the constructs in study were taken after literature review. The SPSS 22.0, AMOS 24.0 and Process (Prof A. Hayes) and Daniel Soper’s statistical tool called “Interaction” for moderation graph were employed for data examination and hypothesis analysis.

Findings

It was found that brand communication mediated the relationship between consumer engagement on SNSs and brand attachment significantly. The availability of emojis for a company during a conversation or in digital ad campaigns on SNSs acts as a mediating moderator and its impact on consumers’ brand attachment behavior is very strong through brand communication.

Originality/value

The study is original in the sense it provides insights into understanding consumer brand attachment behavior on SNSs.
The convergence of National Professional Qualifications in educational leadership and master’s level study
Authors: Lambert Steve
Published: October 2018

Purpose

In 2017 the UK Government decided that the suite of National Professional Qualifications (National Professional Qualifications for Middle Leadership, National Professional Qualifications for Senior Leadership and National Professional Qualifications for Headship) needs to be updated in order to ensure they remained relevant to the changing shape of the educational landscape, particularly through the expansion of multi-academy trusts (MATs). At the same time, the Government proposed a new National Professional Qualification for Executive Leadership aimed at the CEOs of MATs. The purpose of this paper is to explore the way in which the new National Professional Qualification (NPQ) programmes are having master’s level criteria embedded into them to facilitate a seamless progression into the master’s level study.

Design/methodology/approach

The paper combines desk research with reflections on the experience of developing the new NPQ programme within higher education institutions (HEIs) and considers the implications of this upon current and emerging HEI practice and research into educational leadership.

Findings

There were a number of key issues highlighted by the paper. Notably, the process of embedding academic criteria into a training programme, which was not used to support the notion of critical reflection. Also, the associated mechanisms of accreditation, existing professional networks and the upskilling of staff delivering the NPQ programme, and a professionally oriented interface between the university, employer and deliverer of the training.

Originality/value

This paper provides an original perspective involving the embedding of master’s level criteria into professional qualifications in the field of educational leadership.
Modeling MHD swirling flow due to rough rotating disk with non-linear radiation and chemically reactive solute
Authors: Mustafa M. , Mushtaq Ammar , Hayat T. , Alsaedi A.
Published: October 2018

Purpose

This study aims to deal with the laminar flow owing to rough rotating disk in the existence of vertical magnetic field and partial slip effects. The aim is to resolve heat transfer problem in the existence of non-linear radiative flux and thermal slip effects. The study also analyzes the mass transfer process when the flow field contains chemically reacting species.

Design/methodology/approach

Modified von-Kármán transformations are applied to change the conservation equations into similar forms. The transformed equations are treated by a convenient shooting method and by contemporary built in routine bvp4c of MATLAB.

Findings

The numerical solutions are used to address the role of main ingredients of the problem, namely, wall roughness, radiation and chemical reaction on the flow fields.

Research limitations/implications

Temperature profiles are considerably affected by a parameter measuring wall to ambient temperature ratio. Furthermore, behavior of concentration field is highly influenced by the reaction rate of the diffusing species.

Originality/value

The concept of non-linear radiation in chemically reactive flow over a rotating disk is just introduced here.
Cultural identity in WHS tourist destinations: the case of Cordoba (Spain)
Authors: Lopez-Guzman Tomas , Pérez Gálvez Jesús Claudio , Muñoz-Fernández Guzmán Antonio , Medina-Viruel Miguel Jesús
Published: October 2018

Purpose

The purpose of this paper is to conduct an analysis of the relationships existing among three basic constructs in the visitor’s decision-making process (motivation and satisfaction) in a tourist destination that is a World Heritage Site, such as the city of Cordoba (Spain). Bearing in mind the perception of heritage by the foreign visitors, the following four types were determined: alternative tourists, cultural tourists, emotional tourists and heritage tourists.

Design/methodology/approach

This paper uses the multivariate technique of grouping cases (K-means clusters) to analyse the similarity existing among the surveyed persons. From the groups or segments obtained, statistics and measurements of association were applied that provide the information necessary to study the possible trends of association existing between variables from a table of bidimensional contingencies. In the same way, non-parametric statistical procedures were used (Kruskal–Wallis H test and the Mann–Whitney U test).

Findings

The results show the existence of four diverse motivational dimensions among the foreign tourists to visit it: hedonic, cultural, convenience and circumstantial. Of the four dimensions, the hedonic and the cultural are the most relevant. The results show the existence of a common cultural identity: the Arabic cultural identity.

Originality/value

This paper contributes to complete the academic literature existing on the links of the tourist with the historical and monumental heritage that he visits, and with the tourist’s behaviour.
Adoption of light steel (LS) for building projects in South Africa
Authors: Dosumu Oluwaseun , Aigbavboa Clinton Ohis
Published: October 2018

Purpose

This paper aims to investigate the level of awareness about, adoption of and willingness to adopt light steel (LS) for building projects. It also assessed the benefits, challenges and solutions to the challenges of adopting LS for building projects.

Design/methodology/approach

The quantitative (questionnaire) research method was used for the study. The research design was survey in nature. The whole-population cluster sampling technique was adopted. The clusters were the LS buildings from two (Western Cape and Gauteng) out of the eight provinces in South Africa. The respondents were the construction organizations that have executed LS building projects in the selected provinces. Hence, 56 firms filled and returned the questionnaire. Data analysis was done with frequency, mean scores, t-test and analysis of variance (normality of data distribution assumed).

Findings

Results indicated that, out of the 29 areas of application of LS identified in literature, respondents were aware of 11 areas, adopted LS for seven areas and were willing to adopt LS for six areas. Respondents also noted that 18 of the 25 identified benefits of LS were relevant to South Africa. Despite the benefits, few developers embrace it, it is a threat to suppliers’ and contractors’ businesses and it delays building approval due to low awareness.

Practical implication

The implication of the results is that there is low awareness about, adoption of and willingness to adopt LS for building projects in South Africa, and this may be due to the identified challenges. To boost the awareness about, adoption of and willingness to adopt LS, LS technologies need to be imported, LS warehouses should be provided in all cities and it must be ensured that LS building projects are cheaper than conventional buildings.

Originality/value

The value of the study is that the adoption of LS for building projects will improve the capacity of sustainable development.
Interactive effects of human capital in finance–economic growth nexus in Sub-Saharan Africa
Authors: Ibrahim Muazu
Published: October 2018

Purpose

The purpose of this paper is to examine the interactive effect of human capital in financial development–economic growth nexus. Relative to the quantity-based measure of enrolment rates, the main aim was to determine how quality of human capital proxied by pupil–teacher ratio influences the relationship between domestic financial sector development and overall economic growth.

Design/methodology/approach

Data are obtained from the World Development Indicators of the World Bank for 29 sub-Saharan African (SSA) countries over the period 1980–2014. The analyses were conducted using the system generalised method of moments within the endogenous growth framework while controlling for country-specific and time effects. The author also follows Papke and Wooldridge procedure in examining the long-run estimates of the variables of interest.

Findings

The key finding is that, while both human capital and financial development unconditionally promotes growth in both the short and long run, results from the interactive terms suggest that, irrespective of the measure of finance, financial sector development largely spurs growth on the back of quality human capital. This finding is also confirmed by the marginal and net effects where the interactive effect of pupil–teacher ratio and indicators of finance are consistently huge relative to the enrolment. Statistically, the results are robust to model specification.

Practical implications

While it is laudable for SSA countries to increase access to education, it is equally more crucial to increase the supply of teachers at the same time improving on the limited teaching and learning materials. Indeed, there are efforts to develop rather low levels of the financial sector owing to its unconditional growth effects. Beyond the direct benefit of finance, however, higher growth effect of finance is conditioned on the quality level of human capital. The outcome of this study should therefore reignite the recognition of the complementarity role of human capital and finance in economic growth process.

Originality/value

The study makes significant contributions to existing finance–growth literature in so many ways: first, the auhor extend the literature by empirically examining how different measures of human capital shape the finance–economic growth nexus. Through this the author is able to bring a different perspective in the literature highlighting the role of countries’ human capital stock in mediating the impact of financial deepening on economic growth. Second, the author makes a more systematic attempt to evaluate the relative importance of finance and human capital in growth process while controlling for several ancillary variables.